A Study to Investigate the Effect of CYP3A4 Inhibition on the Single Dose Pharmacokinetics of ASTX660 and the Effect of a Single Dose of ASTX660 on the Pharmacokinetics of the CYP3A4 Substrate Midazolam

NCT04411030 | Completed Phase 1 FDA Drug

• 1 other identifier: ASTX660-12
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

In Part 1, the primary objective is to investigate the effect of multiple doses of itraconazole, an inhibitor of CYP3A4, on the pharmacokinetic (PK) profile of a single dose of ASTX660. In Part 2, the primary objective is to investigate the effect of a single dose of ASTX660 on the pharmacokinetics of the CYP3A4 substrate midazolam and its metabolite, 1-hydroxy midazolam. Safety and tolerability of a single dose of ASTX660 in the absence and presence of multiple doses of the CYP3A4 inhibitor itraconazole and in the presence of a single dose of the CYP3A4 substrate midazolam will also be evaluated.

Conditions

Healthy Volunteer

Outcome Measures

Primary Outcomes (8)

• Pharmacokinetic parameter of ASTX660: Cmax

  Maximum plasma concentration

  From predose up to Day 14

• Pharmacokinetic parameter of ASTX660: AUC0-t

  Area under the plasma concentration versus time curve from time zero to the last measurable concentration

  From predose up to Day 14

• Pharmacokinetic parameter of ASTX660: AUC0-24

  Area under the plasma concentration versus time curve from time zero to 24 hours

  From predose up to Day 14

• Pharmacokinetic parameter of ASTX660: AUC0-inf

  Area under the plasma concentration versus time curve from time zero extrapolated to infinity

  From predose up to Day 14

• Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: Cmax

  Maximum plasma concentration

  From predose up to Day 9

• Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: AUC0-t

  Area under the plasma concentration versus time curve from time zero to the last measurable concentration

  From predose up to Day 9

• Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: AUC0-24

  Area under the plasma concentration versus time curve from time zero to 24 hours

  From predose up to Day 9

• Pharmacokinetic parameter of midazolam and 1-hydroxyl midazolam: AUC0-inf

  Area under the plasma concentration versus time curve from time zero extrapolated to infinity

  From predose up to Day 9

Secondary Outcomes (5)

• Pharmacokinetic parameter for ASTX660: CL/F

  From predose up to Day 14

• Pharmacokinetic parameter for ASTX660: t1/2

  From predose up to Day 14

• Pharmacokinetic parameter for midazolam: CL/F

  From predose up to Day 9

• Pharmacokinetic parameter for midazolam: t1/2

  From predose up to Day 9

• Safety: Number of participants with adverse events

  Up to Day 35

Study Arms (2)

Part 1

EXPERIMENTAL

Oral administration of ASTX660 and itraconazole at specific time points.

Drug: ASTX660; Drug: Itraconazole

Part 2

EXPERIMENTAL

Oral administration of ASTX660 and midazolam at specific time points.

Drug: ASTX660; Drug: Midazolam

Interventions

ASTX660 DRUG

Form: capsule; Route of administration: oral

Part 1; Part 2

Midazolam DRUG

Form: syrup; Route of administration: oral

Part 2

Itraconazole DRUG

Form: capsule; Route of administration: oral

Part 1

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participant understands the study procedures and agrees to participate by providing written informed consent.
• Participant is willing and able to comply with all study procedures and restrictions.
• Participant is male aged 18 to 45 years, inclusive at Screening.
• Participant has a body mass index (BMI) ≥ 18.5 kg/m2 and ≤ 30.0 kg/m2 at Screening.
• Participant is considered medically healthy as determined by the investigator, based on clinical evaluations including medical history, physical examination, clinical laboratory tests, 12-lead electrocardiogram (ECG) in triplicate, and vital sign measurements performed at Screening.
• Participants must be willing to use adequate contraception (double-barrier) from screening until 3 months after study completion. Male vasectomy is accepted as contraception if the vasectomy took place ≥ 6 months prior to first dose.
• Participants must refrain from sperm donation, from screening until 3 months after study completion.

You may not qualify if:

• Participant is mentally or legally incapacitated or has significant emotional problems at the time of Screening or is expected to have such problems during the conduct of the study.
• Participant has a clinically significant medical or psychiatric condition or disease (acute or chronic) that, as judged by the investigator, would make the participant ineligible for participation in the study (eg, compromises the study data, limits the participant's ability to complete and/or participate in the study).
• Participant has a current condition or history of significant endocrine, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, urological, immunological, or neurological disorders with clinical manifestations that, as judged by the investigator, would make the participant ineligible for participation in the study.
• Participant has a chronic disease requiring medication, dietary restriction, physical therapy, and/or other routine treatment that, as judged by the investigator, would make the participant ineligible for participation in the study.
• Participant has a history of gastrointestinal (GI) surgery including but not limited to gastric resection and/or intestinal resection that resulted in a clinically significant abnormality in GI function.
• Participant has a history or presence of cancer (with the exception of a history of basal cell carcinoma of the skin).
• Participant has a history of drug and/or alcohol addiction or is a current regular user (including recreational use) of any illicit drugs, has a history of drug or alcohol abuse, or has ever undergone drug or alcohol rehabilitation.
• Participant has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerance to food, prescription drugs or non-prescription (over-the-counter) drugs. Note: participants with seasonal allergies may participate.
• Participant has a known history of coronavirus disease 2019 (COVID-19) or has had contact with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive or COVID-19 patient within the 4 weeks prior to admission to the study center.
• Participant has a QTcF interval of \> 450 msec at Screening.
• Participant has an estimated creatinine clearance \< 90 mL/min based on the Cockcroft Gault equation at Screening.
• Participant regularly consumes excessive amounts of caffeine, defined as \> 6 servings of coffee, tea, cola, or other caffeinated beverages, per day (1 serving is approximately equivalent to 120 mg of caffeine).
• Participant regularly consumes excessive amounts of alcohol, defined as \> 3 glasses of alcoholic beverages per day and/or refuses to refrain from consuming such products throughout the study.
• Participant has used any medication (including prescription or non-prescription drugs, dietary or vitamin/mineral supplements or herbal remedies that are known to induce drug-metabolizing enzymes) within 14 days (or 5 half-lives, whichever is longer) prior to study drug administration on Day 1.
• Participant has used any medications known to be significant CYP inducers, including St. John's wort, within 28 days prior to the study drug administration on Day 1.

Sponsors & Collaborators

• Astex Pharmaceuticals, Inc.: lead

Study Sites (1)

QPS Bio-kinetic

Springfield, Missouri, 65802, United States

Location

MeSH Terms

Interventions

ASTX-660; Midazolam; Itraconazole

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Piperazines

Study Design

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

Study Record Dates

• First Submitted: May 29, 2020
• First Posted: June 1, 2020
• Study Start: May 20, 2020
• Primary Completion: August 23, 2020
• Study Completion: August 29, 2020
• Last Updated: August 2, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)