Clinical trial NCT04568603: Islatravir and Methadone Pharmacokinetics (MK-8591-029)
Official title: A Clinical Trial to Study the Effect of a Single Dose of Islatravir (MK-8591) on the Pharmacokinetics of Methadone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV-1 Infection
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2020-09-29
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.


Eligibility criteria: 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

Primary outcomes:
measure: Dose-Normalized Area Under the Plasma Concentration Time Curve From 0-24 Hours Postdose (AUC0-24) of R-Methadone
timeFrame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
measure: Dose-Normalized AUC0-24 of S-Methadone
timeFrame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
Secondary outcomes:
measure: Dose-Normalized Maximum Plasma Concentration (Cmax) of R-Methadone
timeFrame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
measure: Dose-Normalized Plasma Concentration 24 Hours Postdose (C24) of R-Methadone
timeFrame: Days 1 and 2: 24 hours postdose
measure: Time to Maximum Plasma Concentration (Tmax) of R-Methadone
timeFrame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
measure: Dose-Normalized Cmax of S-Methadone
timeFrame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
measure: Dose-Normalized C24 of S-Methadone
timeFrame: Days 1 and 2: 24 hours postdose
measure: Tmax of S-Methadone
timeFrame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
measure: Dose-Normalized AUC0-24 of Total Methadone
timeFrame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
measure: Dose-Normalized Cmax of Total Methadone
timeFrame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
measure: Dose-Normalized C24 of Total Methadone
timeFrame: Days 1 and 2: 24 hours postdose
measure: Tmax of Total Methadone
timeFrame: Days 1 and 2: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose
measure: Number of Participants With Adverse Events (AEs) Following Methadone + ISL Coadministration
timeFrame: Up to 16 days
measure: Number of Participants Discontinuing Study Therapy Due to AEs Following Coadministration of Methadone and ISL
timeFrame: Up to 15 days
Other outcomes:
Locations:
city: Hollywood
country: United States
facility: Research Centers of America, LLC ( Site 0002)
state: Florida
city: Salt Lake City
country: United States
facility: PRA Health Sciences ( Site 0001)
state: Utah
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Matthews RP, Ankrom W, Handy W, Patel M, Matthews C, Xu Z, Gravesande K, Searle S, Schwartz H, Stoch SA, Iwamoto M. A Phase 1 Study to Evaluate the Pharmacokinetic Drug-Drug Interaction Between Islatravir and Methadone in Participants on Stable Methadone Therapy. Clin Pharmacol Drug Dev. 2025 Jan;14(1):36-43. doi: 10.1002/cpdd.1492. Epub 2024 Dec 8.