Islatravir and Methadone Pharmacokinetics (MK-8591-029)

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

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.

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Islatravir

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Hollywood, Florida, United States, 33024
      • Research Centers of America, LLC ( Site 0002)
  • Utah
    • Salt Lake City, Utah, United States, 84124
      • PRA Health Sciences ( Site 0001)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methadone + ISL; 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; ISL 30 mg x 2 (60 mg total) capsules taken by mouth.; Other Names: MK-8591

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2020
• Primary Completion (Actual): July 9, 2021
• Study Completion (Actual): July 9, 2021

Study Registration Dates

• First Submitted: September 23, 2020
• First Submitted That Met QC Criteria: September 23, 2020
• First Posted (Actual): September 29, 2020

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: March 28, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Retroviral Agents; Islatravir
• Other Study ID Numbers: 8591-029; MK-8591-029 (Other Identifier: Merck Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No