Clinical trial NCT03637049: Effect of PBI-4050 on the Pharmacokinetics of Midazolam in Heathy Adult Subjects
Official title: A Phase 1, Drug-Drug Interaction Study to Evaluate the Effect of PBI-4050 on the Pharmacokinetics of Midazolam, a Sensitive Cytochrome P450 3A Substrate, in Healthy Adult Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: PBI-4050
drug-drug interaction
CYP3A
midazolam
healthy subjects
Lead sponsor: Liminal BioSciences Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Celerion
First posted: 2018-08-17
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: This study is designed to evaluate the pharmacokinetics (PK) and safety of multiple doses of PBI-4050 combined with midazolam in healthy adult subjects.

Detailed description: This is a Phase 1, single-center, open-label, 2-period, fixed sequence study to investigate the effect of multiple doses of PBI-4050 on the PK of midazolam, a cytochrome P450 (CYP) 3A substrate, in healthy adult men and healthy women of non-childbearing potential (WONCBP), and to determine the safety and tolerability of PBI-4050, when co-administered with midazolam.

On Day 1 of Period 1, subjects will receive a single oral dose of midazolam followed by PK sampling of midazolam and its metabolite 1-hydroxymidazolam (1-OH-midazolam). In Period 2, subjects will receive multiple daily doses of PBI-4050 for 5 consecutive days (Day 1 to Day 5) with a single oral dose of midazolam co-administered on Day 5. PK sampling for midazolam and 1-OH-midazolam will be collected for 24 hours following dosing on Day 5. PK sampling for PBI-4050 and its major metabolite will be collected at pre-dose on Days 3, 4, and 5.

There will be a washout period of at least 2 days between midazolam dose in Period 1 and the first PBI-4050 dose in Period 2.

Eligibility criteria: Inclusion Criteria:

1. Males or females (WONCBP only).
2. Age 18-65 years.
3. Continuous non-smoker who has not used nicotine-containing products for at least 3 months prior to the first dosing.
4. Body mass index (BMI) ≥ 18.0 and ≤ 32.0 kg/m2 at screening.
5. Generally good health.
6. Males willing to use appropriate contraception.

Exclusion Criteria:

1. Significant medical history or physical findings.
2. History or presence of drug allergy or hypersensitivity to treatment ingredients.
3. Gastrointestinal surgery.
4. Pregnant or lactating.
5. Positive urine drug or alcohol screen.
6. Abnormal heart rate or blood pressure.
7. Prescribed systemic or topical medication taken recently, or supplements/remedies interfering with study procedures or safety.

   • Receiving drugs known as significant inducers of CYP2C9, CYP3A4, CYP2C8 and/or CYP1A2 enzymes and/or P-glycoprotein, including St. John's Wort, for 28 days prior to the first dosing and throughout the study.
8. Has been on a diet incompatible with the on-study diet.
9. Recent blood donation or significant blood loss.
10. Recent blood received.
11. Participation in another clinical study within 30 days prior to the first.

Primary outcomes:
measure: Change in area under the concentration-time curve (AUC0-t) for midazolam and 1-OH-midazolam in presence of PBI-4050
timeFrame: PK sampling at pre-dose; and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose on Day 1 in Period 1 and on Day 5 in Period 2
measure: Change in area under the concentration-time curve (AUC0-inf) for midazolam and 1-OH-midazolam in presence of PBI-4050
timeFrame: PK sampling at pre-dose; and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose on Day 1 in Period 1 and on Day 5 in Period 2
measure: Change in maximum plasma concentration (Cmax) for midazolam and 1-OH-midazolam in presence of PBI-4050
timeFrame: PK sampling at pre-dose; and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose on Day 1 in Period 1 and on Day 5 in Period 2
measure: Change in concentration observed at the end of the dosing interval (Ctrough) for plasma PBI-4050 and its major metabolite
timeFrame: PK sampling for PBI-4050 and its metabolite done at pre-dose on Days 3, 4, and 5 of Peiod 2
Secondary outcomes:
measure: Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 10 days
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Celerion
state: Arizona
Study officials:
References: