Fibrodysplasia Ossificans Progressiva
Conditions
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.
Interventions
DRUGPalovarotene
oral capsules
DRUGmidazolam
oral syrup
Sponsors
Clementia Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Accumulation ratio for DDI cohort | Days 1, 2, 15, 16 | — |
| Area under the plasma concentration time curve from time zero to 24 hours only for DDI cohort | Days 1, 2, 15, 16 | — |
| Apparent total clearance of the drug from plasma after oral administration (cLF) | 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 | — |
| 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) | 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 |
| 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| Occurrence of Adverse Events (AEs) | from baseline until the end of study (16 days) |
Countries
United States
Outcome results
None listed