Trial Outcomes & Findings for Study to Compare a Dose of Telotristat Etiprate in Subjects With Renal Impairment With Matched Subjects With Normal Renal Function (NCT NCT03442725)

Results Overview

Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method with a lower limit of quantitation (LOQ) of 0.5 nanograms (ng)/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757. Cmax was determined using non-compartmental analysis.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

16 participants

Primary outcome timeframe

Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)

Results posted on

2020-04-08

Participant Flow

A total of 16 subjects were recruited in this open label, single dose study between February and May 2018. Recruited subjects were split evenly between 2 groups (control group and test group).

The control group comprised 8 healthy subjects with normal renal function and who were demographically matched to test group by age (±10 years), sex and body mass index (BMI) (±20%). 8 subjects with severely impaired renal function but not requiring dialysis were recruited into the test group.

Participant milestones

Participant milestones
Measure	Healthy Subjects (Control Group) Subjects with normal renal function (estimated glomerular filtration rate \[eGFR\] ≥90 millilitres/minute/1.73 metres squared \[mL/min/1.73 m²\]) received a single oral dose of 250 milligrams (mg) telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Overall Study STARTED	8	8
Overall Study COMPLETED	8	8
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study to Compare a Dose of Telotristat Etiprate in Subjects With Renal Impairment With Matched Subjects With Normal Renal Function

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Total n=16 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	5 Participants n=7 Participants	10 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	0 Participants n=5 Participants	0 Participants n=7 Participants	0 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	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants	8 Participants n=7 Participants	16 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
Region of Enrollment Romania	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Belgium	1 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Moldova	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Region of Enrollment Germany	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants

PRIMARY outcome

Timeframe: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)

Population: The pharmacokinetic (PK) population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method with a lower limit of quantitation (LOQ) of 0.5 nanograms (ng)/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757. Cmax was determined using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Maximum Plasma Concentration (Cmax) of Total Telotristat Ethyl, LP-778902 and LP-951757 Telotristat Ethyl	3.81 ng/mL Geometric Coefficient of Variation 98.9	4.94 ng/mL Geometric Coefficient of Variation 116
Maximum Plasma Concentration (Cmax) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-778902	533 ng/mL Geometric Coefficient of Variation 58.1	759 ng/mL Geometric Coefficient of Variation 52.9
Maximum Plasma Concentration (Cmax) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-951757	65.2 ng/mL Geometric Coefficient of Variation 46.0	45.6 ng/mL Geometric Coefficient of Variation 80.2

PRIMARY outcome

Timeframe: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757. Tmax was determined using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Time to Maximum Observed Plasma Concentration (Tmax) of Total Telotristat Ethyl, LP-778902 and LP-951757 Telotristat Ethyl	1.03 hours Interval 0.5 to 3.0	1.00 hours Interval 0.5 to 3.0
Time to Maximum Observed Plasma Concentration (Tmax) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-778902	2.00 hours Interval 1.0 to 4.0	2.50 hours Interval 1.0 to 3.0
Time to Maximum Observed Plasma Concentration (Tmax) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-951757	4.00 hours Interval 3.0 to 8.0	4.00 hours Interval 2.02 to 6.0

PRIMARY outcome

Timeframe: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757. T1/2 was determined using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Apparent Terminal Elimination Half-Life (t1/2) of Total Telotristat Ethyl, LP-778902 and LP-951757 Telotristat Ethyl	NA hours Standard Deviation NA Result was not calculated when more than one-third of the values were below the limit of quantification (BLQ) at a single time point.	NA hours Standard Deviation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.
Apparent Terminal Elimination Half-Life (t1/2) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-778902	9.05 hours Standard Deviation 3.02	8.31 hours Standard Deviation 1.51
Apparent Terminal Elimination Half-Life (t1/2) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-951757	11.5 hours Standard Deviation 4.65	9.93 hours Standard Deviation 4.45

PRIMARY outcome

Timeframe: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757. AUC0-inf was determined using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Total Telotristat Ethyl, LP-778902 and LP-951757 Telotristat Ethyl	NA ng*hour/mL Geometric Coefficient of Variation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.	NA ng*hour/mL Geometric Coefficient of Variation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-778902	1652 ng*hour/mL Geometric Coefficient of Variation 42.7	2488 ng*hour/mL Geometric Coefficient of Variation 77.9
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-951757	876 ng*hour/mL Geometric Coefficient of Variation 66.0	511 ng*hour/mL Geometric Coefficient of Variation 115

PRIMARY outcome

Timeframe: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757. AUC0-tlast was determined using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Area Under the Plasma Concentration-Time Curve From Time 0 to Time Corresponding to the Last Quantifiable Concentration (AUC0-tlast) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-778902	1637 ng*hour/mL Geometric Coefficient of Variation 43.3	2475 ng*hour/mL Geometric Coefficient of Variation 78.3
Area Under the Plasma Concentration-Time Curve From Time 0 to Time Corresponding to the Last Quantifiable Concentration (AUC0-tlast) of Total Telotristat Ethyl, LP-778902 and LP-951757 Telotristat Ethyl	NA ng*hour/mL Geometric Coefficient of Variation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.	NA ng*hour/mL Geometric Coefficient of Variation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.
Area Under the Plasma Concentration-Time Curve From Time 0 to Time Corresponding to the Last Quantifiable Concentration (AUC0-tlast) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-951757	845 ng*hour/mL Geometric Coefficient of Variation 64.4	494 ng*hour/mL Geometric Coefficient of Variation 118

PRIMARY outcome

Timeframe: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757. λz was determined using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Apparent First Order Terminal Elimination Rate Constant (λz) of Total Telotristat Ethyl, LP-778902 and LP-951757 Telotristat Ethyl	NA hour^-1 Standard Deviation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.	NA hour^-1 Standard Deviation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.
Apparent First Order Terminal Elimination Rate Constant (λz) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-778902	0.0890 hour^-1 Standard Deviation 0.0469	0.0871 hour^-1 Standard Deviation 0.0236
Apparent First Order Terminal Elimination Rate Constant (λz) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-951757	0.0686 hour^-1 Standard Deviation 0.0238	0.0821 hour^-1 Standard Deviation 0.0381

PRIMARY outcome

Timeframe: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

Blood samples were collected to determine plasma levels of telotristat ethyl using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL. CL/F was determined using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=1 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=2 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Apparent Total Clearance From Plasma (CL/F) of Total Telotristat Ethyl	NA Litres/hour Standard Deviation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.	NA Litres/hour Standard Deviation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.

PRIMARY outcome

Timeframe: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

Blood samples were collected to determine plasma levels of telotristat ethyl using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL. Vd/F was determined using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=1 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=2 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Apparent Volume of Distribution (Vd/F) of Total Telotristat Ethyl	NA Litres Standard Deviation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.	NA Litres Standard Deviation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.

PRIMARY outcome

Timeframe: Day 1 (0.5, 1, 2 and 3 hours post-dose)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

Plasma protein binding was assessed using equilibrium dialysis followed by LC-MS/MS for determination of unbound drug concentrations. The plasma protein binding of telotristat ethyl, LP-778902 and LP-951757 was assessed and the percentage of fu was calculated as the mean over time of the mean of the available replicates.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Percentage of Unbound Plasma Fraction (fu) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-951757	0.135 Percentage of fu Standard Deviation 0.295	0.0608 Percentage of fu Standard Deviation 0.0923
Percentage of Unbound Plasma Fraction (fu) of Total Telotristat Ethyl, LP-778902 and LP-951757 Telotristat Ethyl	NA Percentage of fu Standard Deviation NA Not determined as only 1 subject displayed a value above the LOQ.	NA Percentage of fu Standard Deviation NA Not determined as only 1 subject displayed a value above the LOQ.
Percentage of Unbound Plasma Fraction (fu) of Total Telotristat Ethyl, LP-778902 and LP-951757 LP-778902	0.115 Percentage of fu Standard Deviation 0.0589	0.134 Percentage of fu Standard Deviation 0.0524

PRIMARY outcome

Timeframe: Day 1 (0.5, 1, 2 and 3 hours post-dose)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

Cmaxu of unbound telotristat ethyl and its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 was calculated using the unbound fraction fu (defined for each subject as the mean over all time points of the mean of fu) and determined using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Cmax for the Unbound Fraction (Cmaxu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 LP-951757	0.0528 ng/mL Geometric Coefficient of Variation 215	0.0779 ng/mL Geometric Coefficient of Variation 84.0
Cmax for the Unbound Fraction (Cmaxu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 Telotristat Ethyl	NA ng/mL Geometric Coefficient of Variation NA Not determined as only 1 subject displayed an unbound fraction value above the LOQ.	NA ng/mL Geometric Coefficient of Variation NA Not determined as only 1 subject displayed an unbound fraction value above the LOQ.
Cmax for the Unbound Fraction (Cmaxu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 LP-778902	0.554 ng/mL Geometric Coefficient of Variation 113	0.957 ng/mL Geometric Coefficient of Variation 70.7

PRIMARY outcome

Timeframe: Day 1 (0.5, 1, 2 and 3 hours post-dose)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

AUC0-infu of unbound telotristat ethyl and its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 was calculated using the unbound fraction fu (defined for each subject as the mean over all time points of the mean of fu) and determined using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
AUC0-inf for the Unbound Fraction (AUC0-infu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 LP-951757	0.955 ng*hour/mL Geometric Coefficient of Variation 237	1.06 ng*hour/mL Geometric Coefficient of Variation NA Not determined due to insufficient values different from 0.
AUC0-inf for the Unbound Fraction (AUC0-infu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 Telotristat Ethyl	NA ng*hour/mL Geometric Coefficient of Variation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.	NA ng*hour/mL Geometric Coefficient of Variation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.
AUC0-inf for the Unbound Fraction (AUC0-infu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 LP-778902	1.72 ng*hour/mL Geometric Coefficient of Variation 90.3	3.14 ng*hour/mL Geometric Coefficient of Variation 99.2

PRIMARY outcome

Timeframe: Day 1 (0.5, 1, 2 and 3 hours post-dose)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

AUC0-tlastu of unbound telotristat ethyl and its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 was calculated using the unbound fraction fu (defined for each subject as the mean over all time points of the mean of fu) and determined using non-compartmental analysis.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
AUC0-tlast for the Unbound Fraction (AUC0-tlastu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 Telotristat Ethyl	NA ng*hour/mL Geometric Coefficient of Variation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.	NA ng*hour/mL Geometric Coefficient of Variation NA Result was not calculated when more than one-third of the values were BLQ at a single time point.
AUC0-tlast for the Unbound Fraction (AUC0-tlastu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 LP-778902	1.70 ng*hour/mL Geometric Coefficient of Variation 91.2	3.12 ng*hour/mL Geometric Coefficient of Variation 99.6
AUC0-tlast for the Unbound Fraction (AUC0-tlastu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 LP-951757	0.928 ng*hour/mL Geometric Coefficient of Variation 234	1.05 ng*hour/mL Geometric Coefficient of Variation NA Not determined due to insufficient values different from 0.

PRIMARY outcome

Timeframe: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

The following MRs of Cmax were calculated: MRCmax = (Cmax LP-778902)/(Cmax telotristat ethyl) MRCmaxTotal = (Cmax LP-778902)/(Cmax LP-778902+Cmax telotristat ethyl) The ratios were also normalised by molecular weight (MW) of the metabolites (telotristat ethyl: MW=575 grams/mole (g/mol) and LP-778902: MW=547 g/mol). Both the normalised and not normalised ratios are presented.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Metabolic Ratios (MR) of Cmax (LP-778902/Telotristat Ethyl) MRCmax - not normalised	154 Ratio Standard Deviation 68.9	204 Ratio Standard Deviation 143
Metabolic Ratios (MR) of Cmax (LP-778902/Telotristat Ethyl) MRCmax - normalised	162 Ratio Standard Deviation 72.4	215 Ratio Standard Deviation 151
Metabolic Ratios (MR) of Cmax (LP-778902/Telotristat Ethyl) MRCmaxTotal - not normalised	0.992 Ratio Standard Deviation 0.00410	0.991 Ratio Standard Deviation 0.00996
Metabolic Ratios (MR) of Cmax (LP-778902/Telotristat Ethyl) MRCmaxTotal - normalised	0.993 Ratio Standard Deviation 0.00391	0.991 Ratio Standard Deviation 0.00949

SECONDARY outcome

Timeframe: Day 1 (predose and 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, 12 to 24 hours post-dose), Day 2 (24 to 48 hours post-dose), Day 3 (48 to 72 hours post-dose)

Population: The PK population included all subjects who received the single oral dose of study drug and had no major protocol deviations affecting the PK variables and for whom the renal function group was assessable and who had a sufficient number of plasma concentrations to estimate the main PK parameters.

For assessment of urine PK parameters, the amount of unchanged telotristat ethyl and its active metabolite LP-778902 (also known as telotristat) excreted in urine was determined.

Outcome measures

Outcome measures
Measure	Healthy Subjects (Control Group) n=8 Participants Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 Participants Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single oral dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Amount of Unchanged Telotristat Ethyl and LP-778902 Excreted in Urine. LP-778902: 0-4 hours post-dose	88966 ng Standard Deviation 50003	19293 ng Standard Deviation 9447
Amount of Unchanged Telotristat Ethyl and LP-778902 Excreted in Urine. LP-778902: 8-12 hours post-dose	173416 ng Standard Deviation 49499	47955 ng Standard Deviation 25522
Amount of Unchanged Telotristat Ethyl and LP-778902 Excreted in Urine. LP-778902: 12-24 hours post-dose	185970 ng Standard Deviation 47726	51970 ng Standard Deviation 27925
Amount of Unchanged Telotristat Ethyl and LP-778902 Excreted in Urine. LP-778902: Pre-dose	0 ng Standard Deviation 0	0 ng Standard Deviation 0
Amount of Unchanged Telotristat Ethyl and LP-778902 Excreted in Urine. LP-778902: 4-8 hours post-dose	152419 ng Standard Deviation 48649	42976 ng Standard Deviation 22836
Amount of Unchanged Telotristat Ethyl and LP-778902 Excreted in Urine. LP-778902: 24-48 hours post-dose	191999 ng Standard Deviation 48110	53997 ng Standard Deviation 29262
Amount of Unchanged Telotristat Ethyl and LP-778902 Excreted in Urine. LP-778902: 48-72 hours post-dose	193880 ng Standard Deviation 48123	54397 ng Standard Deviation 29546

Adverse Events

Healthy Subjects (Control Group)

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Severe Renal Impairment (Test Group)

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Healthy Subjects (Control Group) n=8 participants at risk Subjects with normal renal function (eGFR ≥90 mL/min/1.73 m²) received a single dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.	Severe Renal Impairment (Test Group) n=8 participants at risk Subjects with severely decreased renal function (eGFR \<30 mL/min/1.73 m², not requiring dialysis) received a single dose of 250 mg telotristat etiprate given under fed conditions (between 15 minutes before and 1 hour after the meal or snack) on Day 1.
Investigations C-reactive protein increased	0.00% 0/8 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).	12.5% 1/8 • Number of events 1 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).
Investigations Heart rate increased	0.00% 0/8 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).	12.5% 1/8 • Number of events 1 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).
Investigations Lymphocyte count decreased	0.00% 0/8 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).	12.5% 1/8 • Number of events 1 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).
Investigations Monocyte count increased	0.00% 0/8 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).	12.5% 1/8 • Number of events 1 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/8 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).	12.5% 1/8 • Number of events 1 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/8 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).	12.5% 1/8 • Number of events 1 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).
Blood and lymphatic system disorders Leukocytosis	12.5% 1/8 • Number of events 1 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).	0.00% 0/8 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).
Gastrointestinal disorders Nausea	0.00% 0/8 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).	12.5% 1/8 • Number of events 1 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).
General disorders Chills	0.00% 0/8 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).	12.5% 1/8 • Number of events 1 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).
Infections and infestations Bronchitis	0.00% 0/8 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).	12.5% 1/8 • Number of events 1 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).
Nervous system disorders Headache	0.00% 0/8 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).	12.5% 1/8 • Number of events 2 • Treatment emergent adverse events were recorded from Day 1 to the end of study visit between Day 8 and Day 15 (overall timeframe: up to 15 days).

Additional Information

Medical Director

Ipsen

Phone: See email

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place