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
- Conditions
- Healthy Volunteers
- Interventions
- Registration Number
- NCT05438303
- Lead Sponsor
- AstraZeneca
- 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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 59
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B (Dabigatran etexilate) Dabigatran Etexilate Participants will receive single oral doses of dabigatran etexilate (Day 1 of Treatment Periods 1 and 2) and single oral dose of AZD9833 (Day 1 of Treatment Period 2) Arm A (midazolam and omeprazole) Omeprazole Participants will receive single oral doses of midazolam and omeprazole together (Day 1 of Treatment Periods 1 and 3) and repeated doses of AZD9833 (Days 1 to 5 of Treatment Period 2 and Day 1 of Treatment Period 3) Arm A (midazolam and omeprazole) AZD9833 Participants will receive single oral doses of midazolam and omeprazole together (Day 1 of Treatment Periods 1 and 3) and repeated doses of AZD9833 (Days 1 to 5 of Treatment Period 2 and Day 1 of Treatment Period 3) Arm B (Dabigatran etexilate) AZD9833 Participants will receive single oral doses of dabigatran etexilate (Day 1 of Treatment Periods 1 and 2) and single oral dose of AZD9833 (Day 1 of Treatment Period 2) Arm C (Celecoxib) AZD9833 Participants will receive single oral doses of celecoxib (Day 1 of Treatment Periods 1 and 3) and repeated oral doses of AZD9833 (Days 1 to 5 of Treatment Period 2 and Day 1 of Treatment Period 3) Arm A (midazolam and omeprazole) Midazolam Participants will receive single oral doses of midazolam and omeprazole together (Day 1 of Treatment Periods 1 and 3) and repeated doses of AZD9833 (Days 1 to 5 of Treatment Period 2 and Day 1 of Treatment Period 3) Arm C (Celecoxib) Celecoxib Participants will receive single oral doses of celecoxib (Day 1 of Treatment Periods 1 and 3) and repeated oral doses of AZD9833 (Days 1 to 5 of Treatment Period 2 and Day 1 of Treatment Period 3)
- Primary Outcome Measures
Name Time Method Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) of midazolam, omeprazole, total dabigatran, and 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) 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 celecoxibMaximum observed plasma concentration (Cmax) of midazolam, omeprazole, dabigatran etexilate and 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) 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 celecoxibArea under plasma concentration time curve from zero to infinity (AUCinf) of midazolam, omeprazole, total dabigatran, and 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) 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
- Secondary Outcome Measures
Name Time Method AUClast for AZD9833 and free dabigatran 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) AZD9833 PK and the effect of AZD9833 on the PK of dabigatran etexilate, and will be further characterized.
Number of participants with Adverse Events (AEs) From Screening until Post study (5 to 7 days post final dose) (assessed up to 6 months) 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.
AUCinf for AZD9833 and free dabigatran 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) AZD9833 PK and the effect of AZD9833 on the PK of dabigatran etexilate will be further characterized.
Cmax for AZD9833 and free dabigatran 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) AZD9833 PK and the effect of AZD9833 on the PK of dabigatran etexilate will be further characterized
Time to reach maximum observed concentration (tmax) for AZD9833 and free dabigatran 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) AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.
Apparent total body clearance from plasma after extravascular administration (CL/F) for AZD9833 and free dabigatran 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) AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.
tmax for midazolam, omeprazole, total dabigatran, and 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) AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.
Area under plasma concentration-time curve in the dose interval (AUCt) for AZD9833 and free dabigatran 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) AZD9833 PK and the effect of AZD9833 on the PK of dabigatran etexilate will be further characterized.
Half-life associated with terminal slope of a semi-logarithmic concentration-time curve (t½λz) for AZD9833 and free dabigatran 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) AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.
Apparent volume of distribution based on terminal phase (Vz/F) for AZD9833 and free dabigatran 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) AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.
t½λz for midazolam, omeprazole, total dabigatran, and 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) AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.
CL/F for midazolam, omeprazole, total dabigatran, and 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) AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.
Vz/F for midazolam, omeprazole, total dabigatran, and 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) AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.
Area under the plasma concentration-curve from zero to 24 hours post dose (AUC0-24) for celecoxib 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) AZD9833 PK and the effect of AZD9833 on the PK of midazolam, omeprazole, dabigatran etexilate, and celecoxib will be further characterized.
Trial Locations
- Locations (1)
Research Site
🇺🇸Berlin, New Jersey, United States