Healthy Subjects
Conditions
Keywords
Apremilast, drug interaction, pharmacokinetics
Brief summary
The purpose of this study is to evaluate how the pharmacokinetics of apremilast may be affected by a single intravenous dose of rifampin and multiple oral doses of rifampin.
Interventions
DRUGApremilast
Tablets for oral administration
Capsules for oral administration
DRUGRifampin IV Solution
Intravenous (IV) solution
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female subjects of any ethnic origin between ages of 18 and 55 with a body mass index between 18 and 33
Exclusion criteria
* Recent history (i.e., within 3 years) of any clinically significant neurological, gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, endocrine, hematological, dermatological, psychological, allergic or other major disorders. * Use of any prescribed or non-prescribed systemic or topical medication (including vitamins and herbal medicines, e.g. St. John's Wort) within 30 days of the first dose, unless an exception is granted by the sponsor. * 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. * Exposure to an investigational drug (new chemical entity) within 30 days prior to the first dose administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUCt) of Apremilast | Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20 | Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay. |
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC∞) of Apremilast | Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20 | Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay. |
| Maximum Observed Plasma Concentration (Cmax) of Apremilast | Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20 | Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay. |
| Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast | Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20 | Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay. |
| Estimate of the Terminal Elimination Half-life (T1/2) of Apremilast in Plasma | Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20 | Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay. |
| Apparent Total Plasma Clearance (CL/F) of Apremilast | Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20 | Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay. |
| Apparent Volume of Distribution (Vz/F) of Apremilast | Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20 | Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at one clinical site in Overland Park, Kansas, USA.
Participants by arm
| Arm | Count |
|---|---|
| Apremilast and Rifampin Participants received the following 3 treatment regimens:
Period 1: A single oral dose of 30 mg apremilast on Day 1; Period 2: A single oral dose of 30 mg apremilast followed 5 minutes later by a 30-minute intravenous infusion of 600 mg rifampin on Day 5; Period 3: Once daily oral doses of 600 mg rifampin for 15 days (from Day 7 to Day 21) with a single oral dose of 30 mg apremilast co-administered with the rifampin dose on Day 20. | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Apremilast and Rifampin |
|---|---|
| Age, Continuous | 34 years STANDARD_DEVIATION 9.6 |
| Body Mass Index (BMI) | 29.14 kg/m² STANDARD_DEVIATION 2.974 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants |
| Race/Ethnicity, Customized White | 12 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 21 | 4 / 20 | 9 / 20 | 12 / 21 |
| serious Total, serious adverse events | 0 / 21 | 0 / 20 | 0 / 20 | 0 / 21 |
Outcome results
Primary
Apparent Total Plasma Clearance (CL/F) of Apremilast
Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20
Population: The pharmacokinetic population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast Alone | Apparent Total Plasma Clearance (CL/F) of Apremilast | 9.60 L/h | Geometric Coefficient of Variation 31.5 |
| Apremilast + IV Rifampin | Apparent Total Plasma Clearance (CL/F) of Apremilast | 10.1 L/h | Geometric Coefficient of Variation 31.2 |
| Apremilast + Multiple Dose Oral Rifampin | Apparent Total Plasma Clearance (CL/F) of Apremilast | 34.5 L/h | Geometric Coefficient of Variation 32.9 |
Primary
Apparent Volume of Distribution (Vz/F) of Apremilast
Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20
Population: The pharmacokinetic population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast Alone | Apparent Volume of Distribution (Vz/F) of Apremilast | 112 liters | Geometric Coefficient of Variation 35.8 |
| Apremilast + IV Rifampin | Apparent Volume of Distribution (Vz/F) of Apremilast | 107 liters | Geometric Coefficient of Variation 43.4 |
| Apremilast + Multiple Dose Oral Rifampin | Apparent Volume of Distribution (Vz/F) of Apremilast | 305 liters | Geometric Coefficient of Variation 51.6 |
Primary
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC∞) of Apremilast
Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20
Population: The pharmacokinetic population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast Alone | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC∞) of Apremilast | 3120 ng*h/mL | Geometric Coefficient of Variation 31.5 |
| Apremilast + IV Rifampin | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC∞) of Apremilast | 2980 ng*h/mL | Geometric Coefficient of Variation 31.2 |
| Apremilast + Multiple Dose Oral Rifampin | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC∞) of Apremilast | 869 ng*h/mL | Geometric Coefficient of Variation 32.9 |
Comparison: The effect of rifampicin on the PK of apremilast was evaluated using a linear mixed effect analysis of variance on the log-transformed values of AUC∞ of apremilast, to estimate the mean ratio of apremilast administered with and without rifampicin treatment. The model included treatment as fixed effect, and subject as a random effect.90% CI: [87.99, 104.12]
Comparison: The effect of rifampicin on the PK of apremilast was evaluated using a linear mixed effect analysis of variance on the log-transformed values of AUC∞ of apremilast, to estimate the mean ratio of apremilast administered with and without rifampicin treatment. The model included treatment as fixed effect, and subject as a random effect.90% CI: [25.7, 30.41]
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUCt) of Apremilast
Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20
Population: The pharmacokinetic population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast Alone | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUCt) of Apremilast | 3070 ng*h/mL | Geometric Coefficient of Variation 31.3 |
| Apremilast + IV Rifampin | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUCt) of Apremilast | 2940 ng*h/mL | Geometric Coefficient of Variation 31.3 |
| Apremilast + Multiple Dose Oral Rifampin | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUCt) of Apremilast | 850 ng*h/mL | Geometric Coefficient of Variation 33.7 |
Comparison: The effect of rifampicin on the PK of apremilast was evaluated using a linear mixed effect analysis of variance on the log-transformed values of AUCt of apremilast, to estimate the mean ratio of apremilast administered with and without rifampicin treatment. The model included treatment as fixed effect, and subject as a random effect.90% CI: [88.56, 104.82]
Comparison: The effect of rifampicin on the PK of apremilast was evaluated using a linear mixed effect analysis of variance on the log-transformed values of AUCt of apremilast, to estimate the mean ratio of apremilast administered with and without rifampicin treatment. The model included treatment as fixed effect, and subject as a random effect.90% CI: [25.63, 30.34]
Primary
Estimate of the Terminal Elimination Half-life (T1/2) of Apremilast in Plasma
Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20
Population: The pharmacokinetic population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast Alone | Estimate of the Terminal Elimination Half-life (T1/2) of Apremilast in Plasma | 8.12 hours | Geometric Coefficient of Variation 14.1 |
| Apremilast + IV Rifampin | Estimate of the Terminal Elimination Half-life (T1/2) of Apremilast in Plasma | 7.35 hours | Geometric Coefficient of Variation 18.5 |
| Apremilast + Multiple Dose Oral Rifampin | Estimate of the Terminal Elimination Half-life (T1/2) of Apremilast in Plasma | 6.13 hours | Geometric Coefficient of Variation 24.8 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Apremilast
Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20
Population: The pharmacokinetic population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apremilast Alone | Maximum Observed Plasma Concentration (Cmax) of Apremilast | 290 ng/mL | Geometric Coefficient of Variation 24.5 |
| Apremilast + IV Rifampin | Maximum Observed Plasma Concentration (Cmax) of Apremilast | 331 ng/mL | Geometric Coefficient of Variation 25.1 |
| Apremilast + Multiple Dose Oral Rifampin | Maximum Observed Plasma Concentration (Cmax) of Apremilast | 166 ng/mL | Geometric Coefficient of Variation 23.2 |
Comparison: The effect of rifampicin on the PK of apremilast was evaluated using a linear mixed effect analysis of variance on the log-transformed values of Cmax of apremilast, to estimate the mean ratio of apremilast administered with and without rifampicin treatment. The model included treatment as fixed effect, and subject as a random effect.90% CI: [103.18, 123.91]
Comparison: The effect of rifampicin on the PK of apremilast was evaluated using a linear mixed effect analysis of variance on the log-transformed values of Cmax of apremilast, to estimate the mean ratio of apremilast administered with and without rifampicin treatment. The model included treatment as fixed effect, and subject as a random effect.90% CI: [51.84, 62.25]
Primary
Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast
Plasma concentrations of apremilast were determined by means of a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometric (LC-MS/MS) assay.
Time frame: Pre-dose and at 0.5, 1, 1.5, 2, 3, 5, 8, 12, 16, 24, 36, and 48 hours following apremilast dosing on Days 1, 5, and 20
Population: The pharmacokinetic population included all participants who received at least one dose of apremilast and had evaluable PK profiles.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Apremilast Alone | Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast | 2.00 hours |
| Apremilast + IV Rifampin | Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast | 1.50 hours |
| Apremilast + Multiple Dose Oral Rifampin | Time to Maximum Observed Plasma Concentration (Tmax) of Apremilast | 1.00 hours |
Comparison: Tmax was analyzed using nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.265690% CI: [-0.75, 0]Wilcoxon signed rank test
Comparison: Tmax was analyzed using nonparametric methods. The median difference and 90% CI of the median difference were calculated from the Hodges-Lehrmann estimate.p-value: 0.114190% CI: [-1, 0]Wilcoxon signed rank test