Healthy Volunteer
Conditions
Keywords
Apremilast,, pharmacokinetic, safety, Safety and pharmacokinetics in healthy volunteer subjects
Brief summary
The purpose of the study is to evaluate the effects of a high fat meal on the pharmacokinetics of a single dose of 30 mg apremilast in healthy adults.
Detailed description
Participants will be randomized to receive a single dose of 30 mg apremilast during each of the 2 periods; once under fasting conditions and once after a high fat meal. Participants will be randomly assigned to receive apremilast either fasted first, then fed, or fed first then fasted. Participants will check into the study center on Day -1 of each period, will be dosed on Day 1, and discharged from the study center on Day 3 after all scheduled pharmacokinetic blood draws and safety evaluations. After a washout of 5 to 10 days, participants will return for period 2 during which they will receive apremilast according to their assigned sequence.
Interventions
DRUGApremilast
Tablet for oral administration
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male or female subjects of any ethnic origin between ages of 18 and 65 inclusive with a body mass index (BMI) between 18 and 33. 2. Females who are able to become pregnant have a negative pregnancy test at screening and baseline, and must agree to use one of the following: * a highly effective form of contraception (ex. Non-oral hormonal, intrauterine device) OR * oral hormonal contraceptive plus one additional form of barrier contraception OR * Two forms of barrier contraception These must be effective by the time of screening. 3. All other females must have been surgically sterilized at least 6 months prior to screening or be postmenopausal (to be confirmed by lab tests). 4. Males must agree to use latex or polyurethane condoms when engaging in sex during the study and for at least 28 days after dosing.
Exclusion criteria
1. Any condition, including the presence of laboratory abnormalities, or psychiatric illness, that would prevent the subject from signing the Informed Consent form, places the subject at unacceptable risk if he were to participate in the study, or confounds the ability to interpret data from the study. 2. Presence of any surgical or medical conditions possibly affecting drug absorption, distribution, metabolism, and excretion, or plans to have elective or medical procedures during the conduct of the trial. 3. 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). 4. Subjects with known serum hepatitis, is a known carrier of hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus antibody. 5. Subjects who have used prescription systemic or topical medications within 30 days of dosing, unless it is being used to treat a stable, chronic medical condition. This includes medication that is an inhibitor or inducer of P-glycoprotein transporter and CYP-3A4/5 used within 14 days of dosing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Total Volume of Distribution When Dosed Orally (Vz/F) of Apremilast | Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing. | Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay. |
| Maximum Observed Plasma Concentration (Cmax) of Apremilast | Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing. | Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay. |
| Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast | Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing. | Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-t) of Apremilast | Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing. | Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay. AUC0-t was calculated using the linear trapezoidal method (linear up log down) when concentrations were increasing and the logarithmic trapezoidal method when concentrations were decreasing. |
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing. | Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay. |
| Estimate of Terminal Elimination Half-life of Apremilast in Plasma (t1/2) | Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing. | Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay. |
| Apparent Total Plasma Clearance When Dosed Orally (CL/F) of Apremilast | Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing. | Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From first dose of study drug in Period 1 up to 5 to 10 days after dosing in Period 2, approximately 20 days. | An adverse event (AE) was any noxious, unintended, or untoward medical occurrence that appeared or worsened in a participant during the course of this study. It could have been 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. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) was considered an AE. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at one clinical research site in the United States.
Pre-assignment details
The study consisted of 2 periods. Participants were randomly assigned to one of two treatment sequences; Fasted then Fed or Fed then Fasted. Each participant was to receive 1 dose of apremilast under fasted conditions and 1 dose of apremilast under fed conditions in each period, respectively, depending on their sequence assignment. There was a 5 to 10 day washout period between each dose.
Participants by arm
| Arm | Count |
|---|---|
| Apremilast Participants received one dose of 30 mg apremilast administered under fasted conditions and one dose of 30 mg apremilast after a full fat meal. | 46 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 | Adverse Event | 0 | 1 |
| Treatment Period 2 | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Apremilast |
|---|---|
| Age, Continuous | 38.5 years STANDARD_DEVIATION 13.45 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 13 Participants |
| Race/Ethnicity, Customized White | 31 Participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 45 | 3 / 46 | 7 / 46 |
| serious Total, serious adverse events | 0 / 45 | 0 / 46 | 0 / 46 |
Outcome results
Primary
Apparent Total Plasma Clearance When Dosed Orally (CL/F) of Apremilast
Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay.
Time frame: Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing.
Population: The PK population included all participants who received at least 1 dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast - Fasted | Apparent Total Plasma Clearance When Dosed Orally (CL/F) of Apremilast | 9499.80 mL/hr | Geometric Coefficient of Variation 34.6 |
| Apremilast - Fed | Apparent Total Plasma Clearance When Dosed Orally (CL/F) of Apremilast | 8556.28 mL/hr | Geometric Coefficient of Variation 33.9 |
Primary
Apparent Total Volume of Distribution When Dosed Orally (Vz/F) of Apremilast
Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay.
Time frame: Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing.
Population: The PK population included all participants who received at least 1 dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast - Fasted | Apparent Total Volume of Distribution When Dosed Orally (Vz/F) of Apremilast | 121735.96 mL | Geometric Coefficient of Variation 38.2 |
| Apremilast - Fed | Apparent Total Volume of Distribution When Dosed Orally (Vz/F) of Apremilast | 98582.15 mL | Geometric Coefficient of Variation 28 |
Primary
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast
Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay.
Time frame: Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing.
Population: The PK population included all participants who received at least 1 dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast - Fasted | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 3157.96 ng*hr/mL | Geometric Coefficient of Variation 34.6 |
| Apremilast - Fed | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Apremilast | 3506.19 ng*hr/mL | Geometric Coefficient of Variation 33.9 |
Comparison: To assess the food effect, an ANOVA with treatment, sequence, and period as fixed effects, and subject nested within sequence as a random effect, was performed on the natural log-transformed AUC0-∞ of apremilast.90% CI: [108.9, 115.1]
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-t) of Apremilast
Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay. AUC0-t was calculated using the linear trapezoidal method (linear up log down) when concentrations were increasing and the logarithmic trapezoidal method when concentrations were decreasing.
Time frame: Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing.
Population: The PK population included all participants who received at least 1 dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast - Fasted | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-t) of Apremilast | 3083.05 ng*hr/mL | Geometric Coefficient of Variation 34 |
| Apremilast - Fed | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-t) of Apremilast | 3436.39 ng*hr/mL | Geometric Coefficient of Variation 33 |
Comparison: To assess the food effect, an analysis of variance model (ANOVA) with treatment, sequence, and period as fixed effects, and subject nested within sequence as a random effect, was performed on the natural log-transformed AUC0-t of apremilast.90% CI: [109.3, 115.6]
Primary
Estimate of Terminal Elimination Half-life of Apremilast in Plasma (t1/2)
Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay.
Time frame: Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing.
Population: The PK population included all participants who received at least 1 dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast - Fasted | Estimate of Terminal Elimination Half-life of Apremilast in Plasma (t1/2) | 8.88 hours | Geometric Coefficient of Variation 21.2 |
| Apremilast - Fed | Estimate of Terminal Elimination Half-life of Apremilast in Plasma (t1/2) | 7.99 hours | Geometric Coefficient of Variation 18.9 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Apremilast
Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay.
Time frame: Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing.
Population: The pharmacokinetic (PK) population included all participants who received at least 1 dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast - Fasted | Maximum Observed Plasma Concentration (Cmax) of Apremilast | 339.86 ng/mL | Geometric Coefficient of Variation 26.5 |
| Apremilast - Fed | Maximum Observed Plasma Concentration (Cmax) of Apremilast | 333.85 ng/mL | Geometric Coefficient of Variation 30 |
Comparison: To assess the food effect, an analysis of variance model (ANOVA) with treatment, sequence, and period as fixed effects, and subject nested within sequence as a random effect, was performed on the natural log-transformed Cmax of apremilast.90% CI: [90.7, 106.6]
Primary
Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast
Plasma concentrations of apremilast were determined by using a validated liquid chromatography-tandem mass spectrometry assay.
Time frame: Day 1 of each treatment period at pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, and 48 hours after dosing.
Population: The PK population included all participants who received at least 1 dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Apremilast - Fasted | Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast | 2.50 hours |
| Apremilast - Fed | Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast | 3.00 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: 0.007790% CI: [0.25, 1.25]Wilcoxon signed-rank test
Secondary
Number of Participants With Adverse Events
An adverse event (AE) was any noxious, unintended, or untoward medical occurrence that appeared or worsened in a participant during the course of this study. It could have been 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. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) was considered an AE.
Time frame: From first dose of study drug in Period 1 up to 5 to 10 days after dosing in Period 2, approximately 20 days.
Population: The safety population included all participants who received at least 1 dose of apremilast.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Apremilast - Fasted | Number of Participants With Adverse Events | Adverse events related to study drug | 4 Participants |
| Apremilast - Fasted | Number of Participants With Adverse Events | Serious adverse events | 0 Participants |
| Apremilast - Fasted | Number of Participants With Adverse Events | Discontinued due to adverse event | 0 Participants |
| Apremilast - Fasted | Number of Participants With Adverse Events | Discontinued due to adverse event related to study drug | 0 Participants |
| Apremilast - Fasted | Number of Participants With Adverse Events | Any adverse event | 9 Participants |
| Apremilast - Fed | Number of Participants With Adverse Events | Adverse events related to study drug | 3 Participants |
| Apremilast - Fed | Number of Participants With Adverse Events | Discontinued due to adverse event related to study drug | 1 Participants |
| Apremilast - Fed | Number of Participants With Adverse Events | Serious adverse events | 0 Participants |
| Apremilast - Fed | Number of Participants With Adverse Events | Any adverse event | 5 Participants |
| Apremilast - Fed | Number of Participants With Adverse Events | Discontinued due to adverse event | 2 Participants |