A Study to Assess the Effect of Multiple Doses of AZD5718 on Pharmacokinetics of Oral Midazolam in Healthy Subjects

NCT04492709 | Completed Phase 1

• 1 other identifier: D7550C00011
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

In clinical practice, AZD5718 will be co-administered with CYP3A substrates. Therefore, it is important to determine the impact of AZD5718 on the pharmacokinetics (PK) of CYP3A4 substrates. The primary objective of this study is to evaluate the effect of AZD5718 on the PK of midazolam, a known sensitive CYP3A4 substrate.

Conditions

Cardiovascular Disease

Keywords

AZD5718, CYP3A4 substrate, Drug-drug Interaction, Fixed sequence, Midazolam, Open-label, Pharmacokinetics

Outcome Measures

Primary Outcomes (6)

• Maximum observed plasma peak concentration (Cmax) of midazolam

  Comparison of Cmax calculated when midazolam alone and calculated when midazolam was taken together with AZD5718

  Day 1-Day 2 and Day 7-Day 8: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours (h) post-dose

• Area under plasma concentration-time curve from time zero to infinity (AUCinf) of midazolam

  Comparison of AUCinf calculated when midazolam alone and calculated when midazolam was taken together with AZD5718

  Day 1-Day 2 and Day 7-Day 8: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 h post-dose

• Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of midazolam

  Comparison of AUClast calculated when midazolam alone and calculated when midazolam was taken together with AZD5718

  Day 1-Day 2 and Day 7-Day 8: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 h post-dose

• Time to reach maximum observed plasma concentration (tmax) of midazolam

  Comparison of tmax calculated when midazolam alone and calculated when midazolam was taken together with AZD5718

  Day 1-Day 2 and Day 7-Day 8: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 h post-dose

• Half-life (t1/2) of midazolam

  Comparison of t1/2 calculated when midazolam alone and calculated when midazolam was taken together with AZD5718

  Day 1-Day 2 and Day 7-Day 8: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 h post-dose

• Plasma concentrations of AZD5718

  AZD5718 Plasma concentrations will be evaluated at trough and also at the expected time of tmax

  Day 2-Day 7: at trough and Day 7: 4 h post-dose

Secondary Outcomes (9)

• Number of subjects with adverse events (AEs) and serious AEs

  AE: From Day 1 to post-treatment follow-up visit (Day 13); SAE: From screening to post-treatment follow-up visit (Day 13)

• Number of subjects with abnormal 12-lead electrocardiogram (ECG)

  At screening and post-treatment follow-up visit (Day 13)

• Number of subjects with abnormal physical examination

  At screening, Day -1, Day 1, Day 4, Day 7, Day 8, and post-treatment follow-up visit (Day 13)

• Number of subjects with abnormal blood pressure (BP)

  For approximately 6 weeks (from screening to post-treatment follow-up)

• Number of subjects with abnormal pulse rate

  For approximately 6 weeks (from screening to post-treatment follow-up)

Study Arms (1)

Treatment

EXPERIMENTAL

The subjects will receive oral midazolam solution of 2 mg as a single dose on 2 occasions, 6 days apart (Days 1 and 7). The first dose will be prior to dosing with oral AZD5718 tablet and the second dose after five administrations of AZD5718 under fasted conditions.

Drug: Midazolam; Drug: AZD5718

Interventions

Midazolam DRUG

The subjects will receive single doses of midazolam solution 2 mg/mL orally on Day 1 alone in Treatment Period 1 and on Day 7 co-administered with oral AZD5718 tablet in Treatment Period 3.

Treatment

AZD5718 DRUG

The subjects will receive oral AZD5718 tablet once daily starting on Day 2 to Day 6 in Treatment Period 2 and on Day 7 co-administered with midazolam in Treatment Period 3.

Treatment

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 subjects aged 18 to 55 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
• 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 by fulfilling one of the following criteria:
• Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle stimulating hormone levels in the postmenopausal range.
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
• Male subject must adhere to the contraception methods details.
• Have a body mass index between 18.5 and 30 kg/m2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive.

You may not qualify if:

• History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study.
• History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• History or presence of acute pulmonary insufficiency, marked neuromuscular respiratory weakness, obsessional states, phobic states, sleep apnea syndrome, or unstable myasthenia gravis.
• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
• Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, at screening and/or on admission to the Clinical Unit, as judged by the Investigator, including:
• Alanine aminotransferase \> 1.5 x upper limit of normal (ULN);
• Aspartate aminotransferase \> 1.5 x ULN;
• Bilirubin (total) \> 1.5 x ULN; and
• Gamma glutamyl transpeptidase \> 1.5 x ULN.
• Any clinically significant abnormal findings in vital signs (blood pressure and pulse; supine) at screening and/or admission to the Clinical Unit, as judged by the Investigator.
• Any clinically significant abnormalities on 12-lead electrocardiogram at screening, as judged by the Investigator.
• Any positive result on screening for serum hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus antibody.
• Known or suspected Gilbert syndrome.
• Known or suspected history of drug abuse in the last 2 years, as judged by the Investigator.
• Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Harrow, HA1 3UJ, United Kingdom

Location

MeSH Terms

Conditions

Cardiovascular Diseases

Interventions

Midazolam; AZD5718

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Dr. Pablo Forte Soto, MD, MSc, PhD

  Parexel Early Phase Clinical Unit London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Fixed sequence

Study Record Dates

• First Submitted: July 28, 2020
• First Posted: July 30, 2020
• Study Start: July 30, 2020
• Primary Completion: October 19, 2020
• Study Completion: October 19, 2020
• Last Updated: November 3, 2020

Record last verified: 2020-10

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

GB (1)