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

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

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: PBI-4050 and midazolam

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 Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tempe, Arizona, United States, 85283
      • Celerion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: PBI-4050 and midazolam; A single oral dose of midazolam (1 mL of 2mg/mL syrup) will be given to all subjects in Period 1 and on Day 5 of Period 2. 1200 mg of PBI-4050 (3 X 400 mg tablets) will be administered for 5 days (Day 1 to Day 5) of Period 2 and a single dose of midazolam (1 mL of 2mg/mL) on Day 5.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in area under the concentration-time curve (AUC0-t) for midazolam and 1-OH-midazolam in presence of PBI-4050	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)	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
Change in area under the concentration-time curve (AUC0-inf) for midazolam and 1-OH-midazolam in presence of PBI-4050	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)	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
Change in maximum plasma concentration (Cmax) for midazolam and 1-OH-midazolam in presence of PBI-4050	Cmax of midazolam and 1-OH-midazolam assessed on Day 1(Period 1) and Day 5 (Period 2)	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
Change in concentration observed at the end of the dosing interval (Ctrough) for plasma PBI-4050 and its major metabolite	Ctrough is the concentration observed at the end of the dosing interval in Period 2.	PK sampling for PBI-4050 and its metabolite done at pre-dose on Days 3, 4, and 5 of Peiod 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events (AEs) and Serious Adverse Events (SAEs)	Number of subjects that experience Adverse Events (AEs).	10 days

Collaborators and Investigators

• Sponsor: Liminal BioSciences Ltd.
• Collaborators: Celerion

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2018
• Primary Completion (Actual): August 9, 2018
• Study Completion (Actual): August 22, 2018

Study Registration Dates

• First Submitted: August 8, 2018
• First Submitted That Met QC Criteria: August 15, 2018
• First Posted (Actual): August 17, 2018

Study Record Updates

• Last Update Posted (Actual): December 8, 2020
• Last Update Submitted That Met QC Criteria: December 7, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: midazolam; healthy subjects; drug-drug interaction; CYP3A; PBI-4050
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: PBI-4050-CT-9-16; CA25590 (Other Identifier: Celerion)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: De-identified individual participant data for all primary and secondary outcome measures may be made available upon request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No