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

Study Overview
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Brief Summary
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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.

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

Conditions
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Human Immunodeficiency Virus (HIV) Infection

Intervention / Treatment
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* Drug: Islatravir


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |