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

Phase 1

Completed

Conditions: Human Immunodeficiency Virus (HIV) Infection

Interventions: Drug: Islatravir

Registration Number: NCT04303156

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Severe Renal Impairment	Islatravir	Participants with severe renal impairment received a single oral dose of 60 mg MK-8591 (Islatravir) administered in capsule form.
Healthy	Islatravir	Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.

Primary Outcome Measures

Name	Time	Method
Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Plasma Islatravir (ISL)	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose	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.
Area Under the Curve From Time 0 to Last Sampling Time (AUC0-last) of Plasma ISL	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose	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.
Maximum Concentration (Cmax) of Plasma ISL	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose	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.
Time of Maximum Concentration (Tmax) of Plasma ISL	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose	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.
Apparent Terminal Half-life (t1/2) of Plasma ISL	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose	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.
Apparent Clearance (CL/F) of Plasma ISL	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose	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.
Apparent Volume of Distribution (Vz/F) of Plasma ISL	Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose	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.

Secondary Outcome Measures

Name	Time	Method
Concentration at 24 Hours Post Dose (C24) of ISL-TP in PBMC	24 hours post-dose	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.
Concentration at 672 Hours Post Dose (C672) of ISL-TP in PBMC	672 hours post-dose	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.
T1/2 of ISL-TP in PBMC	Pre-dose, 4, 24, 48, 96, 168 hours post-dose	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.
Cmax of ISL-TP in PBMC	Pre-dose, 4, 24, 48, 96, 168 hours post-dose	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.
Tmax of ISL-TP in PBMC	Pre-dose, 4, 24, 48, 96, 168 hours post-dose	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.
AUC0-inf of ISL Triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMC)	Pre-dose, 4, 24, 48, 96, 168 hours post-dose	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.
AUC0-last of ISL-TP in PBMC	Pre-dose, 4, 24, 48, 96, 168 hours post-dose	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.
Concentration at 168 Hours Post Dose (C168) of ISL-TP in PBMC	168 hours post-dose	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.
Percentage of Participants Who Discontinued From the Study Due to an AE	Up to Day 29	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.
Percentage of Participants With an Adverse Event (AE)	Up to Day 29	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.

Trial Locations

Locations (2): Clinical Pharmacology of Miami ( Site 0001)
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Miami, Florida, United States
Charite Research Organisation GmbH ( Site 0003)
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Berlin, Germany