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

A Phase I, Fixed Sequence, Open-label, Study to Assess the Pharmacokinetics of AZD9291 in Healthy Male Volunteers When a Single Oral Dose of AZD9291 80 mg is Administered Alone and in Combination With Omeprazole

This is a Phase 1, open-label, 2-period fixed sequence design to evaluate the interaction of AZD9291 with omeprazole in approximately 50 healthy, adult male volunteers. Volunteers will receive Treatment A (AZD9291 and omeprazole) in Period 1 and Treatment B (AZD9291 only) in Period 2. The dose of AZD9291 in Period 1 and the dose of AZD9291 in Period 2 will be separated by a washout of at least 21 days (the washout will not be more than 5 weeks). The study will be performed at up to 2 sites in the USA and will assess the effect of omeprazole (proton pump inhibitor) on AZD9291 exposure

Study Overview

• Status: Completed
• Conditions: Healthy Volunteer
• Intervention / Treatment: Procedure: Pharmacokinetic sampling - AZD9291; Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550; Drug: AZD9291 tablet dosing; Drug: Omeprazole tablet dosing

• Study Type: Interventional
• Enrollment (Actual): 136
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Overland Park, Kansas, United States
      • Research Site
  • Minnesota
    • Minneapolis, Minnesota, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

For inclusion in the study volunteers must fulfil the following criteria.

1. Provision of signed and dated informed consent prior to any study-specific procedures.
2. Healthy male volunteers aged 18 to 55 years. (Healthy as determined by medical history, physical examination, laboratory parameters, ECG, and eye examination performed before the first administration of investigational product.)
3. Body mass index between 19 and 30 kg/m2, and body weight between 50 kg and 100 kg, inclusive.
4. Veins suitable for cannulation or repeated venepuncture.
5. Volunteers must be willing to use reliable methods of contraception (condom and spermicide), even if their partners are postmenopausal, surgically sterile, or using an effective hormonal method of contraception or intrauterine coil. In addition, volunteers must agree to continue to take similar contraceptive precautions and avoid sperm donation for 6 months after the last administration of AZD9291.

Volunteers must not enter the study if any of the following exclusion criteria are fulfilled:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca and Quintiles staff).
2. Previous enrollment in the present study.
3. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the healthy volunteer at risk because of participation in the study, or influence the results or the healthy volunteer's ability to participate in the study.
4. History or presence of gastrointestinal, hepatic, or renal disease or surgical procedure or any other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
5. Any clinically significant abnormalities in physical examination, vital signs (supine blood pressure >140 mmHg systolic, >90 mmHg diastolic, or pulse rate ≤35 or ≥100 beats per minute), or clinical laboratory assessment as judged by the Investigator.
6. Acute illness, surgical procedures, or trauma from within 2 weeks before enrollment until first administration of investigational product (IP).
7. Volunteers who have received live or live-attenuated vaccine in the 2 weeks prior to dosing.
8. Volunteers with active malignancy or neoplastic disease in the previous 12 months.
9. A suspected/manifested infection according to International Airline Transportation Association (IATA) Categories A and B infectious substances.
10. Positive results on screening tests for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, or human immunodeficiency virus (HIV).
11. Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, as judged by the Investigator.
12. Known or suspected history of significant drug abuse as judged by the Investigator.
13. Positive screen for drugs of abuse or cotinine (nicotine level above 400 ng/mL) at screening or positive screen for alcohol, drugs of abuse, or cotinine on admission in Period 1 or Period 2.
14. History of alcohol abuse or excessive intake of alcohol, defined as regular weekly intake of greater than 21 units of alcohol in men (Note: 1 unit=25 mL spirits, 125 mL wine, or 250 mL beer or lager).
15. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to AZD9291, its excipients, or drugs with a similar chemical structure or class.
16. History of hypersensitivity to omeprazole, its excipients, or drugs with a similar chemical structure or class.
17. Use of any prescribed or nonprescribed medication, including drugs with hepatic enzyme-altering properties, such as St John's Wort, antacids, analgesics, herbal remedies, vitamins, and minerals during the 4 weeks (or longer depending on the medication's half-life) prior to the first administration of AZD9291 is not permitted. Occasional use of paracetamol (acetaminophen) and nonsteroidal nasal decongestant is permitted at the discretion of the Investigator.
18. Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of IP.
19. Blood donation within 1 month of screening or any blood donation/blood loss greater than 500 mL during the 3 months prior to screening.
20. Use of another new chemical entity (defined as a compound which has not been approved for marketing) or participation in any other clinical study (including methodology studies where no drugs were given) within 3 months of the first administration of IP in this study.
21. Current smokers or those who have smoked or used nicotine products within the previous 3 months.
22. Planned inpatient surgery, dental procedure, or hospitalisation during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZD9291 and omeprazole; Sequential treatments of AZD9291 + omeprazole followed by AZD9291 alone, with a washout period in between.	Procedure: Pharmacokinetic sampling - AZD9291; Blood sampling to measure AZD9291; Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550; Blood samples to measure levels of AZ5140 and AZ7550; Drug: AZD9291 tablet dosing; AZD9291 80mg tablet taken on Day 5 in Period 1 and Day 1 in Period 2.; Drug: Omeprazole tablet dosing; Omeprzole taken from Days 1 to 5 in Period 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC of AZD9291	Area under the plasma concentration-time curve from zero to infinity for AZD9291	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
Cmax of AZD9291	Rate and extent of absorption of AZD9291 following single oral doses of AZD9291 tablet formulation by assessment of maximum plasma concentration (Cmax).	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC(0-t)	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)	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.
AUC(0-72)	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)	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.
Tmax	Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using time to reach maximum plasma concentration, tmax	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.
Tlag	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	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.
t(1/2)	Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using the terminal half-life, t(1/2)	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.
λz	Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using the terminal rate constant, λz	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.
CL/F of AZD9291	Assessment of the PK of AZD9291 using the apparent plasma clearance, CL/F	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.
Vz/F of AZD9291	Assessment of the PK of AZD9291 using the apparent volume of distribution, Vz/F	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.
Cmax of AZ5104 and AZ7550	Assessment of the PK of AZ5104 and AZ7550 (metabolites to AZD9291) using the maximum plasma concentration, Cmax	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.
AUC of AZ5104 and AZ7550	Area under the plasma concentration-time curve from zero to infinity of AZ5104 and AZ7550 (metabolites to AZD9291)	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.
Parent to Metabolite Ratios of AZ5104 and AZ7550 Cmax	Assessment of the PK of AZ5104 and AZ7550 Cmax using the parent (AZD9291) to metabolite ratios	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.
Parent to Metabolite Ratios of AZ5104 and AZ7550 AUC	Assessment of the PK of AZ5104 and AZ7550 AUC using the parent (AZD9291) to metabolite ratios	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.

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

General Publications

• Vishwanathan K, Dickinson PA, Bui K, Cassier PA, Greystoke A, Lisbon E, Moreno V, So K, Thomas K, Weilert D, Yap TA, Plummer R. The Effect of Food or Omeprazole on the Pharmacokinetics of Osimertinib in Patients With Non-Small-Cell Lung Cancer and in Healthy Volunteers. J Clin Pharmacol. 2018 Apr;58(4):474-484. doi: 10.1002/jcph.1035. Epub 2017 Nov 26.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: August 20, 2014
• First Submitted That Met QC Criteria: August 22, 2014
• First Posted (Estimate): August 25, 2014

Study Record Updates

• Last Update Posted (Estimate): June 24, 2016
• Last Update Submitted That Met QC Criteria: May 23, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: oncology, cancer, non small cell lung cancer, anticancer druge, omeprazole, healthy volunteer
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Gastrointestinal Agents; Protein Kinase Inhibitors; Anti-Ulcer Agents; Proton Pump Inhibitors; Osimertinib; Omeprazole
• Other Study ID Numbers: D5160C00010