Study Evaluating the Effect of Food on the Pharmacokinetics of Palovarotene and the Effect of Palovarotene on the Pharmacokinetics of the CYP3A4 Substrate Midazolam in Two Cohorts of Healthy Adult Subjects

NCT04829773 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: PVO-1A-102
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

Study to evaluate the effect of food and the effect of swallowing capsule whole versus sprinkling on apple sauce on the pharmacokinetics (PK)/bioavailability of palovarotene, and evaluate the effect of palovarotene on the PK of the CYP3A4 substrate midazolam.

Conditions

Fibrodysplasia Ossificans Progressiva

Outcome Measures

Primary Outcomes (14)

• Maximum (peak) observed plasma drug concentration

  Days 1, 2, 3, 6, 7, 8, 11, 12, 13.

• Time to reach maximum (peak) (t max) observed plasma concentration following drug administration

  Days 1, 2, 3, 6, 7, 8, 11, 12, 13

• Area under the plasma concentration time (AUC 0-last) curve from time zero to the last quantifiable time point, calculated by linear-log trapezoidal summation

  Days 1, 2, 3, 6, 7, 8, 11, 12, 13

• Area under the plasma concentration time curve from time zero to infinity (AUC 0-infinity)

  calculated by linear-log trapezoidal summation and extrapolated to infinity by addition of the last quantifiable plasma concentration divided by the elimination rate constant

  Days 1, 2, 3, 6, 7, 8, 11, 12, 13

• Apparent terminal disposition rate constant/terminal rate constant yz

  determined by linear regression of the terminal points of the log-linear plasma concentration-time curve

  Days 1, 2, 3, 6, 7, 8, 11, 12, 13

• Apparent terminal elimination half-life (t1/2)

  Days 1, 2, 3, 6, 7, 8, 11, 12, 13

• Apparent volume of distribution after oral administration (Vd/F)

  Days 1, 2, 3, 6, 7, 8, 11, 12, 13

• Apparent total clearance of the drug from plasma after oral administration (cLF)

  Days 1, 2, 3, 6, 7, 8, 11, 12, 13

• Area under the plasma concentration time curve from time zero to 24 hours only for DDI cohort

  Days 1, 2, 15, 16

• The last concentration before the next study drug administration at steady state for DDI cohort

  Days 1, 2, 15, 16

• Maximum (peak) observed plasma drug concentration at steady state for DDI cohort

  Days 1, 2, 15, 16

• Time to reach maximum (peak) observed plasma concentration following drug administration at steady state for DDI cohort

  Days 1, 2, 15, 16

• Minimum observed plasma concentration at steady state, taken as the lowest plasma concentration during dosing interval for DDI cohort

  Days 1, 2, 15, 16

• Accumulation ratio for DDI cohort

  Days 1, 2, 15, 16

Secondary Outcomes (1)

• Occurrence of Adverse Events (AEs)

  from baseline until the end of study (16 days)

Study Arms (4)

PK Cohort 1

EXPERIMENTAL

Subjects received three single oral doses of palovarotene on Days 1, 6, and 11, separated by 5-day washout periods. Sequence A-B-C: Subjects received a single oral dose of palovarotene whole capsule under fasting conditions (at least a 10-hour overnight fast); followed by a single oral dose of palovarotene whole capsule 30 minutes after the start of a standardized high-fat, high-caloric breakfast; and then followed by a single oral dose of palovarotene sprinkled on 1 teaspoon of apple sauce, administered 30 minutes after the start of a standardized high-fat, high-caloric breakfast.

Drug: Palovarotene

PK Cohort 2

EXPERIMENTAL

Subjects received three single oral doses of palovarotene on Days 1, 6, and 11, separated by 5-day washout periods. Sequence B-C-A: Subjects received a single oral dose of palovarotene whole capsule 30 minutes after the start of a standardized high-fat, high-caloric breakfast; followed by a single oral dose of palovarotene sprinkled on 1 teaspoon of apple sauce, administered 30 minutes after the start of a standardized high-fat, high-caloric breakfast; and then followed by a single oral dose of palovarotene whole capsule under fasting conditions (at least a 10-hour overnight fast).

Drug: Palovarotene

PK Cohort 3

EXPERIMENTAL

Subjects received three single oral doses of palovarotene on Days 1, 6, and 11, separated by 5-day washout periods. Sequence C-A-B: Subjects received a single oral dose of palovarotene sprinkled on 1 teaspoon of apple sauce, administered 30 minutes after the start of a standardized high-fat, high-caloric breakfast; followed by a single oral dose of palovarotene whole capsule under fasting conditions (at least a 10-hour overnight fast); and then followed by a single oral dose of palovarotene whole capsule 30 minutes after the start of a standardized high-fat, high-caloric breakfast.

Drug: Palovarotene

Drug-Drug interaction (DDI) Cohort

EXPERIMENTAL

On the morning of Day 1, subjects received a single dose of midazolam 30 minutes after the start of a standardized breakfast. On Day 2 (after the 24-hour midazolam blood draw) through Day 15, subjects received a daily, single dose of palovarotene in the morning 30 minutes after the start of a standardized breakfast. A second dose of midazolam was administered on Day 15 in the morning (immediately following the palovarotene dose) 30 minutes after the start of a standardized breakfast.

Drug: Palovarotene; Drug: midazolam

Interventions

Palovarotene DRUG

oral capsules

Drug-Drug interaction (DDI) Cohort; PK Cohort 1; PK Cohort 2; PK Cohort 3

midazolam DRUG

oral syrup

Drug-Drug interaction (DDI) Cohort

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Generally healthy male or female aged 18 to 55 years, inclusive; body mass index (BMI) of 18 to 30 kg/m2 and a body weight of \>50 kg; resting pulse of \>45 bpm and \<100 bpm; systolic and diastolic blood pressure of \<140/90 mmHg

You may not qualify if:

• a history or current evidence of a clinically significant or uncontrolled disease, disease or condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs
• exposure to synthetic oral retinoids or creams containing retinoids in the past 30 days prior to the signature of the informed consent.
• history or presence of silent infections, including positive tests for human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), hepatitis B virus (HBV), or hepatitis C virus (HCV)
• history of allergy or hypersensitivity to retinoids, gelatin, or lactose
• For the DDI component only, the subject had a history of allergy or hypersensitivity to benzodiazepines, midazolam, cherries, or midazolam formulation excipients

Sponsors & Collaborators

• Clementia Pharmaceuticals Inc.: lead

Study Sites (1)

Cambridge Ipsen US

Cambridge, Massachusetts, 02142, United States

Location

Related Publications (1)

• Marino R, Dube L, Ogier J, Le Quan Sang KH. The Pharmacokinetic Profile of Palovarotene: An Open-Label Phase I Trial Investigating the Effect of Food and Potential for Drug-Drug Interaction in Healthy Participants. Eur J Drug Metab Pharmacokinet. 2023 Nov;48(6):691-707. doi: 10.1007/s13318-023-00856-2. Epub 2023 Oct 7.

  PMID: 37804430 DERIVED

MeSH Terms

Conditions

Myositis Ossificans

Interventions

Palovarotene; Midazolam

Condition Hierarchy (Ancestors)

Myositis; Muscular Diseases; Musculoskeletal Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Ipsen Medical Director

  Ipsen

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This study had two components. One component evaluated the effect of food and the effect of swallowing capsule whole versus sprinkling on apple sauce on the PK/bioavailability of palovarotene, and the other component evaluated the effect of palovarotene on the PK of the CYP3A4 substrate midazolam. The PK of palovarotene after single and multiple doses was also evaluated as part of the DDI component. Two cohorts of healthy adult subjects were enrolled, one for each component.

Study Record Dates

• First Submitted: April 1, 2021
• First Posted: April 2, 2021
• Study Start: January 3, 2019
• Primary Completion: March 29, 2019
• Study Completion: March 29, 2019
• Last Updated: April 2, 2021

Record last verified: 2021-04

Locations

US (1)