Clinical trial NCT05052710: Study to Assess the Effect of AZD4831 on the Pharmacokinetics (Drug Behavior in the Body) of Midazolam
Official title: A Fixed Sequence, Open-label Study to Assess the Effect of Multiple Doses of AZD4831 on the Pharmacokinetics of Oral Midazolam (a CYP450 3A Probe) in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Cardiovascular Disease
Drug-drug interaction
Pharmacokinetics
Myeloperoxidase inhibitor
Fixed-sequence
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2021-09-22
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The study is an open-label, fixed-sequence, cross-over study conducted at a single Clinical Unit to assess the pharmacokinetics (PK) of midazolam in healthy male and female (non-childbearing potential) subjects when administered alone and in combination with AZD4831 after multiple doses (once daily) of AZD4831 for 10 consecutive days.

Detailed description: The study will consist of 2 treatment periods and will comprise:

* A Screening period of maximum 28 days;
* Treatment Period 1 and Treatment Period 2:

Treatment Period 1: Midazolam only (Day 1). Treatment Period 2: AZD4831 only (Days 2 to 10, once daily dosing) and AZD4831 plus midazolam (Day 11).

- A final Follow-up Visit after the last administration of investigational medicinal product (IMP) (Day 20 \[± 1 day\]).

Each subject will be involved in the study for approximately 7 weeks.

Eligibility criteria: Inclusion Criteria:

* Healthy male and/or female subjects with suitable veins for cannulation or repeated venepuncture.
* Males must be willing to use appropriate contraception methods.
* Females must not be lactating and must be of non-childbearing potential, confirmed at Screening.
* Have a body mass index between 18.5 and 30 kg/m\^2 (inclusive) and weigh at least 50 kg and no more than 100 kg (inclusive) at Screening.

Exclusion Criteria:

* History of any clinically significant disease or 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.
* A positive Corona Virus Disease 2019 test at Screening or admission to the Clinical Unit on Day -1.
* Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results.
* Any clinically significant abnormal findings in vital signs.
* clinically significant abnormalities on 12-lead electrocardiogram.
* Any positive result at the Screening Visit for Hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus antibody.
* Known or suspected history of drug abuse in the last 2 years.
* Current smokers or those who have smoked or used nicotine products within the 3 months prior to the Screening Visit.
* Known or suspected history of alcohol or drug abuse.
* Use of any prescribed or non-prescribed medication.
* Subjects with acute pulmonary insufficiency, marked neuromuscular respiratory weakness, obsessional states, phobic states, sleep apnoea syndrome, or unstable myasthenia gravis.
* History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigatoror history of hypersensitivity to drugs with a similar chemical structure or class to AZD4831 or midazolam.
* History or ongoing allergy/hypersensitivity to drugs(including but not limited to rash, angioedema, acute urticaria).
* Subjects who, in the opinion of the Investigator, have any clinically significant skin condition.

Primary outcomes:
measure: Area under plasma concentration time curve from zero to infinity (AUCinf) of Midazolam
timeFrame: Days 1, 2, 11, and 12
measure: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) of Midazolam
timeFrame: Days 1, 2, 11, and 12
measure: Maximum observed plasma (peak) drug concentration (Cmax) of Midazolam
timeFrame: Days 1, 2, 11, and 12
Secondary outcomes:
measure: Time to reach peak or maximum observed concentration or response following drug administration (tmax) of Midazolam and AZD4831
timeFrame: Midazolam:Days 1, 2, 11, and 12; AZD4831:Days 2-12
measure: Half life associated with terminal slope (λz) of a semi logarithmic concentration timecurve (t½λz) of Midazolam and AZD4831
timeFrame: Midazolam:Days 1, 2, 11, and 12; AZD4831:Days 2-12
measure: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) of Midazolam and AZD4831
timeFrame: Midazolam:Days 1, 2, 11, and 12; AZD4831:Days 2-12
measure: Apparent volume of distribution based on terminal phase (Vz/F) of Midazolam
timeFrame: Days 1, 2, 11, and 12
measure: Area under the plasma concentration-curve across the dosing interval (AUCtau) of AZD4831
timeFrame: Days 2-12
measure: Cmax of AZD4831
timeFrame: Days 2-12
measure: Daily pre-dose plasma concentration (CpreD3 up to CpreD10) of AZD4831
timeFrame: Days 3-10
measure: Plasma concentration 24 hours post the Day 10 dose (C24h) of AZD4831
timeFrame: Day 11
measure: Number of patients with adverse events (AE) and serious AEs (SAE)
timeFrame: From Screening (Day -28 to Day -2) until Follow-up Visit (Day 20)
Other outcomes:
Locations:
city: Harrow
country: United Kingdom
facility: Research Site
Study officials:
References: