Study to Assess the Effect of Co-Administration of AZD9833 on the Pharmacokinetics of Midazolam, of Omeprazole, of Celecoxib and of Dabigatran Etexilate in Healthy Postmenopausal Female Volunteers

Healthy Volunteers Clinical Trial

Official title:

A Phase 1, Multi-center, Open-label, 3-arm, Fixed Sequence Study to Assess the Effect of Co-administration of AZD9833 on the Pharmacokinetics of Midazolam (CYP3A4/5 Substrate), of Omeprazole (CYP2C19 Substrate), of Celecoxib (CYP2C9 Substrate) and of Dabigatran Etexilate (P-gp Transporter Substrate) in Healthy Postmenopausal Female Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05438303
• Other study ID #: D8532C00004
• Status: Completed
• Phase: Phase 1
• Start date: June 13, 2022
• Est. completion date: December 13, 2022

Study information

• Verified date: January 2023
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will be a fixed sequence drug-drug interaction study in healthy postmenopausal females, conducted at multiple study sites

Description:

Participants will be randomized to one of 3 treatment arms on Day 1 prior to Investigational Medicinal Product (IMP) administration:

• Arm A: single oral doses of midazolam and omeprazole administered together + repeated doses of AZD9833 .

• Arm B: single oral doses of dabigatran etexilate + single oral dose of AZD9833 .

• Arm C: single oral doses of celecoxib + repeated oral doses of AZD9833.

Each participant will be involved in the study for up to 7 to 8 weeks

Recruitment information / eligibility

• Status: Completed
• Enrollment: 59
• Est. completion date: December 13, 2022
• Est. primary completion date: December 13, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 50 Years to 70 Years

Eligibility

Inclusion Criteria:

• Healthy postmenopausal female participants aged 50 to 70 years with suitable veins for cannulation or repeated venipuncture.

• Participants must be postmenopausal by fulfilling the following criterion:

• Have a Body mass index (BMI) between 19 and 35 kg/m^2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive as measured at screening.

• Must agree to not use warfarin or phenytoin (and other coumarin-derived vitamin K antagonist anticoagulants) during study, and for 2 weeks after last administration of IMP.

Exclusion Criteria:

• History of any clinically significant disease or disorder as described by the Investigator.

• History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.

• Use of systemic estrogen-containing hormone replacement therapy within 6 months prior to first dose in the study.

• Have taken any proton pump inhibitors (omeprazole, lansoprazole, esomeprazole, pantoprazole, etc.) within 14 days of beginning study treatment (ie, first administration of omeprazole in Arm A.

• Have taken any drug with enzyme-inducing properties such as St John's Wort within 3 weeks of screening.

• Presence of any contraindication to the probe substrates omeprazole, midazolam, dabigatran or celecoxib per the United States Package Insert.

• Any of the following signs or confirmation of COVID-19 infection:

• Subject has a positive RT-PCR test for SARS-CoV-2 prior to randomization.

• Clinical signs and symptoms consistent with COVID-19 (eg, fever, dry cough, dyspnea, sore throat, fatigue) or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or at randomization.

• Subject has been previously hospitalized with COVID-19 infection within the last 12 months.

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Drug:
• AZD9833
AZD9833 tablets will be administered orally once daily on Days 1 - Day 5 (Treatment Period 2) and Day 1 (Treatment Period 3) for participants recruited to Arms A and C and Day 1 for those in Arm B
• Midazolam
Midazolam will be administered orally as a syrup once on Day 1 of Treatment Periods 1 and 3; administered together with Omeprazole
• Omeprazole
An Omeprazole capsule will be administered once on Day 1 of Treatment Periods 1 and 3; administered together with Midazolam
• Dabigatran Etexilate
A Dabigatran Etexilate capsule will be administered once on Day 1 of Treatment Periods 1 and 2
• Celecoxib
A Celecoxib capsule will be administered once on Day 1 of Treatment Periods 1 and 3

Locations

Country	Name	City	State
United States	Research Site	Berlin	New Jersey
United States	Research Site	Long Beach	California

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under plasma concentration time curve from zero to infinity (AUCinf) of midazolam, omeprazole, total dabigatran, and celecoxib	The effects of AZD9833 will be evaluated in healthy postmenopausal female participants on the key pharmacokinetic (PK) variables of: - single-dose midazolam and omeprazole, administered together; single-dose dabigatran etexilate; single-dose celecoxib	For Arm A: Day 1 to Day 2 (Period 1 and 3); For Arm B: Day 1 to Day 3 (Period 1 and 2) (Each Period is 4 days); For Arm C: Day 1 to Day 4 (Period 1 and 3) (For Arm A and C, Period 1 is for 5 days and Period 3 is for 4 days)
Primary	Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) of midazolam, omeprazole, total dabigatran, and celecoxib	The effects of AZD9833 will be evaluated in healthy postmenopausal female participants on the key pharmacokinetic variables of: single-dose midazolam and omeprazole, administered together; single-dose dabigatran etexilate; single-dose celecoxib	For Arm A: Day 1 to Day 2 (Period 1 and 3); For Arm B: Day 1 to Day 3 (Period 1 and 2) (Each Period is 4 days); For Arm C: Day 1 to Day 4 (Period 1 and 3) (For Arm A and C, Period 1 is for 5 days and Period 3 is for 4 days)
Primary	Maximum observed plasma concentration (Cmax) of midazolam, omeprazole, dabigatran etexilate and celecoxib	The effects of AZD9833 will be evaluated in healthy postmenopausal female participants on the key pharmacokinetic variables of: single-dose midazolam and omeprazole administered together; single-dose dabigatran etexilate; single-dose celecoxib	For Arm A: Day 1 to Day 2 (Period 1 and 3); For Arm B: Day 1 to Day 3 (Period 1 and 2) (Each Period is 4 days); For Arm C: Day 1 to Day 4 (Period 1 and 3) (For Arm A and C, Period 1 is for 5 days and Period 3 is for 4 days)
Secondary	Number of participants with Adverse Events (AEs)	The safety and tolerability of AZD9833, alone and in combination with midazolam, omeprazole, dabigatran etexilate, and celecoxib will be evaluated in healthy postmenopausal female participants.	From Screening until Post study (5 to 7 days post final dose) (assessed up to 6 months)
Secondary	AUCinf for AZD9833 and free dabigatran	AZD9833 PK and the effect of AZD9833 on the PK of dabigatran etexilate will be further characterized.	For AZD9833 in Arm A: Day 1 and Day 2 (Period 3); For AZD9833 in Arm B: Day 1 and Day 2 (Period 2); For dabigatran: Day 1 to Day 3 (Period 1 and 2) (Each Period lasts for 4 days)
Secondary	AUClast for AZD9833 and free dabigatran	AZD9833 PK and the effect of AZD9833 on the PK of dabigatran etexilate, and will be further characterized.	For AZD9833 in Arm A: Day 1 and Day 2 (Period 3); For AZD9833 in Arm B: Day 1 and Day 2 (Period 2); For dabigatran: Day 1 to Day 3 (Period 1 and 2) (Each Period lasts for 4 days)
Secondary	Area under plasma concentration-time curve in the dose interval (AUCt) for AZD9833 and free dabigatran	AZD9833 PK and the effect of AZD9833 on the PK of dabigatran etexilate will be further characterized.	For AZD9833 in Arm A: Day 1 and Day 2 (Period 3); For AZD9833 in Arm B: Day 1 and Day 2 (Period 2); For dabigatran: Day 1 to Day 3 (Period 1 and 2) (Each Period lasts for 4 days)
Secondary	Cmax for AZD9833 and free dabigatran	AZD9833 PK and the effect of AZD9833 on the PK of dabigatran etexilate will be further characterized	For AZD9833 in Arm A: Day 1 and Day 2 (Period 3); For AZD9833 in Arm B: Day 1 and Day 2 (Period 2); For dabigatran: Day 1 to Day 3 (Period 1 and 2) (Each Period lasts for 4 days)
Secondary	Time to reach maximum observed concentration (tmax) for AZD9833 and free dabigatran	AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.	For AZD9833 in Arm A: Day 1 and Day 2 (Period 3); For AZD9833 in Arm B: Day 1 and Day 2 (Period 2); For dabigatran: Day 1 to Day 3 (Period 1 and 2) (Each Period lasts for 4 days)
Secondary	Half-life associated with terminal slope of a semi-logarithmic concentration-time curve (t½?z) for AZD9833 and free dabigatran	AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.	For AZD9833 in Arm A: Day 1 and Day 2 (Period 3); For AZD9833 in Arm B: Day 1 and Day 2 (Period 2); For dabigatran: Day 1 to Day 3 (Period 1 and 2) (Each Period lasts for 4 days)
Secondary	Apparent total body clearance from plasma after extravascular administration (CL/F) for AZD9833 and free dabigatran	AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.	For AZD9833 in Arm A: Day 1 and Day 2 (Period 3); For AZD9833 in Arm B: Day 1 and Day 2 (Period 2); For dabigatran: Day 1 to Day 3 (Period 1 and 2) (Each Period lasts for 4 days)
Secondary	Apparent volume of distribution based on terminal phase (Vz/F) for AZD9833 and free dabigatran	AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.	For AZD9833 in Arm A: Day 1 and Day 2 (Period 3); For AZD9833 in Arm B: Day 1 and Day 2 (Period 2); For dabigatran: Day 1 to Day 3 (Period 1 and 2) (Each Period lasts for 4 days)
Secondary	tmax for midazolam, omeprazole, total dabigatran, and celecoxib	AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.	For Arm A: Day 1 to Day 2 (Period 1 and 3); For Arm B: Day 1 to Day 3 (Period 1 and 2) (Each Period is 4 days); For Arm C: Day 1 to Day 4 (Period 1 and 3) (For Arm A and C, Period 1 is for 5 days and Period 3 is for 4 days)
Secondary	t½?z for midazolam, omeprazole, total dabigatran, and celecoxib	AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.	For Arm A: Day 1 to Day 2 (Period 1 and 3); For Arm B: Day 1 to Day 3 (Period 1 and 2) (Each Period is 4 days); For Arm C: Day 1 to Day 4 (Period 1 and 3) (For Arm A and C, Period 1 is for 5 days and Period 3 is for 4 days)
Secondary	CL/F for midazolam, omeprazole, total dabigatran, and celecoxib	AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.	For Arm A: Day 1 to Day 2 (Period 1 and 3); For Arm B: Day 1 to Day 3 (Period 1 and 2) (Each Period is 4 days); For Arm C: Day 1 to Day 4 (Period 1 and 3) (For Arm A and C, Period 1 is for 5 days and Period 3 is for 4 days)
Secondary	Vz/F for midazolam, omeprazole, total dabigatran, and celecoxib	AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.	For Arm A: Day 1 to Day 2 (Period 1 and 3); For Arm B: Day 1 to Day 3 (Period 1 and 2) (Each Period is 4 days); For Arm C: Day 1 to Day 4 (Period 1 and 3) (For Arm A and C, Period 1 is for 5 days and Period 3 is for 4 days)
Secondary	Area under the plasma concentration-curve from zero to 24 hours post dose (AUC0-24) for celecoxib	AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.	Day 1 to Day 4 (Period 1) (Period 1 lasts for 5 days) and Day 1 to Day 4 (Period 3) (Period 3 lasts for 4 days)