A Study to Assess the Effect of AZD5462 on the Pharmacokinetics of Midazolam, Rosuvastatin and Digoxin

NCT05395117 | Completed Phase 1 FDA Drug

• 1 other identifier: D9090C00003
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

This study will assess the effect of multiple doses of AZD5462 on the PK of oral midazolam (CYP3A4 probe), rosuvastatin (OATP1B1/3, BCRP probe), and digoxin (P-gp probe) in healthy participants. This study will consist of 2 treatment arms (Treatment Arms A and B) and within each treatment arm, the participants will first be administered the probe substrates (midazolam, rosuvastatin, and digoxin) alone followed by administration of the probe substrates together with AZD5462. The treatment arms differ in the dose of AZD5462 being administered and will be performed sequentially starting with Treatment Arm A (AZD5462 Dose A, high dose treatment arm) and followed by Treatment Arm B (AZD5462 Dose B, low dose treatment arm). Each treatment arm will include 5 periods. Thirty two participants in total (16 participants per treatment arm) will be enrolled to ensure at least 24 evaluable participants (12 participants per treatment arm) at the end of the last treatment period. A follow-up visit at Day 24 (+-1 Day) will be conducted via a phone call.

Conditions

Healthy Participants

Keywords

Cytochrome P450 enzyme 3A4; Organic Anion Transporting Polypeptide 1B1/1B3; Breast Cancer Resistance Protein; P-glycoprotein

Outcome Measures

Primary Outcomes (3)

• Area under the concentration-versus-time curve from pre-dose (time 0) extrapolated to infinite time (AUCinf)

  The effect of AZD5462 on the AUCinf of oral midazolam, rosuvastatin, and digoxin will be assessed.

  Midazolam: Period 1 (Day 1), and Period 4 (Day 15); Rosuvastatin and Digoxin: Period 2 (Day 2), Period 3 (Days 6 - 14), and Period 5 (Days 16 - 18)

• Area under the concentration-versus-time curve from pre-dose (time 0) to the time of the last quantifiable concentration (AUClast)

  The effect of AZD5462 on the AUClast of oral midazolam, rosuvastatin, and digoxin will be assessed.

  Midazolam: Period 1 (Day 1), and Period 4 (Day 15); Rosuvastatin and Digoxin: Period 2 (Day 2), Period 3 (Days 6 - 14), and Period 5 (Days 16 - 18)

• Maximum observed serum (peak) drug concentration [Cmax]

  The effect of AZD5462 on the Cmax of oral midazolam, rosuvastatin, and digoxin will be assessed.

  Midazolam: Period 1 (Day 1), and Period 4 (Day 15); Rosuvastatin and Digoxin: Period 2 (Day 2), Period 3 (Days 6 - 14), and Period 5 (Days 16 - 18)

Secondary Outcomes (7)

• Time to reach peak or maximum observed concentration or response following drug administration (tmax)

  Midazolam: Period 1 (Day 1), and Period 4 (Day 15); Rosuvastatin and Digoxin: Period 2 (Day 2), Period 3 (Days 6 - 14), and Period 5 (Days 16 - 18)

• Half life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t1/2λz)

  Midazolam: Period 1 (Day 1), and Period 4 (Day 15); Rosuvastatin and Digoxin: Period 2 (Day 2), Period 3 (Days 6 - 14), and Period 5 (Days 16 - 18)

• Partial area under the serum concentration time curve from time 0 to time 12 (AUC0-12h)

  Day 6, and Day 16

• Maximum observed serum (peak) drug concentration [Cmax]

  Day 6, and Day 16

• Time to reach peak or maximum observed concentration or response following drug administration (tmax)

  Day 6, and Day 16

Study Arms (2)

Treatment Arm A: High dose

EXPERIMENTAL

Participants will receive the Investigational Medicinal Product (IMP), AZD5462 Dose A starting on Day 6 and continued until Day 18 and the following approved medicinal products: * Midazolam * Rosuvastatin * Digoxin

Drug: AZD5462; Drug: Midazolam; Drug: Rosuvastatin; Drug: Digoxin

Treatment Arm B: Low dose

EXPERIMENTAL

Participants will receive the IMP, AZD5462 Dose B starting on Day 6 and continued until Day 18 and the following approved medicinal products: * Midazolam * Rosuvastatin * Digoxin

Drug: AZD5462; Drug: Midazolam; Drug: Rosuvastatin; Drug: Digoxin

Interventions

AZD5462 DRUG

Treatment Arm A: Participants will receive the IMP, AZD5462 Dose A starting on Day 6 and continued until Day 18 and the following approved medicinal products: * Midazolam * Rosuvastatin * Digoxin Treatment Arm B: Participants will receive the IMP, AZD5462 Dose B starting on Day 6 and continued until Day 18 and the following approved medicinal products: * Midazolam * Rosuvastatin * Digoxin

Treatment Arm A: High dose; Treatment Arm B: Low dose

Midazolam DRUG

Participants will receive a single dose of midazolam in the morning of Day 1 and in the morning of Day 15 in both the arms.

Treatment Arm A: High dose; Treatment Arm B: Low dose

Rosuvastatin DRUG

Participants will receive rosuvastatin as a single dose administered with digoxin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms.

Treatment Arm A: High dose; Treatment Arm B: Low dose

Digoxin DRUG

Participants will receive digoxin as a single dose administered with rosuvastatin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms.

Treatment Arm A: High dose; Treatment Arm B: Low dose

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Healthy male and female participants aged 18 to 55 years with suitable veins for cannulation or repeated venepuncture.
• Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non childbearing potential confirmed at screening.
• Have a Body Mass Index (BMI) between 18 and 32 kg/m2 inclusive and weigh at least 50 kg and no more than 105 kg inclusive at screening.
• Male subject must adhere to the contraception methods details.

You may not qualify if:

• History of any clinically significant disease or disorder which may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study including but not limited to:
• (i) Systemic sclerosis (ie, scleroderma). (ii) Moderate to severe valvular disease. (iii) Hypertrophic obstructive cardiomyopathy. (iv) Restrictive cardiomyopathy. (v) Gilbert's syndrome. (vi) History of vascular or left ventricular aneurysms or prior dissections. (vii) Any history of joint hypermobility, Marfan's Syndrome, or any connective tissue disorder.
• 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 significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMPs.
• Any laboratory values with deviations at screening or admission to the study centre.
• Any clinically significant abnormalities in clinical biochemistry, haematology, or urinalysis results.
• Any clinically significant abnormal findings in vital signs after 5 minutes supine rest.
• Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12-lead ECG.
• Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
• Known or suspected history of drug abuse.
• Has received another new chemical entity within 3 months of the first administration of IMP in this study.
• Plasma donation within 1 month of screening or any blood donation/loss \> 500 mL during the 3 months prior to screening.
• History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD5462.
• Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening.
• Positive screen for drugs of abuse or cotinine at screening or on each admission to the study centre or positive screen for alcohol on admission to the study centre prior to the first administration of the IMP.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Brooklyn, Maryland, 21225, United States

Location

MeSH Terms

Interventions

Midazolam; Rosuvastatin Calcium; Digoxin

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sulfonamides; Amides; Organic Chemicals; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2022
• First Posted: May 27, 2022
• Study Start: June 30, 2022
• Primary Completion: September 12, 2022
• Study Completion: September 12, 2022
• Last Updated: December 13, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

US (1)