Clinical trial NCT05438303: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Drug-Drug interaction
Midazolam
Omeprazole
Dabigatran etexilate
Celecoxib
Postmenopausal
Breast Cancer
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2022-06-29
Enrollment: 59
Sex: FEMALE
Minimum age (years): 50
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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

Detailed 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

Eligibility criteria: 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.

Primary outcomes:
measure: Area under plasma concentration time curve from zero to infinity (AUCinf) of midazolam, omeprazole, total dabigatran, and celecoxib
timeFrame: 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)
measure: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) of midazolam, omeprazole, total dabigatran, and celecoxib
timeFrame: 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)
measure: Maximum observed plasma concentration (Cmax) of midazolam, omeprazole, dabigatran etexilate and celecoxib
timeFrame: 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 outcomes:
measure: Number of participants with Adverse Events (AEs)
timeFrame: From Screening until Post study (5 to 7 days post final dose) (assessed up to 6 months)
measure: AUCinf for AZD9833 and free dabigatran
timeFrame: 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)
measure: AUClast for AZD9833 and free dabigatran
timeFrame: 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)
measure: Area under plasma concentration-time curve in the dose interval (AUCt) for AZD9833 and free dabigatran
timeFrame: 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)
measure: Cmax for AZD9833 and free dabigatran
timeFrame: 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)
measure: Time to reach maximum observed concentration (tmax) for AZD9833 and free dabigatran
timeFrame: 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)
measure: Half-life associated with terminal slope of a semi-logarithmic concentration-time curve (t½λz) for AZD9833 and free dabigatran
timeFrame: 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)
measure: Apparent total body clearance from plasma after extravascular administration (CL/F) for AZD9833 and free dabigatran
timeFrame: 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)
measure: Apparent volume of distribution based on terminal phase (Vz/F) for AZD9833 and free dabigatran
timeFrame: 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)
measure: tmax for midazolam, omeprazole, total dabigatran, and celecoxib
timeFrame: 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)
measure: t½λz for midazolam, omeprazole, total dabigatran, and celecoxib
timeFrame: 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)
measure: CL/F for midazolam, omeprazole, total dabigatran, and celecoxib
timeFrame: 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)
measure: Vz/F for midazolam, omeprazole, total dabigatran, and celecoxib
timeFrame: 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)
measure: Area under the plasma concentration-curve from zero to 24 hours post dose (AUC0-24) for celecoxib
timeFrame: 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)
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: Research Site
state: California
city: Berlin
country: United States
facility: Research Site
state: New Jersey
Study officials:
References: