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

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

Detailed Description
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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

Official Title
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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

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: AZD9833
* Drug: Midazolam
* Drug: Omeprazole
* Drug: Dabigatran Etexilate
* Drug: Celecoxib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (midazolam and omeprazole)<br>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) | Drug: AZD9833<br>* 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<br>Drug: Midazolam<br>* Midazolam will be administered orally as a syrup once on Day 1 of Treatment Periods 1 and 3; administered together with Omeprazole<br>Drug: Omeprazole<br>* An Omeprazole capsule will be administered once on Day 1 of Treatment Periods 1 and 3; administered together with Midazolam<br>|
| Experimental: Arm B (Dabigatran etexilate)<br>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) | Drug: AZD9833<br>* 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<br>Drug: Dabigatran Etexilate<br>* A Dabigatran Etexilate capsule will be administered once on Day 1 of Treatment Periods 1 and 2<br>|
| Experimental: Arm C (Celecoxib)<br>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) | Drug: AZD9833<br>* 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<br>Drug: Celecoxib<br>* A Celecoxib capsule will be administered once on Day 1 of Treatment Periods 1 and 3<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| Half-life associated with terminal slope of a semi-logarithmic concentration-time curve (t½λz) 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) | 
| 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) | 
| 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) | 
| 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) | 
| t½λz 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) | 
| 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) | 
| 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Drug-Drug interaction, Midazolam, Omeprazole, Dabigatran etexilate, Celecoxib, Postmenopausal