Trial Outcomes & Findings for Drug-Drug Interaction Study With AZD9291 and Omeprazole in Healthy Volunteers (NCT NCT02224053)

NCT ID: NCT02224053

Last Updated: 2016-06-24

Results Overview

Area under the plasma concentration-time curve from zero to infinity for AZD9291

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 136 participants
• Primary outcome timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose
• Results posted on: 2016-06-24

Participant Flow

First subject enrolled: 3 September 2014 Last Subject Last Visit: 5 January 2015 Study was performed at 2 sites in the USA.

136 subjects were enrolled (signed informed consent). Subjects were assigned to treatment if they met all the inclusion and none of the exclusion criteria. 68 subjects were enolled but failed inclusion/exclusion criteria and so were not eligible to be assigned treatment. The remaining 68 subjects started period 1 and received treatment.

Participant milestones

Measure	AZD9291 and Omeprazole Sequential treatments periods of AZD9291 + omeprazole (including a washout) followed by AZD9291 alone.
AZD9291 and Omeprazole Co-administration STARTED	68
AZD9291 and Omeprazole Co-administration COMPLETED	47
AZD9291 and Omeprazole Co-administration NOT COMPLETED	21
AZD9291 Alone STARTED	47
AZD9291 Alone COMPLETED	47
AZD9291 Alone NOT COMPLETED	0

Reasons for withdrawal

Measure	AZD9291 and Omeprazole Sequential treatments periods of AZD9291 + omeprazole (including a washout) followed by AZD9291 alone.
AZD9291 and Omeprazole Co-administration Exceeding PK limits after Period 1	11
AZD9291 and Omeprazole Co-administration Protocol Violation	4
AZD9291 and Omeprazole Co-administration Adverse Event	3
AZD9291 and Omeprazole Co-administration Withdrawal by Subject	1
AZD9291 and Omeprazole Co-administration Protocol non-compliance	2

Baseline Characteristics

Drug-Drug Interaction Study With AZD9291 and Omeprazole in Healthy Volunteers

Baseline characteristics by cohort

Measure	AZD9291 and Omeprazole n=68 Participants Sequential treatments periods of AZD9291 + omeprazole (including a washout) followed by AZD9291 alone.
Age, Continuous	34.0 Years STANDARD_DEVIATION 11.08 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	68 Participants n=5 Participants

PRIMARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Area under the plasma concentration-time curve from zero to infinity for AZD9291

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=53 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
AUC of AZD9291	6690 nM.h Full Range 28.8 • Interval 2340.0 to 10200.0	6269 nM.h Full Range 37.0 • Interval 2670.0 to 14200.0

PRIMARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Rate and extent of absorption of AZD9291 following single oral doses of AZD9291 tablet formulation by assessment of maximum plasma concentration (Cmax).

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=57 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
Cmax of AZD9291	127.8 nM Full Range 26.9 • Interval 47.6 to 200.0	126.1 nM Full Range 31.0 • Interval 49.0 to 200.0

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using area under the plasma concentration curve from zero extrapolated to o the time of the last quantifiable concentration, AUC(0-t)

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=53 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
AUC(0-t) AZD9291	6673 nM.h Interval 2340.0 to 10200.0	6249 nM.h Interval 2660.0 to 14100.0
AUC(0-t) AZ5104	546.5 nM.h Interval 226.0 to 939.0	539.2 nM.h Interval 230.0 to 1110.0
AUC(0-t) AZ7550	520.0 nM.h Interval 208.0 to 1010.0	560.0 nM.h Interval 300.0 to 942.0

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using area under the plasma concentration curve from time zero to 72 hours, AUC(0-72)

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=54 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
AUC(0-72) AZD9291	4404 nM.h Interval 1710.0 to 6410.0	4106 nM.h Interval 1760.0 to 7530.0
AUC(0-72) AZ5104	301.5 nM.h Interval 151.0 to 589.0	304.0 nM.h Interval 153.0 to 540.0
AUC(0-72) AZ7550	216.5 nM.h Interval 82.1 to 398.0	231.3 nM.h Interval 100.0 to 445.0

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using time to reach maximum plasma concentration, tmax

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=57 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
Tmax AZD9291	6 h Interval 5.0 to 48.08	6 h Interval 3.0 to 12.1
Tmax AZ5104	8 h Interval 5.0 to 72.12	7 h Interval 4.0 to 48.05
Tmax AZ7550	10 h Interval 5.0 to 72.42	10 h Interval 5.0 to 71.77

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using lag time before observation of quantifiable analyte concentrations in plasma, tlag

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=57 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
Tlag AZD9291	0.00 h Interval 0.0 to 0.0	0.00 h Interval 0.0 to 0.0
Tlag AZ5104	0.00 h Interval 0.0 to 2.0	0.00 h Interval 0.0 to 1.0
Tlag AZ7550	0.00 h Interval 0.0 to 2.0	0.00 h Interval 0.0 to 1.0

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using the terminal half-life, t(1/2)

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=53 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
t(1/2) AZD9291	58.99 h Interval 39.2 to 77.1	63.60 h Interval 52.3 to 80.4
t(1/2) AZ5104	51.06 h Interval 31.1 to 85.4	54.47 h Interval 34.5 to 87.7
t(1/2) AZ7550	71.34 h Interval 47.0 to 106.0	72.16 h Interval 48.5 to 102.0

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using the terminal rate constant, λz

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=53 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
λz AZD9291	0.011748 1/h Interval 0.00899 to 0.0177	0.010898 1/h Interval 0.00862 to 0.0132
λz AZ5104	0.013577 1/h Interval 0.00812 to 0.0223	0.012722 1/h Interval 0.0079 to 0.0201
λz AZ7550	0.009718 1/h Interval 0.00656 to 0.0147	0.009606 1/h Interval 0.00677 to 0.0143

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Assessment of the PK of AZD9291 using the apparent plasma clearance, CL/F

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=53 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
CL/F of AZD9291	23.93 L/h Interval 15.6 to 68.4	25.55 L/h Interval 11.3 to 60.1

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Assessment of the PK of AZD9291 using the apparent volume of distribution, Vz/F

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=53 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
Vz/F of AZD9291	2037 L Interval 1280.0 to 3870.0	2343 L Interval 1250.0 to 5120.0

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Assessment of the PK of AZ5104 and AZ7550 (metabolites to AZD9291) using the maximum plasma concentration, Cmax

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=57 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
Cmax of AZ5104 and AZ7550 AZ5104	5.543 nM Full Range 26.9 • Interval 2.73 to 12.0	5.889 nM Full Range 31.0 • Interval 2.67 to 12.9
Cmax of AZ5104 and AZ7550 AZ7550	3.913 nM Interval 1.68 to 7.98	4.402 nM Interval 2.04 to 9.69

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Area under the plasma concentration-time curve from zero to infinity of AZ5104 and AZ7550 (metabolites to AZD9291)

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=53 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
AUC of AZ5104 and AZ7550 AZ5104	556.6 nM.h Full Range 28.8 • Interval 231.0 to 948.0	550.7 nM.h Full Range 37.0 • Interval 245.0 to 1130.0
AUC of AZ5104 and AZ7550 AZ7750	536.5 nM.h Interval 231.0 to 1020.0	574.9 nM.h Interval 309.0 to 955.0

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Assessment of the PK of AZ5104 and AZ7550 Cmax using the parent (AZD9291) to metabolite ratios

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=57 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
Parent to Metabolite Ratios of AZ5104 and AZ7550 Cmax AZ5104	0.04335 Ratio Interval 0.0255 to 0.0873	0.04671 Ratio Interval 0.0293 to 0.0908
Parent to Metabolite Ratios of AZ5104 and AZ7550 Cmax AZ7550	0.03061 Ratio Interval 0.0169 to 0.053	0.03491 Ratio Interval 0.0169 to 0.0708

SECONDARY outcome

Timeframe: PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose.

Population: Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product

Assessment of the PK of AZ5104 and AZ7550 AUC using the parent (AZD9291) to metabolite ratios

Outcome measures

Measure	AZD9291 and Omeprazole Co-administration n=53 Participants Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 Participants AZD9291 80 mg single oral dose on Day 1 (Period 2)
Parent to Metabolite Ratios of AZ5104 and AZ7550 AUC AZ5104	0.08318 Ratio Interval 0.0464 to 0.137	0.08785 Ratio Interval 0.0587 to 0.133
Parent to Metabolite Ratios of AZ5104 and AZ7550 AUC AZ7550	0.08019 Ratio Interval 0.0334 to 0.152	0.09166 Ratio Interval 0.0424 to 0.207

Adverse Events

AZD9291 and Omeprazole Co-administration

Serious events: 3 serious events

Other events: 8 other events

Deaths: 0 deaths

AZD9291 Alone

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Measure	AZD9291 and Omeprazole Co-administration n=68 participants at risk Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 participants at risk AZD9291 80 mg single oral dose on Day 1 (Period 2)
Hepatobiliary disorders Cholelithiasis	1.5% 1/68 • Number of events 1 • AEs collected from the day prior to first dose of treatment (omeprazole) until the follow up visit, approximately 3 months.	0.00% 0/47 • AEs collected from the day prior to first dose of treatment (omeprazole) until the follow up visit, approximately 3 months.
Investigations Blood creatine phosphokinase increased	1.5% 1/68 • Number of events 1 • AEs collected from the day prior to first dose of treatment (omeprazole) until the follow up visit, approximately 3 months.	0.00% 0/47 • AEs collected from the day prior to first dose of treatment (omeprazole) until the follow up visit, approximately 3 months.
Investigations Transaminases increased	2.9% 2/68 • Number of events 2 • AEs collected from the day prior to first dose of treatment (omeprazole) until the follow up visit, approximately 3 months.	0.00% 0/47 • AEs collected from the day prior to first dose of treatment (omeprazole) until the follow up visit, approximately 3 months.

Other adverse events

Measure	AZD9291 and Omeprazole Co-administration n=68 participants at risk Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).	AZD9291 Alone n=47 participants at risk AZD9291 80 mg single oral dose on Day 1 (Period 2)
Nervous system disorders Headache	7.4% 5/68 • Number of events 5 • AEs collected from the day prior to first dose of treatment (omeprazole) until the follow up visit, approximately 3 months.	0.00% 0/47 • AEs collected from the day prior to first dose of treatment (omeprazole) until the follow up visit, approximately 3 months.
Investigations Blood creatine phosphokinase increased	4.4% 3/68 • Number of events 3 • AEs collected from the day prior to first dose of treatment (omeprazole) until the follow up visit, approximately 3 months.	4.3% 2/47 • Number of events 2 • AEs collected from the day prior to first dose of treatment (omeprazole) until the follow up visit, approximately 3 months.

Additional Information

Dr Karen So

AstraZeneca

Email: ClinicalTrialTransparency@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee The Principal Investigator (PI) agrees to collaborate on the contents and formation of any publication and to pay due consideration to comments and opinions offered. AstraZeneca have 30 days for final manuscript review and may require that submission for publication be delayed in order to file patent application.
• Publication restrictions are in place

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