Healthy Volunteers
Conditions
Keywords
Apremilast, Healthy male subjects, Pharmacokinetics
Brief summary
This study will assess up to 12 different oral formulations of apremilast to determine how much apremilast is absorbed by the body compared to a reference formulation.
Detailed description
This will be a single-center, open-label, crossover, single modified-release-dose study in adult males to evaluate the pharmacokinetics (PK) of prototype modified-release (MR) formulations compared to the reference immediate-release (IR) apremilast formulation. Within 4 separate groups, participants will be randomly assigned to a treatment sequence. A total of up to 12 test MR formulations may be evaluated. Group 1: A 4-sequence, 4-period design to compare three modified-release prototypes with the reference immediate-release formulation. A total of 16 participants will be enrolled to obtain at least 12 participants who complete all 4 periods. Group 2: A 4-sequence, 4-period design to compare three MR prototypes with the reference IR formulation. Sixteen participants will be enrolled to obtain at least 12 participants who complete all four periods. Group 3: A six-sequence, three-period design to compare two MR prototypes with the reference IR formulation. Eighteen participants will be enrolled to obtain at least 12 participants who complete all three periods. Group 4: A 10-sequence, 5-period design to compare four MR prototypes with the reference IR formulation. Thirty participants will be enrolled to obtain at least 20 participants who complete all five periods.
Interventions
DRUGApremilast Immediate Release
30 mg immediate release tablets
DRUGApremilast Modified Release 1
75 mg oral tablet of prototype modified release (MR) 1
DRUGApremilast Modified Release 2
75 mg oral tablet of prototype MR 2
DRUGApremilast Modified Release 3
75 mg oral capsule of prototype MR 3
DRUGApremilast Modified Release 4
75 mg oral capsule of prototype MR 4
DRUGApremilast Modified Release 5
75 mg oral capsule of prototype MR 5
DRUGApremilast Modified Release 6
75 mg oral capsule of prototype MR 6
DRUGApremilast Modified Release 8
80 mg oral capsule of prototype MR 8
DRUGApremilast Modified Release 9
80 mg oral capsule of prototype MR 9
DRUGApremilast Modified Release 11
80 mg oral capsule of prototype MR 11
DRUGApremilast Modified Release 12
80 mg oral capsule of prototype MR 12
DRUGApremilast Modified Release 13
80 mg oral capsule of prototype MR 13
DRUGApremilast Modified Release 14
80 mg oral capsule of prototype MR 14
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Subjects must satisfy ALL of the following criteria to be eligible for enrollment into the study: 1. Must understand and voluntarily sign a written informed consent form prior to any study-related procedures being performed. 2. Must be able to communicate with the investigator, understand and comply with the requirements of the study, and agree to adhere to restrictions and examination schedules. 3. Male subjects of any race between 18 to 55 years of age (inclusive), and in good health as determined by the Investigator. 4. Has a body mass index between 18 and 33 kg/m\^2 (inclusive). 5. No clinically significant laboratory tests as determined by the investigator. 6. Must not have a fever, with systolic blood pressure: 90 to 140 mmHg and diastolic blood pressure: 60 to 90 mmHg, and pulse rate: 40 to 110 bpm (measurements taken while lying down). 7. Must have a normal or clinically acceptable 12-lead electrocardiogram (ECG). 8. Subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (male latex condom or non-latex condom not made out of natural \[animal\] membrane \[eg, polyurethane\]) while on study medication, and for 28 days after the last dose of study medication. 9. Must agree to refrain from donating sperm, blood or plasma (other than for this study) while participating in this study and for at least 28 days after the last dose of study drug.
Exclusion criteria
The presence of ANY of the following will exclude any healthy subject from enrollment into the study: 1. History of any clinically significant and relevant neurological, gastrointestinal, renal, hepatic, cardiovascular, psychological, pulmonary, metabolic, endocrine, hematological, allergic disease, drug allergies, or other major disorders. 2. Any condition which places the subject at unacceptable risk if he were to participate in the study, or confounds the ability to interpret data from the study. 3. Use of any prescribed systemic or topical medication within 30 days of the first dose administration, unless Sponsor agreement is obtained. 4. Use of any non-prescribed systemic or topical medication (including vitamin/mineral supplements, and herbal medicines) within 14 days of the first dose administration, unless Sponsor agreement is obtained. 5. Any surgical or medical condition possibly affecting drug absorption, distribution, metabolism and excretion, eg, bariatric procedure, colon resection, irritable bowel syndrome, Crohn's disease, etc. Subjects with cholecytectomy and appendectomy may be included. 6. Exposure to an investigational drug (new chemical entity) within 30 days prior to the first dose administration or 5 half-lives of that investigational drug, if known (whichever is longer). 7. Donated blood or plasma within 8 weeks before the first dose administration to a blood bank or blood donation center. 8. History of drug abuse (as defined by the current version of the Diagnostic and Statistical Manual (DSM) within 2 years before dosing, or a positive drug screen reflecting consumption of illicit drugs. 9. History of alcohol abuse (as defined by the current version of the DSM) within 2 years before dosing, or a positive alcohol screen. 10. Known to have serum hepatitis, or known to be a carrier of the hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody, or have a positive result to the test for human immunodeficiency virus (HIV) antibodies at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%. |
| Group 4: Half-life of Apremilast in Terminal Phase (T1/2) | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 4: Apparent Total Plasma Clearance (CL/F) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 4: Apparent Total Volume of Distribution (Vz/F) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%. |
| Group 1: Observed Maximum Plasma Concentration (Cmax) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 1: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 1: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 1: Half-life of Apremilast in Terminal Phase (T1/2) | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 1: Apparent Total Plasma Clearance (CL/F) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 1: Apparent Total Volume of Distribution (Vz/F) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%. |
| Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%. |
| Group 2: Observed Maximum Plasma Concentration (Cmax) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 2: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 2: Half-life of Apremilast in Terminal Phase (T1/2) | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 2: Apparent Total Plasma Clearance (CL/F) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 2: Apparent Total Volume of Distribution (Vz/F) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%. |
| Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%. |
| Group 3: Observed Maximum Plasma Concentration (Cmax) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 3: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 3: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 3: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 3: Half-life of Apremilast in Terminal Phase (T1/2) | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 3: Apparent Total Plasma Clearance (CL/F) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 3: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%. |
| Group 3: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%. |
| Group 4: Observed Maximum Plasma Concentration (Cmax) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 4: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 4: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
| Group 4: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose. | Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Group 2: Number of Participants With Treatment-emergent Adverse Events | Adverse events were collected for 7 to 10 days after each treatment. | An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event. |
| Group 3: Number of Participants With Treatment-emergent Adverse Events | Adverse events were collected for 7 to 10 days after each treatment. | An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event. |
| Group 4: Number of Participants With Treatment-emergent Adverse Events | Adverse events were collected for 7 to 10 days after each treatment. | An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event. |
| Group 1: Number of Participants With Treatment-emergent Adverse Events | Adverse events were collected for 7 to 10 days after each treatment. | An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at a single study site in the United States from July 2013 to September 2014.
Pre-assignment details
This was an open-label crossover study that consisted of 4 groups of participants and tested 12 different modified release (MR) formulations of apremilast versus the reference immediate release (IR) formulation. Within each group participants were randomized to a treatment sequence.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Participants received the following 4 treatments, given in 4 possible sequences (ADBC, BACD, CBDA, and DCAB) with 7 to 10 days between each treatment:
A) Two oral doses of 30 mg apremilast immediate release tablets 12 hours apart (reference formulation) B) A single oral dose 75 mg apremilast tablet prototype MR 1 C) A single oral dose 75 mg apremilast tablet prototype MR 2 D) A single oral dose 75 mg apremilast capsule prototype MR 3 | 16 |
| Group 2 Participants received the following 4 treatments, given in 4 possible sequences (AGEF, EAFG, FEGA, and GFAE) with 7 to 10 days between each treatment:
A) Two oral doses of 30 mg apremilast immediate release tablets 12 hours apart (reference formulation) E) A single oral dose 75 mg apremilast capsule prototype MR 4 F) A single oral dose 75 mg apremilast capsule prototype MR 5 G) A single oral dose 75 mg apremilast capsule prototype MR 6 | 16 |
| Group 3 Participants received the following 3 treatments, given in 6 possible sequences (AIJ, IJA, JAI, AJI, IAJ, or JIA) with 7 to 10 days between each treatment:
A) Two oral doses of 30 mg apremilast immediate release tablets 12 hours apart (reference formulation) I) A single oral dose 80 mg apremilast capsule prototype MR 8 J) A single oral dose 80 mg apremilast capsule prototype MR 9 | 18 |
| Group 4 Participants received the following 5 treatments, given in 10 possible sequences (ALOMN, LMANO, MNLOA, NOMAL, OANLM, NMOLA, ONAML, AOLNM, LAMON, or MLNAO) with 7 to 10 days between each treatment:
A) Two oral doses of 30 mg apremilast immediate release tablets 12 hours apart (reference formulation) L) A single oral dose 80 mg apremilast capsule prototype MR 11 M) A single oral dose 80 mg apremilast capsule prototype MR 12 N) A single oral dose 80 mg apremilast capsule prototype MR 13 O) A single oral dose 80 mg apremilast capsule prototype MR 14 | 30 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Overall Study | Unable to Comply with Study Visits | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Group 2 | Group 3 | Group 1 | Group 4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 34.1 years | 30.4 years | 39.1 years | 33.3 years | 34.0 years |
| Body Mass Index (BMI) | 25.56 kg/m^2 | 24.83 kg/m^2 | 26.82 kg/m^2 | 25.15 kg/m^2 | 25.49 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 0 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 15 Participants | 16 Participants | 28 Participants | 73 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 2 Participants | 3 Participants | 5 Participants | 13 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 12 Participants | 16 Participants | 11 Participants | 21 Participants | 60 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 16 Participants | 18 Participants | 16 Participants | 30 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk | EG020 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 16 | 4 / 16 | 2 / 16 | 1 / 16 | 8 / 16 | 4 / 16 | 4 / 16 | 6 / 16 | 5 / 16 | 8 / 16 | 5 / 18 | 3 / 18 | 3 / 18 | 7 / 18 | 12 / 29 | 5 / 29 | 7 / 28 | 5 / 28 | 7 / 28 | 17 / 30 | 40 / 80 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 18 | 0 / 18 | 0 / 18 | 0 / 18 | 0 / 29 | 0 / 29 | 0 / 28 | 0 / 28 | 0 / 28 | 0 / 30 | 0 / 80 |
Outcome results
Primary
Group 1: Apparent Total Plasma Clearance (CL/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 1: Apparent Total Plasma Clearance (CL/F) of Apremilast | 8.63 L/h | Geometric Coefficient of Variation 47.9 |
| Group 1: Apremilast Modified Release 1 | Group 1: Apparent Total Plasma Clearance (CL/F) of Apremilast | 17.32 L/h | Geometric Coefficient of Variation 88.2 |
| Group 1: Apremilast Modified Release 2 | Group 1: Apparent Total Plasma Clearance (CL/F) of Apremilast | 15.12 L/h | Geometric Coefficient of Variation 67.8 |
| Group 1: Apremilast Modified Release 3 | Group 1: Apparent Total Plasma Clearance (CL/F) of Apremilast | 14.57 L/h | Geometric Coefficient of Variation 54.5 |
Primary
Group 1: Apparent Total Volume of Distribution (Vz/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 1: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 88.65 liters | Geometric Coefficient of Variation 32.5 |
| Group 1: Apremilast Modified Release 1 | Group 1: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 185.65 liters | Geometric Coefficient of Variation 64.7 |
| Group 1: Apremilast Modified Release 2 | Group 1: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 149.97 liters | Geometric Coefficient of Variation 53.5 |
| Group 1: Apremilast Modified Release 3 | Group 1: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 153.23 liters | Geometric Coefficient of Variation 34.8 |
Primary
Group 1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 6955.76 ng*h/mL | Geometric Coefficient of Variation 47.9 |
| Group 1: Apremilast Modified Release 1 | Group 1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 4330.66 ng*h/mL | Geometric Coefficient of Variation 88.2 |
| Group 1: Apremilast Modified Release 2 | Group 1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 4961.51 ng*h/mL | Geometric Coefficient of Variation 67.8 |
| Group 1: Apremilast Modified Release 3 | Group 1: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 5147.83 ng*h/mL | Geometric Coefficient of Variation 54.5 |
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [52.1, 74.4]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [59.7, 85.2]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [62, 88.4]
Primary
Group 1: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 1: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 6918.49 ng*h/mL | Geometric Coefficient of Variation 47.7 |
| Group 1: Apremilast Modified Release 1 | Group 1: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 4277.83 ng*h/mL | Geometric Coefficient of Variation 88.2 |
| Group 1: Apremilast Modified Release 2 | Group 1: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 4925.69 ng*h/mL | Geometric Coefficient of Variation 67.7 |
| Group 1: Apremilast Modified Release 3 | Group 1: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 5103.07 ng*h/mL | Geometric Coefficient of Variation 54.3 |
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [51.7, 73.9]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [59.6, 85.1]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [61.7, 88.2]
Primary
Group 1: Half-life of Apremilast in Terminal Phase (T1/2)
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 1: Half-life of Apremilast in Terminal Phase (T1/2) | 7.12 hours | Geometric Coefficient of Variation 23.3 |
| Group 1: Apremilast Modified Release 1 | Group 1: Half-life of Apremilast in Terminal Phase (T1/2) | 7.43 hours | Geometric Coefficient of Variation 21.7 |
| Group 1: Apremilast Modified Release 2 | Group 1: Half-life of Apremilast in Terminal Phase (T1/2) | 6.88 hours | Geometric Coefficient of Variation 22 |
| Group 1: Apremilast Modified Release 3 | Group 1: Half-life of Apremilast in Terminal Phase (T1/2) | 7.29 hours | Geometric Coefficient of Variation 21.8 |
Primary
Group 1: Observed Maximum Plasma Concentration (Cmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The pharmacokinetic (PK) population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 1: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 409.96 ng/mL | Geometric Coefficient of Variation 34.9 |
| Group 1: Apremilast Modified Release 1 | Group 1: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 267.85 ng/mL | Geometric Coefficient of Variation 56.4 |
| Group 1: Apremilast Modified Release 2 | Group 1: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 329.78 ng/mL | Geometric Coefficient of Variation 52.2 |
| Group 1: Apremilast Modified Release 3 | Group 1: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 345.11 ng/mL | Geometric Coefficient of Variation 41.5 |
Comparison: To compare each test formulation with the reference formulation in each group, an analysis of variance (ANOVA) was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [55, 77.6]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [67.8, 95.5]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [70.9, 99.9]
Primary
Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 62.26 percent availability | Geometric Coefficient of Variation 53.7 |
| Group 1: Apremilast Modified Release 1 | Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 71.33 percent availability | Geometric Coefficient of Variation 47 |
| Group 1: Apremilast Modified Release 2 | Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 74.01 percent availability | Geometric Coefficient of Variation 22.9 |
Primary
Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 39.85 percent availability | Geometric Coefficient of Variation 53.7 |
| Group 1: Apremilast Modified Release 1 | Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 45.65 percent availability | Geometric Coefficient of Variation 47 |
| Group 1: Apremilast Modified Release 2 | Group 1: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 47.37 percent availability | Geometric Coefficient of Variation 22.9 |
Primary
Group 1: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Apremilast Immediate Release | Group 1: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 3.00 hours |
| Group 1: Apremilast Modified Release 1 | Group 1: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 4.00 hours |
| Group 1: Apremilast Modified Release 2 | Group 1: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 4.00 hours |
| Group 1: Apremilast Modified Release 3 | Group 1: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 4.00 hours |
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.00990% CI: [0.5, 2]Wilcoxon signed-rank test
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.007390% CI: [0.5, 3]Wilcoxon signed-rank test
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: <0.000190% CI: [1, 3]Wilcoxon signed-rank test
Primary
Group 2: Apparent Total Plasma Clearance (CL/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 2: Apparent Total Plasma Clearance (CL/F) of Apremilast | 9.00 L/h | Geometric Coefficient of Variation 36 |
| Group 1: Apremilast Modified Release 1 | Group 2: Apparent Total Plasma Clearance (CL/F) of Apremilast | 13.16 L/h | Geometric Coefficient of Variation 40.1 |
| Group 1: Apremilast Modified Release 2 | Group 2: Apparent Total Plasma Clearance (CL/F) of Apremilast | 15.48 L/h | Geometric Coefficient of Variation 38.9 |
| Group 1: Apremilast Modified Release 3 | Group 2: Apparent Total Plasma Clearance (CL/F) of Apremilast | 14.26 L/h | Geometric Coefficient of Variation 35.9 |
Primary
Group 2: Apparent Total Volume of Distribution (Vz/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 2: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 101.23 liters | Geometric Coefficient of Variation 37.2 |
| Group 1: Apremilast Modified Release 1 | Group 2: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 169.71 liters | Geometric Coefficient of Variation 34 |
| Group 1: Apremilast Modified Release 2 | Group 2: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 186.69 liters | Geometric Coefficient of Variation 34.8 |
Primary
Group 2: Apparent Total Volume of Distribution (Vz/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 2: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 105.88 liters | Geometric Coefficient of Variation 35.3 |
| Group 1: Apremilast Modified Release 1 | Group 2: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 170.51 liters | Geometric Coefficient of Variation 34 |
| Group 1: Apremilast Modified Release 2 | Group 2: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 188.24 liters | Geometric Coefficient of Variation 37.5 |
| Group 1: Apremilast Modified Release 3 | Group 2: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 180.10 liters | Geometric Coefficient of Variation 48.3 |
Primary
Group 2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 6669.26 ng*h/mL | Geometric Coefficient of Variation 36 |
| Group 1: Apremilast Modified Release 1 | Group 2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 5700.66 ng*h/mL | Geometric Coefficient of Variation 40.1 |
| Group 1: Apremilast Modified Release 2 | Group 2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 4843.46 ng*h/mL | Geometric Coefficient of Variation 38.9 |
| Group 1: Apremilast Modified Release 3 | Group 2: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 5259.40 ng*h/mL | Geometric Coefficient of Variation 35.9 |
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [78.1, 93.6]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [66.3, 79.5]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [72, 86.4]
Primary
Group 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 6635.78 ng*h/mL | Geometric Coefficient of Variation 35.9 |
| Group 1: Apremilast Modified Release 1 | Group 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 5634.92 ng*h/mL | Geometric Coefficient of Variation 40.2 |
| Group 1: Apremilast Modified Release 2 | Group 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 4780.60 ng*h/mL | Geometric Coefficient of Variation 39.3 |
| Group 1: Apremilast Modified Release 3 | Group 2: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 5177.46 ng*h/mL | Geometric Coefficient of Variation 36.9 |
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [77.5, 93]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [65.8, 78.9]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [71.2, 85.5]
Primary
Group 2: Half-life of Apremilast in Terminal Phase (T1/2)
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 2: Half-life of Apremilast in Terminal Phase (T1/2) | 8.16 hours | Geometric Coefficient of Variation 26.3 |
| Group 1: Apremilast Modified Release 1 | Group 2: Half-life of Apremilast in Terminal Phase (T1/2) | 8.98 hours | Geometric Coefficient of Variation 22.9 |
| Group 1: Apremilast Modified Release 2 | Group 2: Half-life of Apremilast in Terminal Phase (T1/2) | 8.43 hours | Geometric Coefficient of Variation 28.9 |
| Group 1: Apremilast Modified Release 3 | Group 2: Half-life of Apremilast in Terminal Phase (T1/2) | 8.75 hours | Geometric Coefficient of Variation 29.6 |
Primary
Group 2: Observed Maximum Plasma Concentration (Cmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The pharmacokinetic (PK) population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 2: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 405.38 ng/mL | Geometric Coefficient of Variation 30.2 |
| Group 1: Apremilast Modified Release 1 | Group 2: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 368.45 ng/mL | Geometric Coefficient of Variation 37.2 |
| Group 1: Apremilast Modified Release 2 | Group 2: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 298.96 ng/mL | Geometric Coefficient of Variation 34.1 |
| Group 1: Apremilast Modified Release 3 | Group 2: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 325.20 ng/mL | Geometric Coefficient of Variation 35.1 |
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [81.8, 101.1]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [66.3, 82]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [72.2, 89.2]
Primary
Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 85.48 percent availability | Geometric Coefficient of Variation 26 |
| Group 1: Apremilast Modified Release 1 | Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 72.62 percent availability | Geometric Coefficient of Variation 23.5 |
| Group 1: Apremilast Modified Release 2 | Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 78.86 percent availability | Geometric Coefficient of Variation 13.2 |
Primary
Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 54.71 percent availability | Geometric Coefficient of Variation 26 |
| Group 1: Apremilast Modified Release 1 | Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 46.48 percent availability | Geometric Coefficient of Variation 23.5 |
| Group 1: Apremilast Modified Release 2 | Group 2: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 50.47 percent availability | Geometric Coefficient of Variation 13.2 |
Primary
Group 2: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Apremilast Immediate Release | Group 2: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 2.00 hours |
| Group 1: Apremilast Modified Release 1 | Group 2: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 4.00 hours |
| Group 1: Apremilast Modified Release 2 | Group 2: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 3.00 hours |
| Group 1: Apremilast Modified Release 3 | Group 2: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 4.00 hours |
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.000290% CI: [1, 3]Wilcoxon signed-rank test
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.004990% CI: [0.5, 2]Wilcoxon signed-rank test
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.00190% CI: [1, 2]Wilcoxon signed-rank test
Primary
Group 3: Apparent Total Plasma Clearance (CL/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 3: Apparent Total Plasma Clearance (CL/F) of Apremilast | 10.87 L/h | Geometric Coefficient of Variation 33.8 |
| Group 1: Apremilast Modified Release 1 | Group 3: Apparent Total Plasma Clearance (CL/F) of Apremilast | 17.87 L/h | Geometric Coefficient of Variation 32.7 |
| Group 1: Apremilast Modified Release 2 | Group 3: Apparent Total Plasma Clearance (CL/F) of Apremilast | 18.35 L/h | Geometric Coefficient of Variation 35 |
Primary
Group 3: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 3: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 5518.28 ng*h/mL | Geometric Coefficient of Variation 33.8 |
| Group 1: Apremilast Modified Release 1 | Group 3: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 4477.63 ng*h/mL | Geometric Coefficient of Variation 32.7 |
| Group 1: Apremilast Modified Release 2 | Group 3: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 4359.49 ng*h/mL | Geometric Coefficient of Variation 35 |
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [74.3, 88.6]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [72.3, 86.3]
Primary
Group 3: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 3: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 5493.38 ng*h/mL | Geometric Coefficient of Variation 33.7 |
| Group 1: Apremilast Modified Release 1 | Group 3: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 4427.56 ng*h/mL | Geometric Coefficient of Variation 32.7 |
| Group 1: Apremilast Modified Release 2 | Group 3: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 4310.62 ng*h/mL | Geometric Coefficient of Variation 35 |
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [73.8, 88]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [71.9, 85.7]
Primary
Group 3: Half-life of Apremilast in Terminal Phase (T1/2)
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 3: Half-life of Apremilast in Terminal Phase (T1/2) | 6.45 hours | Geometric Coefficient of Variation 23.8 |
| Group 1: Apremilast Modified Release 1 | Group 3: Half-life of Apremilast in Terminal Phase (T1/2) | 6.58 hours | Geometric Coefficient of Variation 29.2 |
| Group 1: Apremilast Modified Release 2 | Group 3: Half-life of Apremilast in Terminal Phase (T1/2) | 7.05 hours | Geometric Coefficient of Variation 27 |
Primary
Group 3: Observed Maximum Plasma Concentration (Cmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 3: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 378.59 ng/mL | Geometric Coefficient of Variation 31.6 |
| Group 1: Apremilast Modified Release 1 | Group 3: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 344.61 ng/mL | Geometric Coefficient of Variation 28.7 |
| Group 1: Apremilast Modified Release 2 | Group 3: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 334.51 ng/mL | Geometric Coefficient of Variation 33.6 |
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [80.4, 103]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [78.1, 100]
Primary
Group 3: Relative Bioavailability of Apremilast Test Formulations Relative to Reference
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 3: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 81.14 percent availability | Geometric Coefficient of Variation 21.4 |
| Group 1: Apremilast Modified Release 1 | Group 3: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 79.00 percent availability | Geometric Coefficient of Variation 21.1 |
Primary
Group 3: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 3: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 45.64 percent availability | Geometric Coefficient of Variation 21.4 |
| Group 1: Apremilast Modified Release 1 | Group 3: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 44.44 percent availability | Geometric Coefficient of Variation 21.1 |
Primary
Group 3: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Apremilast Immediate Release | Group 3: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 3.00 hours |
| Group 1: Apremilast Modified Release 1 | Group 3: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 4.00 hours |
| Group 1: Apremilast Modified Release 2 | Group 3: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 4.00 hours |
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.037490% CI: [0.02, 1.5]Wilcoxon signed-rank test
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.190790% CI: [0, 1.5]Wilcoxon signed-rank test
Primary
Group 4: Apparent Total Plasma Clearance (CL/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 4: Apparent Total Plasma Clearance (CL/F) of Apremilast | 8.57 L/h | Geometric Coefficient of Variation 32.2 |
| Group 1: Apremilast Modified Release 1 | Group 4: Apparent Total Plasma Clearance (CL/F) of Apremilast | 13.92 L/h | Geometric Coefficient of Variation 34 |
| Group 1: Apremilast Modified Release 2 | Group 4: Apparent Total Plasma Clearance (CL/F) of Apremilast | 13.62 L/h | Geometric Coefficient of Variation 28.6 |
| Group 1: Apremilast Modified Release 3 | Group 4: Apparent Total Plasma Clearance (CL/F) of Apremilast | 16.83 L/h | Geometric Coefficient of Variation 40.1 |
| Group 4: Apremilast Modified Release 14 | Group 4: Apparent Total Plasma Clearance (CL/F) of Apremilast | 14.88 L/h | Geometric Coefficient of Variation 36.8 |
Primary
Group 4: Apparent Total Volume of Distribution (Vz/F) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 4: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 77.30 liters | Geometric Coefficient of Variation 36 |
| Group 1: Apremilast Modified Release 1 | Group 4: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 148.66 liters | Geometric Coefficient of Variation 32.5 |
| Group 1: Apremilast Modified Release 2 | Group 4: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 147.59 liters | Geometric Coefficient of Variation 41.5 |
| Group 1: Apremilast Modified Release 3 | Group 4: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 172.16 liters | Geometric Coefficient of Variation 44.6 |
| Group 4: Apremilast Modified Release 14 | Group 4: Apparent Total Volume of Distribution (Vz/F) of Apremilast | 153.18 liters | Geometric Coefficient of Variation 36.1 |
Primary
Group 4: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 4: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 7000.35 ng*h/mL | Geometric Coefficient of Variation 32.2 |
| Group 1: Apremilast Modified Release 1 | Group 4: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 5747.12 ng*h/mL | Geometric Coefficient of Variation 34 |
| Group 1: Apremilast Modified Release 2 | Group 4: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 5875.19 ng*h/mL | Geometric Coefficient of Variation 28.6 |
| Group 1: Apremilast Modified Release 3 | Group 4: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 4753.79 ng*h/mL | Geometric Coefficient of Variation 40.1 |
| Group 4: Apremilast Modified Release 14 | Group 4: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 5374.83 ng*h/mL | Geometric Coefficient of Variation 36.8 |
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [75.6, 88.6]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [76.5, 90.1]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [63.4, 74.5]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-∞ value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [71.8, 84.4]
Primary
Group 4: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The pharmacokinetic (PK) population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 4: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 6976.02 ng*h/mL | Geometric Coefficient of Variation 32.3 |
| Group 1: Apremilast Modified Release 1 | Group 4: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 5701.21 ng*h/mL | Geometric Coefficient of Variation 34.1 |
| Group 1: Apremilast Modified Release 2 | Group 4: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 5811.24 ng*h/mL | Geometric Coefficient of Variation 29 |
| Group 1: Apremilast Modified Release 3 | Group 4: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 4700.70 ng*h/mL | Geometric Coefficient of Variation 40.2 |
| Group 4: Apremilast Modified Release 14 | Group 4: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measured Time Point (AUC0-t) of Apremilast | 5324.80 ng*h/mL | Geometric Coefficient of Variation 36.5 |
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [75.2, 88.3]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [75.9, 89.5]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [62.9, 74]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed AUC0-t value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [71.3, 84]
Primary
Group 4: Half-life of Apremilast in Terminal Phase (T1/2)
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 4: Half-life of Apremilast in Terminal Phase (T1/2) | 6.25 hours | Geometric Coefficient of Variation 24.8 |
| Group 1: Apremilast Modified Release 1 | Group 4: Half-life of Apremilast in Terminal Phase (T1/2) | 7.40 hours | Geometric Coefficient of Variation 25.2 |
| Group 1: Apremilast Modified Release 2 | Group 4: Half-life of Apremilast in Terminal Phase (T1/2) | 7.51 hours | Geometric Coefficient of Variation 34.9 |
| Group 1: Apremilast Modified Release 3 | Group 4: Half-life of Apremilast in Terminal Phase (T1/2) | 7.09 hours | Geometric Coefficient of Variation 31 |
| Group 4: Apremilast Modified Release 14 | Group 4: Half-life of Apremilast in Terminal Phase (T1/2) | 7.13 hours | Geometric Coefficient of Variation 32.5 |
Primary
Group 4: Observed Maximum Plasma Concentration (Cmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The pharmacokinetic (PK) population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 4: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 438.90 ng/mL | Geometric Coefficient of Variation 29.1 |
| Group 1: Apremilast Modified Release 1 | Group 4: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 480.59 ng/mL | Geometric Coefficient of Variation 24.9 |
| Group 1: Apremilast Modified Release 2 | Group 4: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 481.10 ng/mL | Geometric Coefficient of Variation 29.3 |
| Group 1: Apremilast Modified Release 3 | Group 4: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 316.43 ng/mL | Geometric Coefficient of Variation 48.5 |
| Group 4: Apremilast Modified Release 14 | Group 4: Observed Maximum Plasma Concentration (Cmax) of Apremilast | 450.23 ng/mL | Geometric Coefficient of Variation 32.5 |
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [98.6, 121.3]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [96.4, 119.2]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [65.5, 80.8]
Comparison: To compare each test formulation with the reference formulation in each group, an ANOVA was performed on the natural log-transformed Cmax value. The ANOVA model included treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect.90% CI: [93.1, 114.9]
Primary
Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞\[test\]) / (AUC0-∞\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 82.10 percent availability | Geometric Coefficient of Variation 22.3 |
| Group 1: Apremilast Modified Release 1 | Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 83.31 percent availability | Geometric Coefficient of Variation 27.7 |
| Group 1: Apremilast Modified Release 2 | Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 68.71 percent availability | Geometric Coefficient of Variation 34 |
| Group 1: Apremilast Modified Release 3 | Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference | 77.68 percent availability | Geometric Coefficient of Variation 26.9 |
Primary
Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose
Relative bioavailability of each test formulation compared to the reference formulation corrected by dose, calculated as: (AUC0-∞/Dose\[test\]) / (AUC0-∞/Dose\[reference\]) \* 100%.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 46.18 percent availability | Geometric Coefficient of Variation 22.3 |
| Group 1: Apremilast Modified Release 1 | Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 46.86 percent availability | Geometric Coefficient of Variation 27.7 |
| Group 1: Apremilast Modified Release 2 | Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 38.65 percent availability | Geometric Coefficient of Variation 34 |
| Group 1: Apremilast Modified Release 3 | Group 4: Relative Bioavailability of Apremilast Test Formulations Relative to Reference Corrected by Dose | 43.70 percent availability | Geometric Coefficient of Variation 26.9 |
Primary
Group 4: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast
Concentrations of apremilast in plasma were measured using a validated liquid chromatography tandem mass spectrometry assay.
Time frame: IR reference formulation: predose and at 0.5, 1, 2, 3, 5, 8, 12, 12.5, 13, 14, 15, 17, 20, 24, 36, 48, 60, and 72 hours after the first dose; MR formulations: predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 30, 36, 48, and 72 hours postdose.
Population: The PK population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Apremilast Immediate Release | Group 4: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 3.00 hours |
| Group 1: Apremilast Modified Release 1 | Group 4: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 4.00 hours |
| Group 1: Apremilast Modified Release 2 | Group 4: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 4.00 hours |
| Group 1: Apremilast Modified Release 3 | Group 4: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 4.01 hours |
| Group 4: Apremilast Modified Release 14 | Group 4: Time to Observed Maximum Plasma Concentration (Tmax) of Apremilast | 3.52 hours |
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.052390% CI: [0.03, 1.5]Wilcoxon signed-rank test
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.259890% CI: [0, 1]Wilcoxon signed-rank test
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.005390% CI: [1, 3]Wilcoxon signed-rank test
Comparison: Tmax was analyzed by nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.109390% CI: [0, 1]Wilcoxon signed-rank test
Secondary
Group 1: Number of Participants With Treatment-emergent Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event.
Time frame: Adverse events were collected for 7 to 10 days after each treatment.
Population: Participants who received at least one dose of apremilast.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 1: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 5 Participants |
| Group 1: Apremilast Immediate Release | Group 1: Number of Participants With Treatment-emergent Adverse Events | TEAEs related to study drug | 4 Participants |
| Group 1: Apremilast Immediate Release | Group 1: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 1: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 1: Number of Participants With Treatment-emergent Adverse Events | Discontinuations due to adverse events | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 1: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 4 Participants |
| Group 1: Apremilast Modified Release 1 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 1: Number of Participants With Treatment-emergent Adverse Events | TEAEs related to study drug | 1 Participants |
| Group 1: Apremilast Modified Release 1 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Discontinuations due to adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 1: Number of Participants With Treatment-emergent Adverse Events | TEAEs related to study drug | 2 Participants |
| Group 1: Apremilast Modified Release 2 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Discontinuations due to adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 2 Participants |
| Group 1: Apremilast Modified Release 3 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Discontinuations due to adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 3 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 3 | Group 1: Number of Participants With Treatment-emergent Adverse Events | TEAEs related to study drug | 1 Participants |
| Group 1: Apremilast Modified Release 3 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 3 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 1 Participants |
| Group 1: Apremilast Modified Release 3 | Group 1: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
Secondary
Group 2: Number of Participants With Treatment-emergent Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event.
Time frame: Adverse events were collected for 7 to 10 days after each treatment.
Population: Participants who received at least one dose of apremilast.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 4 Participants |
| Group 1: Apremilast Immediate Release | Group 2: Number of Participants With Treatment-emergent Adverse Events | TEAEs related to study drug | 4 Participants |
| Group 1: Apremilast Immediate Release | Group 2: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 2: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 2: Number of Participants With Treatment-emergent Adverse Events | Discontinuations due to adverse events | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 2: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 4 Participants |
| Group 1: Apremilast Modified Release 1 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 2: Number of Participants With Treatment-emergent Adverse Events | TEAEs related to study drug | 2 Participants |
| Group 1: Apremilast Modified Release 1 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Discontinuations due to adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 2: Number of Participants With Treatment-emergent Adverse Events | TEAEs related to study drug | 5 Participants |
| Group 1: Apremilast Modified Release 2 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Discontinuations due to adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 6 Participants |
| Group 1: Apremilast Modified Release 3 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Discontinuations due to adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 3 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 3 | Group 2: Number of Participants With Treatment-emergent Adverse Events | TEAEs related to study drug | 4 Participants |
| Group 1: Apremilast Modified Release 3 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 3 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 5 Participants |
| Group 1: Apremilast Modified Release 3 | Group 2: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
Secondary
Group 3: Number of Participants With Treatment-emergent Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event.
Time frame: Adverse events were collected for 7 to 10 days after each treatment.
Population: Participants who received at least one dose of apremilast.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 5 Participants |
| Group 1: Apremilast Immediate Release | Group 3: Number of Participants With Treatment-emergent Adverse Events | TEAEs related to study drug | 1 Participants |
| Group 1: Apremilast Immediate Release | Group 3: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 3: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 3: Number of Participants With Treatment-emergent Adverse Events | Discontinuations due to adverse events | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 3: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 3: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 3 Participants |
| Group 1: Apremilast Modified Release 1 | Group 3: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 3: Number of Participants With Treatment-emergent Adverse Events | Discontinuations due to adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 3: Number of Participants With Treatment-emergent Adverse Events | TEAEs related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 3: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 3: Number of Participants With Treatment-emergent Adverse Events | TEAEs related to study drug | 2 Participants |
| Group 1: Apremilast Modified Release 2 | Group 3: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 3: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 3: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 3: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 3 Participants |
| Group 1: Apremilast Modified Release 2 | Group 3: Number of Participants With Treatment-emergent Adverse Events | Discontinuations due to adverse events | 0 Participants |
Secondary
Group 4: Number of Participants With Treatment-emergent Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A treatment-emergent AE (TEAE) was defined as any AE that occurred after dosing of the study drug. A serious adverse event (SAE) is any AE occurring at any dose that: * Resulted in death; * Was life-threatening; * Required inpatient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly/birth defect; * Constituted an important medical event.
Time frame: Adverse events were collected for 7 to 10 days after each treatment.
Population: Participants who received at least one dose of apremilast.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: Apremilast Immediate Release | Group 4: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 4: Number of Participants With Treatment-emergent Adverse Events | Discontinuation due to adverse events | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 4: Number of Participants With Treatment-emergent Adverse Events | TEAE related to study drug | 9 Participants |
| Group 1: Apremilast Immediate Release | Group 4: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 13 Participants |
| Group 1: Apremilast Immediate Release | Group 4: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Immediate Release | Group 4: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Discontinuation due to adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 1 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 7 Participants |
| Group 1: Apremilast Modified Release 1 | Group 4: Number of Participants With Treatment-emergent Adverse Events | TEAE related to study drug | 7 Participants |
| Group 1: Apremilast Modified Release 2 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Discontinuation due to adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 7 Participants |
| Group 1: Apremilast Modified Release 2 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 2 | Group 4: Number of Participants With Treatment-emergent Adverse Events | TEAE related to study drug | 6 Participants |
| Group 1: Apremilast Modified Release 3 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 1: Apremilast Modified Release 3 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 1: Apremilast Modified Release 3 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 7 Participants |
| Group 1: Apremilast Modified Release 3 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 3 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Discontinuation due to adverse events | 0 Participants |
| Group 1: Apremilast Modified Release 3 | Group 4: Number of Participants With Treatment-emergent Adverse Events | TEAE related to study drug | 6 Participants |
| Group 4: Apremilast Modified Release 14 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Deaths | 0 Participants |
| Group 4: Apremilast Modified Release 14 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Group 4: Apremilast Modified Release 14 | Group 4: Number of Participants With Treatment-emergent Adverse Events | TEAE related to study drug | 7 Participants |
| Group 4: Apremilast Modified Release 14 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Discontinuation due to adverse events | 0 Participants |
| Group 4: Apremilast Modified Release 14 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Serious adverse events related to study drug | 0 Participants |
| Group 4: Apremilast Modified Release 14 | Group 4: Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 9 Participants |