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

Study Overview
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Brief Summary
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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.

Official Title
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An Open-Label 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

Conditions
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Fibrodysplasia Ossificans Progressiva

Intervention / Treatment
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* Drug: Palovarotene
* Drug: midazolam


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 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 Key Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PK Cohort 1<br>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<br>* oral capsules<br>|
| Experimental: PK Cohort 2<br>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<br>* oral capsules<br>|
| Experimental: PK Cohort 3<br>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<br>* oral capsules<br>|
| Experimental: Drug-Drug interaction (DDI) Cohort<br>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<br>* oral capsules<br>Drug: midazolam<br>* oral syrup<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Adverse Events (AEs) |  | from baseline until the end of study (16 days) |