Healthy Volunteers
Conditions
Keywords
Drug-Drug interaction, Midazolam, Omeprazole, Dabigatran etexilate, Celecoxib, Postmenopausal, Breast Cancer
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
Interventions
DRUGAZD9833
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
DRUGMidazolam
Midazolam will be administered orally as a syrup once on Day 1 of Treatment Periods 1 and 3; administered together with Omeprazole
DRUGOmeprazole
An Omeprazole capsule will be administered once on Day 1 of Treatment Periods 1 and 3; administered together with Midazolam
DRUGDabigatran Etexilate
A Dabigatran Etexilate capsule will be administered once on Day 1 of Treatment Periods 1 and 2
DRUGCelecoxib
A Celecoxib capsule will be administered once on Day 1 of Treatment Periods 1 and 3
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
50 Years to 70 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area 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 |
| 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 celecoxib |
| Maximum 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 celecoxib |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Outcome results
None listed