A Study to Investigate How Multiple Oral Doses of AZD2389 Affect the Pharmacokinetics of Midazolam, Caffeine, and Bupropion in Healthy Participants
- Conditions
- Advanced Chronic Liver DiseaseHealthy Participants
- Interventions
- Registration Number
- NCT06973005
- Lead Sponsor
- AstraZeneca
- Brief Summary
The purpose of this study is to measure the effect of multiple doses of AZD2389 on the pharmacokinetics (PK) of midazolam, caffeine, and bupropion in healthy participants.
- Detailed Description
This study is an open-label, fixed sequence, 3-period, drug-drug interaction (DDI) study in healthy participants performed at a single Clinical Unit.
The study will comprise:
* A Screening Period of maximum 28 days.
* A Treatment Phase, separated into 3 different periods. Period 1 (Day -2 to Day 4): Participants will receive midazolam and caffeine in combination on Day 1. Participants will receive bupropion on Day 2.
Period 2 (Day 5 to Day 13): Participants will receive AZD2389 for 9 days. Period 3 (Day 14 to Day 18): Participants will first receive AZD2389 with midazolam and caffeine in combination on Day 14. On Day 15, participants will first receive AZD2389 with bupropion. On Days 16 and 17, participants will receive AZD2389.
- A final Follow-up Visit, 7 to 14 days after the last AZD2389 PK sample is taken in Period 3.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 16
- Provision of signed and dated, written informed consent prior to any study-specific procedures.
- Participants with suitable veins for cannulation or repeated venipuncture.
- Have a body mass index (BMI) between 18 and 32 kilograms per meter squared (kg/m2) inclusive and weigh at least 50 kilograms (kg) at Screening.
- History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the participant at risk.
- History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
- Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
- Any clinically important abnormalities in clinical chemistry, coagulation, hematology, or urinalysis results.
- Any positive result at the Screening Visit for serum hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).
- Abnormal vital signs, after 10 minutes supine rest, at the Screening Visit and/or admission to the Clinical Unit (Day -2).
- Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead safety ECG.
- History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity.
- History of hypersensitivity to DPP4 inhibitors, as judged by the investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to DPP4 inhibitors.
- History of severe dermatological disorders, eg, bullous pemphigoid or Stevens-Johnson syndrome, as judged by the investigator.
- Participants who have previously received AZD2389 within the last 12 months prior to the Screening Visit.
- Known hypersensitivity or previous adverse events associated with midazolam, caffeine, or bupropion.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment Arm AZD2389 In Period 1, participants will receive midazolam and caffeine in combination on Day 1. Participants will receive bupropion on Day 2. In Period 2, participants will receive AZD2389 for 9 days from Day 5 to Day 13. In Period 3, participants will first receive AZD2389 with midazolam and caffeine in combination on Day 14. On Day 15, participants will first receive AZD2389 with bupropion. On Days 16 and 17, participants will receive AZD2389. Treatment Arm Midazolam In Period 1, participants will receive midazolam and caffeine in combination on Day 1. Participants will receive bupropion on Day 2. In Period 2, participants will receive AZD2389 for 9 days from Day 5 to Day 13. In Period 3, participants will first receive AZD2389 with midazolam and caffeine in combination on Day 14. On Day 15, participants will first receive AZD2389 with bupropion. On Days 16 and 17, participants will receive AZD2389. Treatment Arm Caffeine In Period 1, participants will receive midazolam and caffeine in combination on Day 1. Participants will receive bupropion on Day 2. In Period 2, participants will receive AZD2389 for 9 days from Day 5 to Day 13. In Period 3, participants will first receive AZD2389 with midazolam and caffeine in combination on Day 14. On Day 15, participants will first receive AZD2389 with bupropion. On Days 16 and 17, participants will receive AZD2389. Treatment Arm Bupropion In Period 1, participants will receive midazolam and caffeine in combination on Day 1. Participants will receive bupropion on Day 2. In Period 2, participants will receive AZD2389 for 9 days from Day 5 to Day 13. In Period 3, participants will first receive AZD2389 with midazolam and caffeine in combination on Day 14. On Day 15, participants will first receive AZD2389 with bupropion. On Days 16 and 17, participants will receive AZD2389.
- Primary Outcome Measures
Name Time Method Ratio of treatment to reference based on Cmax (RCmax) Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To assess the PK parameter RCmax for midazolam, caffeine, and bupropion in combination with AZD2389 compared to midazolam, caffeine, and bupropion alone.
Ratio of treatment to reference based on AUCinf (RAUCinf) Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To assess the PK parameter RAUCinf for midazolam, caffeine, and bupropion in combination with AZD2389 compared to midazolam, caffeine, and bupropion alone.
Ratio of treatment to reference based on AUClast (RAUClast) Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To assess the PK parameter RAUClast for midazolam, caffeine, and bupropion in combination with AZD2389 compared to midazolam, caffeine, and bupropion alone.
Ratio of area under concentration-curve from time 0 to 24 hours post-dose (AUC0-24) Period 1: Days 1-3; Period 3: Days 15-18. To assess the PK parameter ratio of AUC0-24 for caffeine in combination with AZD2389 compared to caffeine alone.
- Secondary Outcome Measures
Name Time Method Time to reach maximum observed concentration (tmax) Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To describe the plasma PK of midazolam, caffeine, bupropion, and their metabolites (1'-OH-midazolam, paraxanthine, and hydroxy-bupropion) when midazolam, caffeine, or bupropion is administered alone and in combination with AZD2389. To describe the plasma PK of AZD2389 after multiple dose administration.
Terminal elimination half-life (t1/2λz) Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To describe the plasma PK of midazolam, caffeine, bupropion, and their metabolites (1'-OH-midazolam, paraxanthine, and hydroxy-bupropion) when midazolam, caffeine, or bupropion is administered alone and in combination with AZD2389. To describe the plasma PK of AZD2389 after multiple dose administration.
Terminal rate constant (λz) Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To describe the plasma PK of midazolam, caffeine, bupropion, and their metabolites (1'-OH-midazolam, paraxanthine, and hydroxy-bupropion) when midazolam, caffeine, or bupropion is administered alone and in combination with AZD2389. To describe the plasma PK of AZD2389 after multiple dose administration.
Apparent total body clearance (CL/F) Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To describe the plasma PK of midazolam, caffeine, bupropion, and their metabolites (1'-OH-midazolam, paraxanthine, and hydroxy-bupropion) when midazolam, caffeine, or bupropion is administered alone and in combination with AZD2389. To describe the plasma PK of AZD2389 after multiple dose administration.
Apparent volume of distribution based on the terminal phase (Vz/F) Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To describe the plasma PK of midazolam, caffeine, bupropion, and their metabolites (1'-OH-midazolam, paraxanthine, and hydroxy-bupropion) when midazolam, caffeine, or bupropion is administered alone and in combination with AZD2389. To describe the plasma PK of AZD2389 after multiple dose administration.
Maximum observed concentration (Cmax) Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To describe the plasma PK of midazolam, caffeine, bupropion, and their metabolites (1'-OH-midazolam, paraxanthine, and hydroxy-bupropion) when midazolam, caffeine, or bupropion is administered alone and in combination with AZD2389. To describe the plasma PK of AZD2389 after multiple dose administration.
Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast) Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To describe the plasma PK of midazolam, caffeine, bupropion, and their metabolites (1'-OH-midazolam, paraxanthine, and hydroxy-bupropion) when midazolam, caffeine, or bupropion is administered alone and in combination with AZD2389. To describe the plasma PK of AZD2389 after multiple dose administration.
Area under concentration-time curve from time 0 to infinity (AUCinf) Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To describe the plasma PK of midazolam, caffeine, bupropion, and their metabolites (1'-OH-midazolam, paraxanthine, and hydroxy-bupropion) when midazolam, caffeine, or bupropion is administered alone and in combination with AZD2389. To describe the plasma PK of AZD2389 after multiple dose administration.
AUC0-24 Period 1: Days 1-3; Period 3: Days 15-18. To describe the plasma PK of caffeine and its metabolites (paraxanthine) when caffeine is administered alone and in combination with AZD2389.
RCmax Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To assess the RCmax for the metabolites of midazolam, caffeine, and bupropion (1'-OH-midazolam, paraxanthine, OH-bupropion) when midazolam, caffeine, or bupropion is administered alone and in combination with AZD2389.
RAUCinf Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To assess the RAUCinf for the metabolites of midazolam, caffeine, and bupropion (1'-OH-midazolam, paraxanthine, OH-bupropion) when midazolam, caffeine, or bupropion is administered alone and in combination with AZD2389.
RAUClast Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To assess the RAUClast for the metabolites of midazolam, caffeine, and bupropion (1'-OH-midazolam, paraxanthine, OH-bupropion) when midazolam, caffeine, or bupropion is administered alone and in combination with AZD2389.
Ratio of treatment to reference based on AUC0-24 (RAUC0-24) Period 1: Days 1-3; Period 3: Days 15-18. To assess the RAUC0-24 for the metabolites of caffeine, (paraxanthine) when caffeine is administered alone and in combination with AZD2389.
Metabolite to parent ratio of the AUCinf Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18. To assess the metabolite to parent ratio of the AUCinf for midazolam, caffeine, and bupropion.
Metabolite to parent ratio of the AUC0-24 Period 1: Days 1-3; Period 3: Days 15-18. To assess the metabolite to parent ratio of the AUC0-24 for caffeine and its metabolite (paraxanthine) when caffeine is administered alone and in combination with AZD2389.
Area under concentration-time curve in the dose interval (AUCtau) Period 2: Days 5-13; Period 3: Day 14. To describe the plasma PK of AZD2389 after multiple dose administration.
Observed lowest concentration before the next dose is administered (Ctrough) Period 2: Days 5-13; Period 3: Day 14. To describe the plasma PK of AZD2389 after multiple dose administration.
Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) Only SAE: -30 to -3 to Day -1. AE and SAE: From Day 1 to Follow-up/Early Termination Visit (Days 25-32) To assess the safety and tolerability of multiple oral doses of AZD2389 alone or in combination with midazolam, caffeine and bupropion in healthy participants.
Trial Locations
- Locations (1)
Research Site
🇺🇸Brooklyn, Maryland, United States