Islatravir and Methadone Pharmacokinetics (MK-8591-029)

Study Overview
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Brief Summary
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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.

Official Title
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A Clinical Trial to Study the Effect of a Single Dose of Islatravir (MK-8591) on the Pharmacokinetics of Methadone

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Islatravir


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria 7), or opiates/opioids on Day -1 Presents any concern by the investigator regarding safe participation in the study or for any other reason the investigator considers the participant inappropriate for participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methadone + ISL<br>Methadone-maintained participants (20 to 200 mg [locally-provided] once daily [QD] from Day -14 to Day -1 and Day 10 to Day 15) receive methadone 20 to 200 mg QD on Day 1 to Day 9; ISL 60 mg is co-administered with methadone on Day 2. | Drug: Islatravir<br>* ISL 30 mg x 2 (60 mg total) capsules taken by mouth.<br>* Other names: MK-8591;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | 
| 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. | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | 
| 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. | Days 1 and 2: 24 hours postdose | 
| 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). | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | 
| 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. | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | 
| 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. | Days 1 and 2: 24 hours postdose | 
| Tmax of S-Methadone | The Tmax of S-methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | 
| 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. | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | 
| 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. | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | 
| 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. | Days 1 and 2: 24 hours postdose | 
| Tmax of Total Methadone | The Tmax of total methadone was determined on Day 1 (methadone) and Day 2 (methadone + ISL). | Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose | 
| 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. | Up to 16 days | 
| 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. | Up to 15 days |