A Phase 1 interventional study of AZD2389 and Midazolam in Advanced Chronic Liver Disease and Healthy Participants, sponsored by AstraZeneca. Completed at 1 site in United States. Open to participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2025-07-24.
Sponsored by AstraZeneca · Phase 1, Interventional, and Treatment
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.
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:
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.
1,642 studies on the registry are indexed under Liver Cirrhosis; 358 are open to participants now.
This study's enrollment of 16 is below the median of 72 across 995 interventional studies indexed under Liver Cirrhosis.
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Exclusion Criteria:
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.
Drug: AZD2389 · Drug: Midazolam · Drug: Caffeine · Drug: Bupropion
Oral dose on Days 5 to 13, Day 16, and Day 17. On Day 14 co-administered with a combination of midazolam and caffeine. On Day 15 co-administered with bupropion.
Single oral dose on: * Day 1 (co-administered with caffeine) * Day 14 (co-administered with caffeine and AZD2389)
Single oral dose on: * Day 1 (co-administered with midazolam) * Day 14 (co-administered with midazolam and AZD2389)
Single oral dose on: * Day 2 (alone) * Day 15 (co-administered with AZD2389)
Ratio of treatment to reference based on Cmax (RCmax)
To assess the PK parameter RCmax for midazolam, caffeine, and bupropion in combination with AZD2389 compared to midazolam, caffeine, and bupropion alone.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Ratio of treatment to reference based on AUCinf (RAUCinf)
To assess the PK parameter RAUCinf for midazolam, caffeine, and bupropion in combination with AZD2389 compared to midazolam, caffeine, and bupropion alone.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Ratio of treatment to reference based on AUClast (RAUClast)
To assess the PK parameter RAUClast for midazolam, caffeine, and bupropion in combination with AZD2389 compared to midazolam, caffeine, and bupropion alone.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Ratio of area under concentration-curve from time 0 to 24 hours post-dose (AUC0-24)
To assess the PK parameter ratio of AUC0-24 for caffeine in combination with AZD2389 compared to caffeine alone.
Time frame: Period 1: Days 1-3; Period 3: Days 15-18.
Apparent total body clearance (CL/F)
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.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Apparent volume of distribution based on the terminal phase (Vz/F)
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.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Terminal elimination half-life (t1/2λz)
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.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Terminal rate constant (λz)
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.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Time to reach maximum observed concentration (tmax)
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.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Maximum observed concentration (Cmax)
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.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast)
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.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Area under concentration-time curve from time 0 to infinity (AUCinf)
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.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
AUC0-24
To describe the plasma PK of caffeine and its metabolites (paraxanthine) when caffeine is administered alone and in combination with AZD2389.
Time frame: Period 1: Days 1-3; Period 3: Days 15-18.
RCmax
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.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
RAUCinf
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.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
RAUClast
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.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Ratio of treatment to reference based on AUC0-24 (RAUC0-24)
To assess the RAUC0-24 for the metabolites of caffeine, (paraxanthine) when caffeine is administered alone and in combination with AZD2389.
Time frame: Period 1: Days 1-3; Period 3: Days 15-18.
Metabolite to parent ratio of the AUCinf
To assess the metabolite to parent ratio of the AUCinf for midazolam, caffeine, and bupropion.
Time frame: Period 1: Days 1-4; Period 2: Days 5-13; Period 3: Days 14-18.
Metabolite to parent ratio of the AUC0-24
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.
Time frame: Period 1: Days 1-3; Period 3: Days 15-18.
Area under concentration-time curve in the dose interval (AUCtau)
To describe the plasma PK of AZD2389 after multiple dose administration.
Time frame: Period 2: Days 5-13; Period 3: Day 14.
Observed lowest concentration before the next dose is administered (Ctrough)
To describe the plasma PK of AZD2389 after multiple dose administration.
Time frame: Period 2: Days 5-13; Period 3: Day 14.
Number of Adverse Events (AEs) and Serious Adverse Events (SAEs)
To assess the safety and tolerability of multiple oral doses of AZD2389 alone or in combination with midazolam, caffeine and bupropion in healthy participants.
Time frame: Only SAE: -30 to -3 to Day -1. AE and SAE: From Day 1 to Follow-up/Early Termination Visit (Days 25-32)
Plan to share: Yes — Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
Supporting information: Study protocol
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