Trial Outcomes & Findings for Voxelotor CYP and Transporter Cocktail Interaction Study (NCT NCT05981365)

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

44 participants

Primary outcome timeframe

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Results posted on

2024-11-22

Participant Flow

A total of 44 participants (26 in Part A and 18 in Part B) were enrolled in the study.

Participant milestones

Participant milestones
Measure	Part A:Treatment Sequence ABCDEFG On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (bupropion 150 milligrams \[mg\], flurbiprofen 50 mg, omeprazole 20 mg, and midazolam 2 mg) and on Day 4, participants received a single oral dose of repaglinide 0.5 mg (Treatment B). Period 1 for Part A was of 5 days. In Period 2, participants were administered once daily oral dose of voxelotor 1500 mg (Treatment C) for 13 days. On Day 2, a single oral dose of bupropion 150 mg (Treatment D) was administered immediately following voxelotor administration. On Day 4, single oral dose of Treatment E (flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg) was administered immediately following voxelotor administration. Participants received Treatment F (single oral dose of repaglinide 0.5 mg) and Treatment G (single oral dose of bupropion 150 mg) on Day 6 and Day 12, immediately following voxelotor administration. Period 2 for Part A was of 15 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 28.	Part B: Treatment Sequence ABCD On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg). Period 1 for Part B was of 4 days. In Period 2, from Day 1 to Day 3, participants were administered Treatment B (oral doses of voxelotor 1500 mg) orally for 3 days. On Day 4, participants were administered Treatment C (single oral doses of metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg) immediately following voxelotor administration. On Day 5, participants were administered Treatment D (single oral dose of voxelotor 1500 mg). Period 2 for Part B was of 7 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 18.
Period 1 STARTED	26	18
Period 1 COMPLETED	25	18
Period 1 NOT COMPLETED	1	0
Washout Period STARTED	25	18
Washout Period COMPLETED	25	18
Washout Period NOT COMPLETED	0	0
Period 2 STARTED	25	18
Period 2 COMPLETED	25	18
Period 2 NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Part A:Treatment Sequence ABCDEFG On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (bupropion 150 milligrams \[mg\], flurbiprofen 50 mg, omeprazole 20 mg, and midazolam 2 mg) and on Day 4, participants received a single oral dose of repaglinide 0.5 mg (Treatment B). Period 1 for Part A was of 5 days. In Period 2, participants were administered once daily oral dose of voxelotor 1500 mg (Treatment C) for 13 days. On Day 2, a single oral dose of bupropion 150 mg (Treatment D) was administered immediately following voxelotor administration. On Day 4, single oral dose of Treatment E (flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg) was administered immediately following voxelotor administration. Participants received Treatment F (single oral dose of repaglinide 0.5 mg) and Treatment G (single oral dose of bupropion 150 mg) on Day 6 and Day 12, immediately following voxelotor administration. Period 2 for Part A was of 15 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 28.	Part B: Treatment Sequence ABCD On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg). Period 1 for Part B was of 4 days. In Period 2, from Day 1 to Day 3, participants were administered Treatment B (oral doses of voxelotor 1500 mg) orally for 3 days. On Day 4, participants were administered Treatment C (single oral doses of metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg) immediately following voxelotor administration. On Day 5, participants were administered Treatment D (single oral dose of voxelotor 1500 mg). Period 2 for Part B was of 7 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 18.
Period 1 Adverse Event	1	0

Baseline Characteristics

Voxelotor CYP and Transporter Cocktail Interaction Study

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part A:Treatment Sequence ABCDEFG n=26 Participants On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg, and midazolam 2 mg) and on Day 4, participants received a single oral dose of repaglinide 0.5 mg (Treatment B). Period 1 for Part A was of 5 days. In Period 2, participants were administered once daily oral dose of voxelotor 1500 mg (Treatment C) for 13 days. On Day 2, a single oral dose of bupropion 150 mg (Treatment D) was administered immediately following voxelotor administration. On Day 4, single oral dose of Treatment E (flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg) was administered immediately following voxelotor administration. Participants received Treatment F (single oral dose of repaglinide 0.5 mg) and Treatment G (single oral dose of bupropion 150 mg) on Day 6 and Day 12, immediately following voxelotor administration. Period 2 for Part A was of 15 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 28.	Part B: Treatment Sequence ABCD n=18 Participants On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg). Period 1 for Part B was of 4 days. In Period 2, from Day 1 to Day 3, participants were administered Treatment B (oral doses of voxelotor 1500 mg) orally for 3 days. On Day 4, participants were administered Treatment C (single oral doses of metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg) immediately following voxelotor administration. On Day 5, participants were administered Treatment D (single oral dose of voxelotor 1500 mg). Period 2 for Part B was of 7 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 18.	Total n=44 Participants Total of all reporting groups
Age, Continuous	41.9 Years STANDARD_DEVIATION 8.89 • n=5 Participants	36.9 Years STANDARD_DEVIATION 10.08 • n=7 Participants	39.8 Years STANDARD_DEVIATION 9.61 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	5 Participants n=7 Participants	14 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	13 Participants n=7 Participants	30 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=5 Participants	8 Participants n=7 Participants	14 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=5 Participants	10 Participants n=7 Participants	30 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	9 Participants n=5 Participants	7 Participants n=7 Participants	16 Participants n=5 Participants
Race (NIH/OMB) White	16 Participants n=5 Participants	10 Participants n=7 Participants	26 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Population: Pharmacokinetic (PK) evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G n=24 Participants On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion	160.5 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 31	201.3 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 35	191.1 Nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 36

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Cmax for Repaglinide	10.85 ng/ml Geometric Coefficient of Variation 41	12.89 ng/ml Geometric Coefficient of Variation 37	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Cmax for Flurbiprofen	6923 ng/ml Geometric Coefficient of Variation 25	7820 ng/ml Geometric Coefficient of Variation 20	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Cmax for Omeprazole	458.1 ng/ml Geometric Coefficient of Variation 58	374.3 ng/ml Geometric Coefficient of Variation 57	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Cmax for Midazolam	10.33 ng/ml Geometric Coefficient of Variation 38	15.99 ng/ml Geometric Coefficient of Variation 23	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCt was calculated using the linear/log trapezoidal rule.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G n=24 Participants On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUCt) for Bupropion	845.3 Hour* nanogram/milliliter (h*ng/mL) Geometric Coefficient of Variation 29	963.9 Hour* nanogram/milliliter (h*ng/mL) Geometric Coefficient of Variation 28	812.1 Hour* nanogram/milliliter (h*ng/mL) Geometric Coefficient of Variation 28

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCt was calculated using the linear/log trapezoid rule.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCt for Repaglinide	15.47 h*ng/mL Geometric Coefficient of Variation 40	20.59 h*ng/mL Geometric Coefficient of Variation 34	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCt was calculated using the linear/log trapezoid rule.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCt for Flurbiprofen	39639 h*ng/mL Geometric Coefficient of Variation 26	44940 h*ng/mL Geometric Coefficient of Variation 24	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCt was calculated using the linear/log trapezoid rule.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCt for Omeprazole	889.4 h*ng/mL Geometric Coefficient of Variation 62	721.8 h*ng/mL Geometric Coefficient of Variation 68	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCt was calculated using the linear/log trapezoid rule.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCt for Midazolam	25.78 h*ng/mL Geometric Coefficient of Variation 42	52.58 h*ng/mL Geometric Coefficient of Variation 27	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure.

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=24 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G n=24 Participants On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion	883.3 Hour*nanogram/milliliter Geometric Coefficient of Variation 30	985.4 Hour*nanogram/milliliter Geometric Coefficient of Variation 28	839.1 Hour*nanogram/milliliter Geometric Coefficient of Variation 28

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure.

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=19 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=20 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCinf for Repaglinide	16.49 h*ng/mL Geometric Coefficient of Variation 40	21.74 h*ng/mL Geometric Coefficient of Variation 33	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCinf for Flurbiprofen	40047 h*ng/mL Geometric Coefficient of Variation 26	45361 h*ng/mL Geometric Coefficient of Variation 25	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure.

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=24 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=24 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCinf for Omeprazole	932.3 h*ng/mL Geometric Coefficient of Variation 62	743.1 h*ng/mL Geometric Coefficient of Variation 69	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCinf for Midazolam	27.15 h*ng/mL Geometric Coefficient of Variation 40	54.42 h*ng/mL Geometric Coefficient of Variation 28	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: Cmax for Metformin	55.84 ng/mL Geometric Coefficient of Variation 35	44.17 ng/mL Geometric Coefficient of Variation 36	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: Cmax for Furosemide	48.58 ng/mL Geometric Coefficient of Variation 32	52.62 ng/mL Geometric Coefficient of Variation 35	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: Cmax for Rosuvastatin	5.545 ng/mL Geometric Coefficient of Variation 46	7.286 ng/mL Geometric Coefficient of Variation 53	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCt was calculated using the linear/log trapezoid rule.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: AUCt for Metformin	303.8 h*ng/mL Geometric Coefficient of Variation 26	241.7 h*ng/mL Geometric Coefficient of Variation 30	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCt was calculated using the linear/log trapezoid rule.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: AUCt for Furosemide	105.0 h*ng/mL Geometric Coefficient of Variation 28	108.4 h*ng/mL Geometric Coefficient of Variation 33	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Day 1 and Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCt was calculated using the linear/log trapezoid rule.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: AUCt for Rosuvastatin	50.29 h*ng/mL Geometric Coefficient of Variation 46	60.22 h*ng/mL Geometric Coefficient of Variation 45	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: AUCinf for Metformin	310.5 h*ng/mL Geometric Coefficient of Variation 25	249.0 h*ng/mL Geometric Coefficient of Variation 29	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure.

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=15 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=17 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: AUCinf for Furosemide	108.4 h*ng/mL Geometric Coefficient of Variation 29	113.3 h*ng/mL Geometric Coefficient of Variation 30	—

PRIMARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure.

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=16 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: AUCinf for Rosuvastatin	50.87 h*ng/mL Geometric Coefficient of Variation 45	63.16 h*ng/mL Geometric Coefficient of Variation 43	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G n=24 Participants On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Cmax for 6-Hydroxybupropion	351.1 ng/mL Geometric Coefficient of Variation 45	376.3 ng/mL Geometric Coefficient of Variation 45	489.1 ng/mL Geometric Coefficient of Variation 49

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Cmax for 5-Hydroxyomeprazole	179.8 ng/mL Geometric Coefficient of Variation 29	216.8 ng/mL Geometric Coefficient of Variation 27	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Cmax for 1-Hydroxymidazolam	5.984 ng/ml Geometric Coefficient of Variation 44	7.291 ng/ml Geometric Coefficient of Variation 28	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCt was calculated using the linear/log trapezoid rule.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G n=24 Participants On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCt for 6-Hydroxybupropion	11529 h*ng/mL Geometric Coefficient of Variation 49	11223 h*ng/mL Geometric Coefficient of Variation 44	13453 h*ng/mL Geometric Coefficient of Variation 53

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCt was calculated using the linear/log trapezoid rule.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCt for 5-Hydroxyomeprazole	504.1 h*ng/mL Geometric Coefficient of Variation 21	611.4 h*ng/mL Geometric Coefficient of Variation 21	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCt was calculated using the linear/log trapezoid rule.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCt for 1-Hydroxymidazolam	12.73 h*ng/mL Geometric Coefficient of Variation 43	20.07 h*ng/mL Geometric Coefficient of Variation 27	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure.

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=19 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=24 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G n=24 Participants On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCinf for 6-Hydroxybupropion	11692 h*ng/mL Geometric Coefficient of Variation 47	12407 h*ng/mL Geometric Coefficient of Variation 44	14990 h*ng/mL Geometric Coefficient of Variation 55

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCinf for 5-Hydroxyomeprazole	510.3 h*ng/mL Geometric Coefficient of Variation 21	615.5 h*ng/mL Geometric Coefficient of Variation 22	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure.

AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=23 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: AUCinf for 1-Hydroxymidazolam	12.72 h*ng/mL Geometric Coefficient of Variation 43	20.92 h*ng/mL Geometric Coefficient of Variation 26	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

The time that Cmax was observed.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G n=24 Participants On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion	1.500 Hours Interval 1.0 to 3.0	1.500 Hours Interval 1.0 to 3.0	1.500 Hours Interval 1.0 to 3.0

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

The time that Cmax was observed for 6-Hydroxybupropion.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G n=24 Participants On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Tmax for 6-Hydroxybupropion	3.015 Hours Interval 1.13 to 8.05	4.000 Hours Interval 2.0 to 8.0	3.000 Hours Interval 1.5 to 4.0

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

The time that Cmax was observed for Repaglinide.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Tmax for Repaglinide	0.500 Hours Interval 0.5 to 1.07	0.500 Hours Interval 0.5 to 2.0	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

The time that Cmax was observed for Flurbiprofen.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Tmax for Flurbiprofen	2.000 Hours Interval 0.5 to 6.0	1.500 Hours Interval 0.5 to 3.13	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

The time that Cmax was observed for Omeprazole.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Tmax for Omeprazole	2.000 Hours Interval 1.0 to 4.0	2.000 Hours Interval 1.0 to 3.13	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

The time that Cmax was observed for 5-Hydroxyomeprazole.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Tmax for 5-Hydroxyomeprazole	2.000 Hours Interval 1.0 to 4.02	2.000 Hours Interval 1.0 to 4.0	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

The time that Cmax was observed for Midazolam.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Tmax for Midazolam	1.000 Hours Interval 0.5 to 3.0	1.000 Hours Interval 0.5 to 1.0	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

The time that Cmax was observed for 1-Hydroxymidazolam.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Tmax for 1-Hydroxymidazolam	1.000 Hours Interval 0.5 to 3.0	1.000 Hours Interval 0.5 to 1.03	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure.

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=24 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G n=24 Participants On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Terminal Elimination Half-life (T½) for Bupropion	20.577 Hours Standard Deviation 2.6082	19.203 Hours Standard Deviation 2.6331	19.383 Hours Standard Deviation 2.6591

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G n=24 Participants On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: t1/2 6-Hydroxybupropion	26.228 Hours Standard Deviation 5.9780	23.220 Hours Standard Deviation 4.9391	21.500 Hours Standard Deviation 4.3406

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=19 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: T1/2 for Repaglinide	4.684 Hours Standard Deviation 1.6568	6.242 Hours Standard Deviation 1.3469	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: T1/2 for Flurbiprofen	6.906 Hours Standard Deviation 1.2545	6.855 Hours Standard Deviation 1.2666	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=24 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=24 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: T1/2 for Omeprazole	0.945 Hours Standard Deviation 0.3240	0.891 Hours Standard Deviation 0.2785	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: T1/2 for 5-Hydroxyomeprazole	1.455 Hours Standard Deviation 0.5103	1.387 Hours Standard Deviation 0.2029	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: T1/2 for Midazolam	4.502 Hours Standard Deviation 1.7340	5.497 Hours Standard Deviation 0.6465	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure.

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=23 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: T1/2 for 1-Hydroxymidazolam	3.346 Hours Standard Deviation 4.0653	3.172 Hours Standard Deviation 0.9569	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G n=24 Participants On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion	12.79 Ratio Geometric Coefficient of Variation 40	10.92 Ratio Geometric Coefficient of Variation 39	15.53 Ratio Geometric Coefficient of Variation 47

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for 5-Hydroxyomeprazole/Omeprazole	0.5417 Ratio Geometric Coefficient of Variation 52	0.8096 Ratio Geometric Coefficient of Variation 60	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for Hydroxymidazolam/Midazolam	0.4704 Ratio Geometric Coefficient of Variation 43	0.3638 Ratio Geometric Coefficient of Variation 26	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: Tmax for Metformin	1.500 Hours Interval 1.0 to 5.0	2.000 Hours Interval 1.5 to 4.0	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: Tmax for Furosemide	0.510 Hours Interval 0.5 to 1.0	0.775 Hours Interval 0.5 to 1.5	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: Tmax for Rosuvastatin	5.000 Hours Interval 2.5 to 5.05	2.500 Hours Interval 1.5 to 5.02	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: T½ for Metformin	3.554 Hours Standard Deviation 0.9523	3.324 Hours Standard Deviation 0.8515	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=15 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=17 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: T½ for Furosemide	7.786 Hours Standard Deviation 5.1296	4.757 Hours Standard Deviation 2.1595	—

SECONDARY outcome

Timeframe: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively

Population: PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs \[probe substrates\]) and had a sufficient PK profile to derive at least 1 PK parameter.

T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=17 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: T½ for Rosuvastatin	11.436 Hours Standard Deviation 8.9813	8.852 Hours Standard Deviation 3.1587	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)

Population: Safety analysis set (SAS) included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.

An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs \[probe substrates\]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	4 Participants	9 Participants	—
Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	0 Participants	0 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)

Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs \[probe substrates\]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: Number of Participants With TEAEs and SAEs TEAEs	1 Participants	2 Participants	—
Part B: Number of Participants With TEAEs and SAEs SAEs	0 Participants	0 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)

Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.

The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests	0 Participants	0 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)

Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.

A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Number of Participants With Clinically Significant Abnormalities in Physical Examinations	1 Participants	0 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days)

Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.

Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=26 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=25 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs	0 Participants	1 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)

Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.

The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests	0 Participants	0 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)

Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.

A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: Number of Participants With Clinically Significant Abnormalities in Physical Examinations	0 Participants	0 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)

Population: SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.

Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator.

Outcome measures

Outcome measures
Measure	Part A: Period 1: Treatment A n=18 Participants On Period 1 Day 1, participants were administered Treatment A (single oral dose of bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg).	Part A: Period 2: Treatment D n=18 Participants On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor.	Part A: Period 2: Treatment G On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor.
Part B: Number of Participants With Clinically Significant Abnormalities in Vital Signs	0 Participants	0 Participants	—

Adverse Events

Part A: Period 1

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Part A: Period 2

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Part B: Period 1

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Part B: Period 2

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Part A: Period 1 n=26 participants at risk On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg, and midazolam 2 mg) and on Day 4, participants received a single oral dose of repaglinide 0.5 mg (Treatment B). Period 1 for Part A was of 5 days.	Part A: Period 2 n=25 participants at risk In Period 2, participants were administered once daily oral dose of voxelotor 1500 mg (Treatment C) for 13 days. On Day 2, a single oral dose of bupropion 150 mg (Treatment D) was administered immediately following voxelotor administration. On Day 4, single oral dose of Treatment E (flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg) was administered immediately following voxelotor administration. Participants received Treatment F (single oral dose of repaglinide 0.5 mg) and Treatment G (single oral dose of bupropion 150 mg) on Day 6 and Day 12, immediately following voxelotor administration. Period 2 for Part A was of 15 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 28.	Part B: Period 1 n=18 participants at risk On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg). Period 1 for Part B was of 4 days.	Part B: Period 2 n=18 participants at risk In Period 2, from Day 1 to Day 3, participants were administered Treatment B (oral doses of voxelotor 1500 mg) orally for 3 days. On Day 4, participants were administered Treatment C (single oral doses of metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg) immediately following voxelotor administration. On Day 5, participants were administered Treatment D (single oral dose of voxelotor 1500 mg). Period 2 for Part B was of 7 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 18.
Nervous system disorders Headache	0.00% 0/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	28.0% 7/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	5.6% 1/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	11.1% 2/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
Nervous system disorders Dizziness	0.00% 0/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	4.0% 1/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
Nervous system disorders Somnolence	3.8% 1/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
Gastrointestinal disorders Abdominal pain	3.8% 1/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	5.6% 1/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
Gastrointestinal disorders Constipation	0.00% 0/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	4.0% 1/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
Gastrointestinal disorders Diarrhoea	0.00% 0/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	4.0% 1/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
General disorders Influenza like illness	0.00% 0/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	8.0% 2/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
Injury, poisoning and procedural complications Muscle strain	3.8% 1/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	4.0% 1/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
Cardiac disorders Atrial fibrillation	3.8% 1/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
Infections and infestations COVID-19	0.00% 0/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	4.0% 1/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
Skin and subcutaneous tissue disorders Rash	0.00% 0/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	4.0% 1/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
Gastrointestinal disorders Nausea	0.00% 0/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	5.6% 1/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
Infections and infestations Tooth abscess	0.00% 0/26 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/25 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	0.00% 0/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.	5.6% 1/18 • Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs \[probe substrates\]). As prespecified in the statistical analysis plan, safety data is reported period-wise.

Additional Information

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Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publication until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER