Hepatitis C Virus
Conditions
Brief summary
In this study, participants on methadone or buprenorphine/naloxone maintenance therapy will be given boceprevir. Blood samples will be taken at specified intervals to find out whether boceprevir affects the pharmacokinetics of methadone, buprenorphine, or naloxone.
Interventions
DRUGboceprevir
boceprevir 800 mg (4 x 200 mg capsules), orally, every 8 hours, Day 2 through Day 7
DRUGmethadone
methadone, 20-150 mg tablets, liquid, or disket, orally, once per day, Day 1 through Day 8
DRUGbuprenorphine/naloxone
buprenorphine/naloxone 8/2-24/6 mg, tablets, sublingual, once per day, Day 1 through Day 8
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Body Mass Index (BMI) between 18 and 36, inclusive * Reliable participation in a methadone maintenance or buprenorphine maintenance or buprenorphine/naloxone maintenance program for at least two (2) months prior to Day 1. * Is receiving once daily oral dose of methadone therapy at a stable individualized dose for at least 4 weeks, receiving once daily buprenorphine dose at a stable individualized dose for at 4 weeks with, if on buprenorphine only therapy, naloxone added for at least 2 weeks prior to Day 1. * 12-lead electrocardiogram (ECG) conduction intervals within gender-specific normal range * Vital signs within normal range * Clinical laboratory tests within normal range * Women who are postmenopausal, surgically sterilized, or premenopausal and use a medically-accepted method of contraception.
Exclusion criteria
* Pregnancy, breast feeding, or intention to become pregnant or father a child while on study or within 3 months after end of trial * History or presence of inflammatory bowel disease, ulcers, or gastrointestinal or rectal bleeding * History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection * History of pancreatic injury or pancreatitis * History or presence of liver disease or liver injury * History or presence of impaired renal function * History of urinary obstruction or difficulty in voiding * 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 * Positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV) * Positive screen for drugs with a high potential for abuse such as cocaine, amphetamines, methylenedioxymethamphetamine (MDMA), barbiturates, benzodiazepines, or opiates/opioids * Excessive use of alcohol in the 2 weeks prior to Day -1, defined as greater than 3 glasses of alcoholic beverages (1 is approximately equivalent to: beer \[284 mL/10 oz\], wine \[125 mL/4 oz\], or distilled spirits \[25 mL/1 oz\]) per day. * Blood donation in the past 60 days * Previous administration of SCH 503034 (boceprevir) * Current participation in another clinical study or participation in a clinical study (e.g., laboratory or clinical evaluation) within 30 days of baseline * Study staff personnel or family members of the study staff personnel * Demonstrated allergic reactions (eg, food, drug, atopic reactions or asthmatic episodes) that, in the opinion of the investigator and sponsor, interfere with their ability to participate in the trial * History of malignancy within 5 years from Screening * Consumption of excessive amounts (equivalent to \> 6 cups of brewed coffee/day) of coffee, tea, cola or other caffeinated beverages * Receipt of any of the following more recently than the washout period prior to Baseline: inhibitors or inducers of cytochrome (CYP) P450, CYP2B6, CYP3A4, and CYP2D6; or oral contraceptives containing drospirenone
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration Versus Time Curve (AUC) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir | Methadone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and methadone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6. | AUC is a measure of the amount of drug in the blood over time, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for methadone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for methadone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for methadone + boceprevir. |
| Maximum Concentration (Cmax) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir | Methadone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and methadone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6. | Cmax is a measure of the maximum level of drug in the blood, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for methadone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for methadone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for methadone + boceprevir. |
| AUC of Buprenorphine (Administered in Combination With Naloxone) at Steady State With or Without Boceprevir | Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6. | AUC is a measure of the amount of drug in the blood over time, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir. |
| Cmax of Buprenorphine (Administered in Combination With Naloxone) at Steady State With or Without Boceprevir | Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6. | Cmax is a measure of the maximum level of drug in the blood, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC of Naloxone (Administered in Combination With Buprenorphine) at Steady State With or Without Boceprevir | Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6. | AUC is a measure of the amount of drug in the blood over time, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir. |
| Cmax of Naloxone (Administered in Combination With Buprenorphine) at Steady State With or Without Boceprevir | Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6. | Cmax is a measure of the maximum level of drug in the blood, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Methadone + Boceprevir Participants receive standard methadone maintenance therapy (20-150 mg tablets, liquid, or disket, orally, once per day) on Days 1 through 8 + boceprevir (800 mg \[4 x 200 mg capsules\], orally, every 8 hours) on Days 2 through 7) | 10 |
| Buprenorphine/Naloxone + Boceprevir Participants receive standard buprenorphine/naloxone maintenance therapy (8/2-24/6 mg, tablets, sublingual, once per day) on Days 1 through 8 + boceprevir (800 mg \[4 x 200 mg capsules\], orally, every 8 hours) on Days 2 through 7 | 11 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Non-compliance with protocol | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Methadone + Boceprevir | Buprenorphine/Naloxone + Boceprevir | Total |
|---|---|---|---|
| Age, Continuous | 34.2 years STANDARD_DEVIATION 10.2 | 33.2 years STANDARD_DEVIATION 29 | 33.7 years STANDARD_DEVIATION 10.1 |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 9 / 11 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 |
Outcome results
Primary
Area Under the Concentration Versus Time Curve (AUC) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir
AUC is a measure of the amount of drug in the blood over time, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for methadone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for methadone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for methadone + boceprevir.
Time frame: Methadone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and methadone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.
Population: All participants receiving standard methadone maintenance therapy + boceprevir
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Methadone Alone | Area Under the Concentration Versus Time Curve (AUC) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir | R-methadone | 50.1 (ng.hr/mL)/mg | Geometric Coefficient of Variation 29 |
| Methadone Alone | Area Under the Concentration Versus Time Curve (AUC) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir | S-methadone | 56.9 (ng.hr/mL)/mg | Geometric Coefficient of Variation 52 |
| Methadone + Boceprevir | Area Under the Concentration Versus Time Curve (AUC) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir | R-methadone | 42.4 (ng.hr/mL)/mg | Geometric Coefficient of Variation 23 |
| Methadone + Boceprevir | Area Under the Concentration Versus Time Curve (AUC) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir | S-methadone | 44.6 (ng.hr/mL)/mg | Geometric Coefficient of Variation 43 |
Primary
AUC of Buprenorphine (Administered in Combination With Naloxone) at Steady State With or Without Boceprevir
AUC is a measure of the amount of drug in the blood over time, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir.
Time frame: Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.
Population: All participants on Day 1; 2 participants were discontinued from study (Days 2-8).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Methadone Alone | AUC of Buprenorphine (Administered in Combination With Naloxone) at Steady State With or Without Boceprevir | 3020 (pg.hr/mL)/mg | Geometric Coefficient of Variation 55 |
| Methadone + Boceprevir | AUC of Buprenorphine (Administered in Combination With Naloxone) at Steady State With or Without Boceprevir | 4040 (pg.hr/mL)/mg | Geometric Coefficient of Variation 43 |
Primary
Cmax of Buprenorphine (Administered in Combination With Naloxone) at Steady State With or Without Boceprevir
Cmax is a measure of the maximum level of drug in the blood, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir.
Time frame: Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.
Population: All participants on Day 1; 1 participant discontinued from study on Day 6.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Methadone Alone | Cmax of Buprenorphine (Administered in Combination With Naloxone) at Steady State With or Without Boceprevir | 440 (pg/mL)/mg | Geometric Coefficient of Variation 52 |
| Methadone + Boceprevir | Cmax of Buprenorphine (Administered in Combination With Naloxone) at Steady State With or Without Boceprevir | 545 (pg/mL)/mg | Geometric Coefficient of Variation 45 |
Primary
Maximum Concentration (Cmax) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir
Cmax is a measure of the maximum level of drug in the blood, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for methadone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for methadone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for methadone + boceprevir.
Time frame: Methadone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and methadone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.
Population: All participants receiving standard methadone maintenance therapy + boceprevir
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Methadone Alone | Maximum Concentration (Cmax) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir | R-methadone | 2.94 (ng/mL)/mg | Geometric Coefficient of Variation 22 |
| Methadone Alone | Maximum Concentration (Cmax) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir | S-methadone | 3.69 (ng/mL)/mg | Geometric Coefficient of Variation 39 |
| Methadone + Boceprevir | Maximum Concentration (Cmax) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir | R-methadone | 2.63 (ng/mL)/mg | Geometric Coefficient of Variation 59 |
| Methadone + Boceprevir | Maximum Concentration (Cmax) at Steady State of Methadone Enantiomers When Administered With or Without Boceprevir | S-methadone | 3.07 (ng/mL)/mg | Geometric Coefficient of Variation 69 |
Secondary
AUC of Naloxone (Administered in Combination With Buprenorphine) at Steady State With or Without Boceprevir
AUC is a measure of the amount of drug in the blood over time, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir.
Time frame: Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.
Population: All participants on Day 1; 2 participants were discontinued from study (Days 2-8).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Methadone Alone | AUC of Naloxone (Administered in Combination With Buprenorphine) at Steady State With or Without Boceprevir | 157 (pg.hr/mL)/mg | Geometric Coefficient of Variation 62 |
| Methadone + Boceprevir | AUC of Naloxone (Administered in Combination With Buprenorphine) at Steady State With or Without Boceprevir | 224 (pg.hr/mL)/mg | Geometric Coefficient of Variation 56 |
Secondary
Cmax of Naloxone (Administered in Combination With Buprenorphine) at Steady State With or Without Boceprevir
Cmax is a measure of the maximum level of drug in the blood, measured at steady state (time at which the amount of drug eliminated by the body is in equilibrium with the amount taken in). The Day 1, 0 through 24 hour samples were for buprenorphine/naloxone levels in the absence of boceprevir co-administration. The Day 7, 0 through 24 hour samples were for buprenorphine/naloxone levels in the presence of boceprevir co-administration. The Day 5 and 6 predose samples were to check steady state for buprenorphine/naloxone + boceprevir.
Time frame: Buprenorphine/naloxone samples collected Day 1, 0 (predose) through 24 hours post-dose (Day 2). Boceprevir and buprenorphine/naloxone samples collected Day 7, 0 (predose) through 24 hours post-dose (Day 8). Predose samples also collected on Days 5-6.
Population: All participants on Day 1; 1 participant discontinued on Day 6.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Methadone Alone | Cmax of Naloxone (Administered in Combination With Buprenorphine) at Steady State With or Without Boceprevir | 58.5 (pg/mL)/mg | Geometric Coefficient of Variation 87 |
| Methadone + Boceprevir | Cmax of Naloxone (Administered in Combination With Buprenorphine) at Steady State With or Without Boceprevir | 65.2 (pg/mL)/mg | Geometric Coefficient of Variation 70 |