Effect of PBI-4050 on the Pharmacokinetics of Midazolam in Heathy Adult Subjects

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: PBI-4050 and midazolam

• Registration Number: NCT03637049
• Lead Sponsor: Liminal BioSciences Ltd.

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.

Study Timeline

• Study Start: 2018-07-17
• Study First Submitted: 2018-08-08
• Primary Completion: 2018-08-09
• Study First Submitted QC: 2018-08-15
• Study First Posted: 2018-08-17
• Study Completion: 2018-08-22
• Status Verified: 2020-12
• Last Update Submitted: 2020-12-07
• Last Update Posted: 2020-12-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 22

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PBI-4050 and midazolam	PBI-4050 and midazolam	Midazolam 2 mg solution once (Period 1), PBI-4050 1200 mg (3 x 400 mg tablets) once per day for 5 days and midazolam 2 mg solution once on last day (Period 2).

Primary Outcome Measures

Name	Time	Method
Change in concentration observed at the end of the dosing interval (Ctrough) for plasma PBI-4050 and its major metabolite	PK sampling for PBI-4050 and its metabolite done at pre-dose on Days 3, 4, and 5 of Peiod 2	Ctrough is the concentration observed at the end of the dosing interval in Period 2.
Change in area under the concentration-time curve (AUC0-inf) for midazolam and 1-OH-midazolam in presence of PBI-4050	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	AUC0-inf (AUC from time 0 extrapolated to infinity) of midazolam and 1-OH-midazolam assessed on Day 1 (Period 1) and Day 5 (Period 2)
Change in area under the concentration-time curve (AUC0-t) for midazolam and 1-OH-midazolam in presence of PBI-4050	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	AUC0-t (AUC from time 0 to last observed non-zero concentration) of midazolam and 1-OH-midazolam assessed on Day 1 (Period 1) and Day 5 (Period 2)
Change in maximum plasma concentration (Cmax) for midazolam and 1-OH-midazolam in presence of PBI-4050	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	Cmax of midazolam and 1-OH-midazolam assessed on Day 1(Period 1) and Day 5 (Period 2)

Secondary Outcome Measures

Name	Time	Method
Adverse Events (AEs) and Serious Adverse Events (SAEs)	10 days	Number of subjects that experience Adverse Events (AEs).

Trial Locations

Locations (1)

Celerion; 🇺🇸 Tempe, Arizona, United States