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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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). |
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| 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Palovarotene | Drug | oral capsules |
|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Occurrence of Adverse Events (AEs) | from baseline until the end of study (16 days) |
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Key Inclusion Criteria:
Key Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ipsen Medical Director | Ipsen | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cambridge Ipsen US | Cambridge | Massachusetts | 02142 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37804430 | Derived | 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. |
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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.
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| 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. |
|
| midazolam | Drug | oral syrup |
|
| 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 |
| ID | Term |
|---|---|
| D009221 | Myositis Ossificans |
| ID | Term |
|---|---|
| D009220 | Myositis |
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
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| ID | Term |
|---|---|
| C546535 | Palovarotene |
| D008874 | Midazolam |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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