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
Phase 1
Completed
- Conditions
- Fibrodysplasia Ossificans Progressiva
- Interventions
- Registration Number
- NCT04829773
- Lead Sponsor
- Clementia Pharmaceuticals Inc.
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 48
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description PK Cohort 1 Palovarotene 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. PK Cohort 2 Palovarotene 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). PK Cohort 3 Palovarotene 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-Drug interaction (DDI) Cohort Palovarotene 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-Drug interaction (DDI) Cohort midazolam 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.
- Primary Outcome Measures
Name Time Method Minimum observed plasma concentration at steady state, taken as the lowest plasma concentration during dosing interval for DDI cohort Days 1, 2, 15, 16 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 Accumulation ratio for DDI cohort Days 1, 2, 15, 16 Area under the plasma concentration time curve from time zero to infinity (AUC 0-infinity) Days 1, 2, 3, 6, 7, 8, 11, 12, 13 calculated by linear-log trapezoidal summation and extrapolated to infinity by addition of the last quantifiable plasma concentration divided by the elimination rate constant
Apparent terminal disposition rate constant/terminal rate constant yz Days 1, 2, 3, 6, 7, 8, 11, 12, 13 determined by linear regression of the terminal points of the log-linear plasma concentration-time curve
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
- Secondary Outcome Measures
Name Time Method Occurrence of Adverse Events (AEs) from baseline until the end of study (16 days)
Trial Locations
- Locations (1)
Cambridge Ipsen US
🇺🇸Cambridge, Massachusetts, United States