Hepatitis C
Conditions
Keywords
boceprevir, hepatitis C, bioequivalence, SCH 503034
Brief summary
This is a single-dose, randomized, cross-sectional comparison study examining the relative safety and resulting blood level profiles after administration of a new boceprevir tablet formulation versus its current capsule formulation for treatment of chronic hepatitis C. In Part 1 of the study participants will receive boceprevir tablets and capsules under fed conditions. In Part 2 of the study a new group of participants will receive boceprevir tablets and capsules under fasted conditions.
Interventions
DRUGboceprevir
Boceprevir (tablet or capsule) at 800 mg administered under either fed or fasted conditions.
Sponsors
Merck Sharp & Dohme LLC
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
* Subjects must be willing to give written informed consent for the trial and able to adhere to dose and visit schedules. * Subjects must be willing to give written informed consent for pharmacogenetic testing, and able to adhere to applicable visit schedules. \- Subjects of either gender and of any race between the ages of 18 and 65 years, inclusive, having a Body Mass Index (BMI) between 18 and 32, inclusive. BMI = weight (kg)/height (m)\^2. (Individuals with values outside (or indicate lower or higher) of these ranges may be enrolled if clinically acceptable to the investigator and sponsor.) * Subjects' clinical laboratory tests (complete blood count \[CBC\], blood chemistry, and urinalysis) must be within normal limits or clinically acceptable to the investigator and within an allowed expanded range supplied by sponsor. However, subject's liver function test results (ie, aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\]) must not be elevated above normal limits at Screening and on Day -1. No rescreening of liver function tests will be allowed. * Subjects must be free of any clinically significant disease that would interfere with the study evaluations. * The Screening 12 lead electrocardiogram \[ECG\] conduction intervals must be within gender specific normal range (e.g, ECG QTcB,measure in males ≤430 msec and QTcB measure in females ≤450 msec, PR interval ≤200 msec). * Vital sign measurements (taken after \ 3 minutes in a sitting position) must be within the following ranges: (Individuals with values outside of these ranges may be enrolled if clinically acceptable to the investigator and sponsor.) 1. oral body temperature, between 35.0°C and 37.5°C 2. systolic blood pressure, 90 to 140 mm Hg 3. diastolic blood pressure, 45 to 90 mm Hg 4. pulse rate, 40 to 100 bpm * Female subjects must be: <!-- --> 1. postmenopausal (defined as 12 months with no menses, age \> 40 years and with a follicle-stimulating hormone \[FSH\] level of \>40 u/mL, and serum E2 \< 73 pmol/L), or 2. surgically sterilized at least 3 months prior to baseline (eg, documented hysterectomy or tubal ligation), or 3. premenopausal and if unsterilized must have used a medically accepted method of contraception for 3 months (or abstained from sexual intercourse) prior to the screening period, and agree to use a medically accepted method of contraception during the trial (including the screening period prior to receiving trial medication) and for 2 months after stopping the trial medication. An acceptable method of contraception includes one of the following: i. stable oral, transdermal, injectable, or sustained-release vaginal hormonal contraceptive regimen without breakthrough uterine bleeding for 3 months prior to Screening; in addition, during study use of condom and/or spermicide (when marketed in the country). ii. intrauterine device (inserted at least 2 months prior to Screening visit); in addition, during study use of condom and/or spermicide (when marketed in the country). iii. condom (male or female) with spermicide (when marketed within the country), iv. diaphragm or cervical cap with spermicide (when marketed within the country) and condom (male), \- Non-vasectomized men must agree to use a condom with spermicide or abstain from sexual intercourse, during the trial and for 1 month after stopping the medication.
Exclusion criteria
* Female subjects who are pregnant, intend to become pregnant (within 3 months of ending the study), or are breastfeeding. * Subjects who, in the opinion of the investigator, will not be able to participate optimally in the study. * Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of any drug. The investigator should be guided by evidence of any of the following, and be discussed with the sponsor prior to enrollment into the trial: 1. history or presence of inflammatory bowel disease, ulcers, gastrointestinal or rectal bleeding; 2. history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection; 3. history of pancreatic injury or pancreatitis; 4. history or presence of liver disease or liver injury; 5. history or presence of impaired renal function as indicated by clinically significant elevation in creatinine, blood urea nitrogen \[BUN\]/urea, urinary albumin, or clinically significant urinary cellular constituents ; or 6. history of urinary obstruction or difficulty in voiding. \- Subject who has a history of any infectious disease within 4 weeks prior to drug administration that in the opinion of the investigator, affects the subject's ability to participate in the trial. * Subjects who are positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus \[HIV\]. \- Subjects who have a positive screen for drugs with a high potential for abuse (during the Screening period or clinical conduct of the trial). \- Subjects with a history of psychiatric or personality disorders that in the opinion of the investigator and sponsor, affects the subject's ability to participate in the trial. \- Subjects with a history of alcohol or drug abuse in the past 2 years.- Subjects who have donated blood in the past 60 days. \- Subjects who have previously received boceprevir. * Subjects who are currently participating in another clinical study or have participated in a clinical study (e.g., laboratory or clinical evaluation) within 30 days of baseline. \- Subjects who are part of the study staff personnel or family members of the study staff personnel. * Subjects who have demonstrated allergic reactions (eg, food, drug, atopic reactions or asthmatic episodes) which, in the opinion of the investigator and sponsor, interfere with their ability to participate in the trial. \- Subjects who smoke more than 10 cigarettes or equivalent tobacco use per day. * Subjects who have a history of malignancy. * Subjects who have received any prohibited treatment (prescription and non prescription medication except acetaminophen, potent inhibitors and inducers of cytochrome P3A \[CYP3A4\], or vitamins and herbals) more recently than the indicated washout period prior to Randomization which, in the opinion of the investigator and sponsor, interferes with their ability to participate in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration Curve (AUC) From Hour 0 to the Final Quantifiable Sample (AUCtf) for Boceprevir Tablets Versus Capsules in Fed State | Predose through 72 hours post-dose | AUC is the measure of total plasma exposure of a drug over a given time period. AUC is derived from the area under the plasma drug concentration-time curve. |
| Maximum Plasma Concentration (Cmax) of Boceprevir Tablets Versus Capsules in Fed State | Predose through 72 hours post-dose | Cmax is the highest plasma drug concentration observed on the plasma concentration-time curve. |
| AUCtf for Boceprevir Tablets Versus Capsules in Fasted State | Predose through 72 hours post-dose | AUC is the measure of total plasma exposure of a drug over a given time period. AUC is derived from the area under the plasma drug concentration-time curve. |
| Cmax of Boceprevir Tablets Versus Capsules in Fasted State | Predose through 72 hours post-dose | Cmax is the highest plasma drug concentration observed on the plasma concentration-time curve. |
| AUC From Hour 0 to Infinity (AUCinf) in Fed State | Predose through 72 hours post-dose | AUC is the measure of total plasma exposure of a drug over a given time period. AUC is derived from the area under the plasma drug concentration-time curve. |
| AUCinf in Fasted State | Predose through 72 hours post-dose | AUC is the measure of total plasma exposure of a drug over a given time period. AUC is derived from the area under the plasma drug concentration-time curve. |
| Half Life (t1/2) of Boceprevir in Fed State | Predose through 72 hours post-dose | T1/2 is the time required for a given drug concentration to decrease by 50%. |
| t1/2 Boceprevir in Fasted State | Predose through 72 hours post-dose | T1/2 is the time required for a given drug concentration to decrease by 50%. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Boceprevir Tablets Then Capsules (Fed) Participants will start therapy with a single dose of boceprevir tablets, orally, in fed condition, and then 4 days later will take a single dose of boceprevir capsules, orally, in fed condition. | 30 |
| Boceprevir Capsules Then Tablets (Fed) Participants will start therapy with a single dose of boceprevir capsules, orally, in fed condition, and then 4 days later will take a single dose of boceprevir tablets, orally, in fed condition. | 30 |
| Boceprevir Tablets Then Capsules (Fasted) Participants will start therapy with a single dose of boceprevir tablets, orally, following an overnight fast and then 4 days later will receive a single dose of boceprevir capsules, orally, following and overnight fast. | 59 |
| Boceprevir Capsules Then Tablets (Fasted) Participants will start therapy with a single dose of boceprevir capsules, orally, following an overnight fast and then 4 days later will receive a single dose of boceprevir tablets, orally, following and overnight fast. | 58 |
| Total | 177 |
Baseline characteristics
| Characteristic | Boceprevir Tablets Then Capsules (Fed) | Boceprevir Capsules Then Tablets (Fed) | Boceprevir Tablets Then Capsules (Fasted) | Boceprevir Capsules Then Tablets (Fasted) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 30 Participants | 59 Participants | 58 Participants | 177 Participants |
| Sex: Female, Male Female | 10 Participants | 18 Participants | 27 Participants | 39 Participants | 94 Participants |
| Sex: Female, Male Male | 20 Participants | 12 Participants | 32 Participants | 19 Participants | 83 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 | 13 / 60 | 6 / 60 | 7 / 117 | 5 / 117 |
| serious Total, serious adverse events | 0 / 60 | 0 / 60 | 0 / 117 | 0 / 117 |
Outcome results
Primary
Area Under the Concentration Curve (AUC) From Hour 0 to the Final Quantifiable Sample (AUCtf) for Boceprevir Tablets Versus Capsules in Fed State
AUC is the measure of total plasma exposure of a drug over a given time period. AUC is derived from the area under the plasma drug concentration-time curve.
Time frame: Predose through 72 hours post-dose
Population: Analysis is per protocol; all available data are included in the model. No imputation is used for missing data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Boceprevir Tablets (Fed) | Area Under the Concentration Curve (AUC) From Hour 0 to the Final Quantifiable Sample (AUCtf) for Boceprevir Tablets Versus Capsules in Fed State | 7385 ng*hr/mL |
| Boceprevir Capsules (Fed) | Area Under the Concentration Curve (AUC) From Hour 0 to the Final Quantifiable Sample (AUCtf) for Boceprevir Tablets Versus Capsules in Fed State | 6644 ng*hr/mL |
90% CI: [1.07, 1.15]ANOVA
Primary
AUC From Hour 0 to Infinity (AUCinf) in Fed State
AUC is the measure of total plasma exposure of a drug over a given time period. AUC is derived from the area under the plasma drug concentration-time curve.
Time frame: Predose through 72 hours post-dose
Population: Analysis is per protocol; all available data are included in the model. No imputation is used for missing data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Boceprevir Tablets (Fed) | AUC From Hour 0 to Infinity (AUCinf) in Fed State | 7457 ng*hr/mL |
| Boceprevir Capsules (Fed) | AUC From Hour 0 to Infinity (AUCinf) in Fed State | 6879 ng*hr/mL |
Primary
AUCinf in Fasted State
AUC is the measure of total plasma exposure of a drug over a given time period. AUC is derived from the area under the plasma drug concentration-time curve.
Time frame: Predose through 72 hours post-dose
Population: Analysis is per protocol; all available data are included in the model. No imputation is used for missing data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Boceprevir Tablets (Fed) | AUCinf in Fasted State | 4534 ng*hr/mL |
| Boceprevir Capsules (Fed) | AUCinf in Fasted State | 4119 ng*hr/mL |
Primary
AUCtf for Boceprevir Tablets Versus Capsules in Fasted State
AUC is the measure of total plasma exposure of a drug over a given time period. AUC is derived from the area under the plasma drug concentration-time curve.
Time frame: Predose through 72 hours post-dose
Population: Analysis is per protocol; all available data are included in the model. No imputation is used for missing data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Boceprevir Tablets (Fed) | AUCtf for Boceprevir Tablets Versus Capsules in Fasted State | 4329 ng*hr/mL |
| Boceprevir Capsules (Fed) | AUCtf for Boceprevir Tablets Versus Capsules in Fasted State | 3935 ng*hr/mL |
95% CI: [1.06, 1.14]ANOVA
Primary
Cmax of Boceprevir Tablets Versus Capsules in Fasted State
Cmax is the highest plasma drug concentration observed on the plasma concentration-time curve.
Time frame: Predose through 72 hours post-dose
Population: Analysis is per protocol; all available data are included in the model. No imputation is used for missing data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Boceprevir Tablets (Fed) | Cmax of Boceprevir Tablets Versus Capsules in Fasted State | 1263 ng/mL |
| Boceprevir Capsules (Fed) | Cmax of Boceprevir Tablets Versus Capsules in Fasted State | 1103 ng/mL |
90% CI: [1.09, 1.21]ANOVA
Primary
Half Life (t1/2) of Boceprevir in Fed State
T1/2 is the time required for a given drug concentration to decrease by 50%.
Time frame: Predose through 72 hours post-dose
Population: Analysis is per protocol; all available data are included in the model. No imputation is used for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Boceprevir Tablets (Fed) | Half Life (t1/2) of Boceprevir in Fed State | 1.61 hours | Standard Deviation 0.46 |
| Boceprevir Capsules (Fed) | Half Life (t1/2) of Boceprevir in Fed State | 1.46 hours | Standard Deviation 0.34 |
Primary
Maximum Plasma Concentration (Cmax) of Boceprevir Tablets Versus Capsules in Fed State
Cmax is the highest plasma drug concentration observed on the plasma concentration-time curve.
Time frame: Predose through 72 hours post-dose
Population: Analysis is per protocol; all available data are included in the model. No imputation is used for missing data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Boceprevir Tablets (Fed) | Maximum Plasma Concentration (Cmax) of Boceprevir Tablets Versus Capsules in Fed State | 2161 ng*hr/mL |
| Boceprevir Capsules (Fed) | Maximum Plasma Concentration (Cmax) of Boceprevir Tablets Versus Capsules in Fed State | 1515 ng*hr/mL |
90% CI: [1.32, 1.54]ANOVA
Primary
t1/2 Boceprevir in Fasted State
T1/2 is the time required for a given drug concentration to decrease by 50%.
Time frame: Predose through 72 hours post-dose
Population: Analysis is per protocol; all available data are included in the model. No imputation is used for missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Boceprevir Tablets (Fed) | t1/2 Boceprevir in Fasted State | 5.33 hours | Standard Deviation 0.73 |
| Boceprevir Capsules (Fed) | t1/2 Boceprevir in Fasted State | 6.39 hours | Standard Deviation 0.84 |