Back to resultsPharmacokinetics of Islatravir in Participants With Severe Renal Impairment (MK-8591-026)
Primary Purpose
Human Immunodeficiency Virus (HIV) Infection
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Islatravir
Sponsored by
About this trial
This is an interventional treatment trial for Human Immunodeficiency Virus (HIV) Infection
Eligibility Criteria
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.
Sites / Locations
- Clinical Pharmacology of Miami ( Site 0001)
- Charite Research Organisation GmbH ( Site 0003)
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Severe Renal Impairment
Healthy
Arm Description
Participants with severe renal impairment received a single oral dose of 60 mg MK-8591 (Islatravir) administered in capsule form.
Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Outcomes
Primary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Full Information
NCT ID
NCT04303156
First Posted
March 9, 2020
Last Updated
September 29, 2021
Sponsor
Merck Sharp & Dohme LLC
1. Study Identification
Unique Protocol Identification Number
NCT04303156
Brief Title
Pharmacokinetics of Islatravir in Participants With Severe Renal Impairment (MK-8591-026)
Official Title
An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of Islatravir (MK-8591) in Subjects With Severe Renal Impairment
Study Type
Interventional
2. Study Status
Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
June 18, 2020 (Actual)
Primary Completion Date
October 19, 2020 (Actual)
Study Completion Date
October 19, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck Sharp & Dohme LLC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Human Immunodeficiency Virus (HIV) Infection
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Severe Renal Impairment
Arm Type
Experimental
Arm Description
Participants with severe renal impairment received a single oral dose of 60 mg MK-8591 (Islatravir) administered in capsule form.
Arm Title
Healthy
Arm Type
Experimental
Arm Description
Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Intervention Type
Drug
Intervention Name(s)
Islatravir
Other Intervention Name(s)
MK-8591
Intervention Description
Single oral dose of 60 mg Islatravir administered in capsule form
Primary Outcome Measure Information:
Title
Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Plasma Islatravir (ISL)
Description
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.
Time Frame
Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Title
Area Under the Curve From Time 0 to Last Sampling Time (AUC0-last) of Plasma ISL
Description
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 Frame
Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Title
Maximum Concentration (Cmax) of Plasma ISL
Description
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 Frame
Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Title
Time of Maximum Concentration (Tmax) of Plasma ISL
Description
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.
Time Frame
Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Title
Apparent Terminal Half-life (t1/2) of Plasma ISL
Description
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.
Time Frame
Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Title
Apparent Clearance (CL/F) of Plasma ISL
Description
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 Frame
Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Title
Apparent Volume of Distribution (Vz/F) of Plasma ISL
Description
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 Frame
Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
Secondary Outcome Measure Information:
Title
AUC0-inf of ISL Triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMC)
Description
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.
Time Frame
Pre-dose, 4, 24, 48, 96, 168 hours post-dose
Title
AUC0-last of ISL-TP in PBMC
Description
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.
Time Frame
Pre-dose, 4, 24, 48, 96, 168 hours post-dose
Title
Cmax of ISL-TP in PBMC
Description
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.
Time Frame
Pre-dose, 4, 24, 48, 96, 168 hours post-dose
Title
Tmax of ISL-TP in PBMC
Description
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.
Time Frame
Pre-dose, 4, 24, 48, 96, 168 hours post-dose
Title
Concentration at 24 Hours Post Dose (C24) of ISL-TP in PBMC
Description
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.
Time Frame
24 hours post-dose
Title
Concentration at 168 Hours Post Dose (C168) of ISL-TP in PBMC
Description
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.
Time Frame
168 hours post-dose
Title
Concentration at 672 Hours Post Dose (C672) of ISL-TP in PBMC
Description
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.
Time Frame
672 hours post-dose
Title
T1/2 of ISL-TP in PBMC
Description
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.
Time Frame
Pre-dose, 4, 24, 48, 96, 168 hours post-dose
Title
Percentage of Participants With an Adverse Event (AE)
Description
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.
Time Frame
Up to Day 29
Title
Percentage of Participants Who Discontinued From the Study Due to an AE
Description
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.
Time Frame
Up to Day 29
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Merck Sharp & Dohme LLC
Official's Role
Study Director
Facility Information:
Facility Name
Clinical Pharmacology of Miami ( Site 0001)
City
Miami
State/Province
Florida
ZIP/Postal Code
33014
Country
United States
Facility Name
Charite Research Organisation GmbH ( Site 0003)
City
Berlin
ZIP/Postal Code
10117
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php
Citations:
PubMed Identifier
36346229
Citation
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.
Results Reference
derived
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Pharmacokinetics of Islatravir in Participants With Severe Renal Impairment (MK-8591-026)
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