HIV-1 Infection
Conditions
Brief summary
The present study is designed to determine the effect of islatravir (ISL) \[MK-8591\] on methadone pharmacokinetics (PK). The primary objective is to assess whether ISL impacts the area under the plasma concentration time curve from dosing to 24 hours postdose (AUC0-24) of S-methadone and R-methadone in participants on oral methadone therapy. It is hypothesized that the plasma AUC0-24hr for S- and R-methadone will be similar after methadone alone compared to methadone and ISL 60 mg coadministration.
Interventions
DRUGIslatravir
ISL 30 mg x 2 (60 mg total) capsules taken by mouth.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Has a body mass index (BMI) \> 18 and ≤ 35 kg/m\^2 * Is in good health based on laboratory safety tests obtained at the screening visit and prior to administration of study drug * Is in good health based on medical history, physical examination, vital sign measurements, and electrocardiograms (ECGs) performed prior to randomization. * Has a negative human immunodeficiency virus (HIV) antigen/antibody test at screening * For male participants, follows contraception guidance consistent with local regulations * For female participants: * Is not a woman of childbearing potential (WOCBP) or * Is a WOCBP and using acceptable contraception or is abstinent * Is reliably participating in a methadone maintenance program for at least two (2) months prior to Day 1 * Agrees to not change their current maintenance methadone dose of 20-200 mg administered as a single daily dose
Exclusion criteria
* Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases * Is mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder of the last 5 years * Has a history of cancer (malignancy) * Has a history of significant multiple and/or severe allergies (eg, food, drug, latex) or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic reaction) to prescription or non-prescription drugs or food * Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the screening visit * With the exception of methadone, is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to the first dose of the 14-day methadone maintenance run-in phase prior to Day 1, throughout the trial, until the AE follow-up call (Day 16) * Has participated in another investigational study within 4 weeks (or 5 half-lives) prior to the prestudy (screening) visit. * Has a QTc interval \>450 msec (males) or \>470 msec (females), has a history of risk factors for Torsades de Pointes (eg, heart failure/cardiomyopathy or family history of long QT syndrome), has uncorrected hypokalemia or hypomagnesemia, is taking concomitant medications that prolong the QT/QTc interval other than methadone * Does not limit smoking to no more than 10 cigarettes per day while in the clinical research unit (CRU) * Consumes greater than 3 glasses of alcoholic beverages per day * Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day * With the exception of tetrahydrocannabinol (THC), has a positive screen for drugs with a high potential for abuse such as cocaine, amphetamines, methylenedioxymethamphetamine (MDMA), barbiturates, benzodiazepines (with the exception noted in
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Normalized Area Under the Plasma Concentration Time Curve From 0-24 Hours Postdose (AUC0-24) of R-Methadone | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | The AUC0-24 of R-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean. |
| Dose-Normalized AUC0-24 of S-Methadone | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | The AUC0-24hr of S-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Plasma Concentration (Tmax) of R-Methadone | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | The Tmax of R-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). |
| Dose-Normalized Cmax of S-Methadone | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | The Cmax of S-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean. |
| Dose-Normalized C24 of S-Methadone | Days 1 and 2: 24 hours postdose | The C24 of S-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean. |
| Tmax of S-Methadone | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | The Tmax of S-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). |
| Number of Participants Discontinuing Study Therapy Due to AEs Following Coadministration of Methadone and ISL | Up to 15 days | The number of participants discontinuing study therapy due to AEs after methadone + ISL on Day 2 will be determined. |
| Dose-Normalized Maximum Plasma Concentration (Cmax) of R-Methadone | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | The Cmax of R-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean. |
| Dose-Normalized Cmax of Total Methadone | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | The Cmax of total methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean. |
| Dose-Normalized C24 of Total Methadone | Days 1 and 2: 24 hours postdose | The C24 of total methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean. |
| Tmax of Total Methadone | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | The Tmax of total methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). |
| Number of Participants With Adverse Events (AEs) Following Methadone + ISL Coadministration | Up to 16 days | The number of participants with AEs will be determined for 14 days after coadministration of methadone and ISL on Day 2. |
| Dose-Normalized AUC0-24 of Total Methadone | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | The AUC0-24hr of total methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean. |
| Dose-Normalized Plasma Concentration 24 Hours Postdose (C24) of R-Methadone | Days 1 and 2: 24 hours postdose | The C24 of R-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean. |
Countries
United States
Participant flow
Recruitment details
Methadone-maintained participants were recruited at 2 study sites in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Methadone + ISL Methadone-maintained participants (20 to 200 mg \[locally-provided\] QD from Day -14 to Day -1) receive their usual methadone dose on Day 1 and Days 3 to 14. On Day 2, methadone is coadministered with ISL 60 mg. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Methadone + ISL |
|---|---|
| Age, Continuous | 43.5 Years STANDARD_DEVIATION 12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 14 |
| other Total, other adverse events | 4 / 14 |
| serious Total, serious adverse events | 0 / 14 |
Outcome results
Primary
Dose-Normalized Area Under the Plasma Concentration Time Curve From 0-24 Hours Postdose (AUC0-24) of R-Methadone
The AUC0-24 of R-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean.
Time frame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Methadone + ISL | Dose-Normalized Area Under the Plasma Concentration Time Curve From 0-24 Hours Postdose (AUC0-24) of R-Methadone | Day 1: Methadone Alone | 61.9 ng*h/mL/mg |
| Methadone + ISL | Dose-Normalized Area Under the Plasma Concentration Time Curve From 0-24 Hours Postdose (AUC0-24) of R-Methadone | Day 2: Methadone + ISL | 63.9 ng*h/mL/mg |
90% CI: [1, 1.07]
Primary
Dose-Normalized AUC0-24 of S-Methadone
The AUC0-24hr of S-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean.
Time frame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Methadone + ISL | Dose-Normalized AUC0-24 of S-Methadone | Day 1: Methadone Alone | 63.1 ng*h/mL/mg |
| Methadone + ISL | Dose-Normalized AUC0-24 of S-Methadone | Day 2: Methadone + ISL | 65.1 ng*h/mL/mg |
90% CI: [0.99, 1.07]
Secondary
Dose-Normalized AUC0-24 of Total Methadone
The AUC0-24hr of total methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean.
Time frame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Methadone + ISL | Dose-Normalized AUC0-24 of Total Methadone | Day 1: Methadone Alone | 126 ng*h/mL/mg |
| Methadone + ISL | Dose-Normalized AUC0-24 of Total Methadone | Day 2: Methadone + ISL | 129 ng*h/mL/mg |
90% CI: [0.99, 1.07]
Secondary
Dose-Normalized C24 of S-Methadone
The C24 of S-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean.
Time frame: Days 1 and 2: 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Methadone + ISL | Dose-Normalized C24 of S-Methadone | Day 1: Methadone Alone | 1.91 ng/ml/mg |
| Methadone + ISL | Dose-Normalized C24 of S-Methadone | Day 2: Methadone + ISL | 2.07 ng/ml/mg |
90% CI: [1.04, 1.13]
Secondary
Dose-Normalized C24 of Total Methadone
The C24 of total methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean.
Time frame: Days 1 and 2: 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Methadone + ISL | Dose-Normalized C24 of Total Methadone | Day 1: Methadone Alone | 4.03 ng/ml/mg |
| Methadone + ISL | Dose-Normalized C24 of Total Methadone | Day 2: Methadone + ISL | 4.32 ng/ml/mg |
90% CI: [1.03, 1.11]
Secondary
Dose-Normalized Cmax of S-Methadone
The Cmax of S-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean.
Time frame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Methadone + ISL | Dose-Normalized Cmax of S-Methadone | Day 1: Methadone Alone | 4.25 ng/mL/mg |
| Methadone + ISL | Dose-Normalized Cmax of S-Methadone | Day 2: Methadone + ISL | 4.31 ng/mL/mg |
90% CI: [0.94, 1.09]
Secondary
Dose-Normalized Cmax of Total Methadone
The Cmax of total methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean.
Time frame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Methadone + ISL | Dose-Normalized Cmax of Total Methadone | Day 1: Methadone Alone | 7.91 ng/mL/mg |
| Methadone + ISL | Dose-Normalized Cmax of Total Methadone | Day 2: Methadone + ISL | 8.02 ng/mL/mg |
90% CI: [0.95, 1.08]
Secondary
Dose-Normalized Maximum Plasma Concentration (Cmax) of R-Methadone
The Cmax of R-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean.
Time frame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Methadone + ISL | Dose-Normalized Maximum Plasma Concentration (Cmax) of R-Methadone | Day 1: Methadone Alone | 3.64 ng/mL/mg |
| Methadone + ISL | Dose-Normalized Maximum Plasma Concentration (Cmax) of R-Methadone | Day 2: Methadone + ISL | 3.71 ng/mL/mg |
90% CI: [0.96, 1.09]
Secondary
Dose-Normalized Plasma Concentration 24 Hours Postdose (C24) of R-Methadone
The C24 of R-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). Back-transformed least-squares mean and confidence interval from mixed effects model were performed on natural log-transformed values; data show the geometric least squares mean.
Time frame: Days 1 and 2: 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Methadone + ISL | Dose-Normalized Plasma Concentration 24 Hours Postdose (C24) of R-Methadone | Day 1: Methadone Alone | 2.09 ng/ml/mg |
| Methadone + ISL | Dose-Normalized Plasma Concentration 24 Hours Postdose (C24) of R-Methadone | Day 2: Methadone + ISL | 2.23 ng/ml/mg |
90% CI: [1.03, 1.1]
Secondary
Number of Participants Discontinuing Study Therapy Due to AEs Following Coadministration of Methadone and ISL
The number of participants discontinuing study therapy due to AEs after methadone + ISL on Day 2 will be determined.
Time frame: Up to 15 days
Population: All participants who received ISL on Day 2 are included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methadone + ISL | Number of Participants Discontinuing Study Therapy Due to AEs Following Coadministration of Methadone and ISL | 0 Participants |
Secondary
Number of Participants With Adverse Events (AEs) Following Methadone + ISL Coadministration
The number of participants with AEs will be determined for 14 days after coadministration of methadone and ISL on Day 2.
Time frame: Up to 16 days
Population: All participants who received ISL on Day 2 are included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Methadone + ISL | Number of Participants With Adverse Events (AEs) Following Methadone + ISL Coadministration | 4 Participants |
Secondary
Time to Maximum Plasma Concentration (Tmax) of R-Methadone
The Tmax of R-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL).
Time frame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Methadone + ISL | Time to Maximum Plasma Concentration (Tmax) of R-Methadone | Day 1: Methadone Alone | 2.00 hours |
| Methadone + ISL | Time to Maximum Plasma Concentration (Tmax) of R-Methadone | Day 2: Methadone + ISL | 2.00 hours |
Secondary
Tmax of S-Methadone
The Tmax of S-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL).
Time frame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Methadone + ISL | Tmax of S-Methadone | Day 1: Methadone Alone | 1.50 hours |
| Methadone + ISL | Tmax of S-Methadone | Day 2:Methadone + ISL | 2.00 hours |
Secondary
Tmax of Total Methadone
The Tmax of total methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL).
Time frame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
Population: All participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Methadone + ISL | Tmax of Total Methadone | Day 1: Methadone Alone | 2.00 hours |
| Methadone + ISL | Tmax of Total Methadone | Day 2: Methadone + ISL | 2.00 hours |