Pharmacokinetics of Islatravir in Participants With Severe Renal Impairment (MK-8591-026)

An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of Islatravir (MK-8591) in Subjects With Severe Renal Impairment

This study will evaluate the general tolerability and pharmacokinetics (PK) of a single 60 mg dose of MK-8591 (Islatravir) in participants with severe renal insufficiency, compared to participants in good health.

Study Overview

• Status: Completed
• Conditions: Human Immunodeficiency Virus (HIV) Infection
• Intervention / Treatment: Drug: Islatravir

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Charite Research Organisation GmbH ( Site 0003)
• United States
  • Florida
    • Miami, Florida, United States, 33014
      • Clinical Pharmacology of Miami ( Site 0001)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Healthy participants must have the following:

• Is in good health
• Has a body mass index (BMI) ≥18.5 and ≤40 kg/m2.
• Female is not pregnant or breastfeeding, and is not one of the following: a woman of childbearing potential (WOCBP); if a WOCBP, is using an acceptable contraceptive method, or is abstinent from heterosexual intercourse as their preferred and usual lifestyle; a WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention

Renally impaired participants must have the following:

• With the exception of renal impairment, is in generally good health
• Has a BMI ≥ 18.5 and ≤ 40 kg/m2
• Female is not pregnant or breastfeeding, and is not one of the following: a woman of childbearing potential (WOCBP); if a WOCBP, is using an acceptable contraceptive method, or is abstinent from heterosexual intercourse as their preferred and usual lifestyle; a WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention

Exclusion Criteria:

Healthy participants must have the following:

• 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
• Has known hypersensitivity to the active substance or any of the excipients of the study drug
• Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic allergic reaction) to prescription or non-prescription drugs or food.
• Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
• Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within prior 4 weeks
• Is taking medications to treat chronic medical conditions and/or conditions associated with renal disease
• Has participated in another investigational study within prior 4 weeks

Other exclusions for healthy participants:

• Does not agree to follow the smoking restrictions
• Consumes greater than 1 glass for women, or 2 glasses for men of alcoholic beverages per day
• Consumes excessive amounts,of caffeinated beverages per day.
• Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately prior 3 months.

Renally impaired participants must have the following:

• Has a history or presence of renal artery stenosis.
• Has had a renal transplant or nephrectomy.
• Has rapidly fluctuating renal function as determined by historical measurements.
• Has known hypersensitivity to the active substance or any of the excipients of the study drug.
• Has a history of cancer (malignancy).
• Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic allergic reaction) to prescription or non-prescription drugs or food.
• Is positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV).
• Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the prestudy (screening) visit.
• Is taking medications to treat chronic medical conditions and/or conditions associated with renal disease and has not been on a stable regimen for at least 1 month and/or is unable to withhold the use of the medication(s) within 4 hours prior to and 8 hours after administration of the study drug.
• Has participated in another investigational study within 4 weeks (or 5 half-lives, whichever is greater) prior to the prestudy (screening) visit.

Other exclusions for renally impaired participants

• Does not agree to follow the smoking restrictions.
• Consumes greater than 1 glass for women, or 2 glasses for men of alcoholic beverages per day.
• Consumes excessive amounts of caffeinated beverages per day.
• Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Severe Renal Impairment; Participants with severe renal impairment received a single oral dose of 60 mg MK-8591 (Islatravir) administered in capsule form.	Drug: Islatravir; Single oral dose of 60 mg Islatravir administered in capsule form; Other Names: MK-8591
EXPERIMENTAL: Healthy; Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.	Drug: Islatravir; Single oral dose of 60 mg Islatravir administered in capsule form; Other Names: MK-8591

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Plasma Islatravir (ISL)	Participants were treated with islatravir (ISL), and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Area Under the Curve From Time 0 to Last Sampling Time (AUC0-last) of Plasma ISL	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Maximum Concentration (Cmax) of Plasma ISL	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Time of Maximum Concentration (Tmax) of Plasma ISL	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The Tmax of plasma ISL was expressed as a median.	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Apparent Terminal Half-life (t1/2) of Plasma ISL	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The Geometric Coefficient of Variation was expressed as a percent (%CV), and is calculated from the square root of corresponding estimated variance obtained for each population in fixed effect model multiplied by 100.	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Apparent Clearance (CL/F) of Plasma ISL	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Apparent Volume of Distribution (Vz/F) of Plasma ISL	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC0-inf of ISL Triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMC)	Participants were treated with ISL, and peripheral blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Pre-dose, 4, 24, 48, 96, 168 hours post-dose
AUC0-last of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Pre-dose, 4, 24, 48, 96, 168 hours post-dose
Cmax of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	Pre-dose, 4, 24, 48, 96, 168 hours post-dose
Tmax of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The Tmax of ISL-TP was expressed as a median.	Pre-dose, 4, 24, 48, 96, 168 hours post-dose
Concentration at 24 Hours Post Dose (C24) of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected at 24 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	24 hours post-dose
Concentration at 168 Hours Post Dose (C168) of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected at 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	168 hours post-dose
Concentration at 672 Hours Post Dose (C672) of ISL-TP in PBMC	Participants were treated with ISL and peripheral blood samples were collected at 672 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.	672 hours post-dose
T1/2 of ISL-TP in PBMC	Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The t1/2 of plasma ISL was expressed as a geometric mean. The Geometric Coefficient of Variation was expressed as a percent (%CV), and is calculated from the square root of corresponding estimated variance obtained for each population in fixed effect model multiplied by 100.	Pre-dose, 4, 24, 48, 96, 168 hours post-dose
Percentage of Participants With an Adverse Event (AE)	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to Day 29
Percentage of Participants Who Discontinued From the Study Due to an AE	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.	Up to Day 29

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Matthews RP, Cao Y, Patel M, Weissler VL, Bhattacharyya A, De Lepeleire I, Last S, Rondon JC, Vargo R, Stoch SA, Iwamoto M. Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency. Antimicrob Agents Chemother. 2022 Dec 20;66(12):e0093122. doi: 10.1128/aac.00931-22. Epub 2022 Nov 8.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 18, 2020
• Primary Completion (ACTUAL): October 19, 2020
• Study Completion (ACTUAL): October 19, 2020

Study Registration Dates

• First Submitted: March 9, 2020
• First Submitted That Met QC Criteria: March 9, 2020
• First Posted (ACTUAL): March 10, 2020

Study Record Updates

• Last Update Posted (ACTUAL): October 28, 2021
• Last Update Submitted That Met QC Criteria: September 29, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; 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: 8591-026; 2020-000153-27 (EUDRACT_NUMBER); MK-8591-026 (OTHER: 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