Pharmacokinetics of MK-3682B in Participants With Moderate to Severe Renal Insufficiency (MK-3682B-030)

Merck Sharp & Dohme LLC16 enrolled

Overview

The purpose of this study is to compare the plasma pharmacokinetics (PK) of single doses of MK-3682B, a fixed dose combination (FDC) tablet containing uprifosbuvir (MK-3682) + grazoprevir (MK-5172) + ruzasvir (MK-8408) in participants with moderate (Part 1) and severe (Part 2) renal insufficiency (RI) to plasma PK in healthy participants.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Hepatitis C

Interventions

MK-3682BDRUG

FDC oral tablet containing 225 mg uprifosbuvir + 50 mg grazoprevir + 30 mg ruzasvir.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: All Participants: * Healthy adult males or females 18-80 years of age at screening * Continuous non-smokers or moderate smokers (≤ 20 cigarettes/day or the equivalent) and agrees to consume no more than 10 cigarettes per day during the study period * BMI ≥ 18 and ≤ 40.0 kg/m\^2 * Agrees not to become pregnant or father a child during participation in the study * Females of childbearing potential must either be abstinent for 14 days prior to dosing and throughout the study or be using an acceptable birth control method * Vasectomized or non-vasectomized males must agree to use a condom with spermicide or abstain from sexual intercourse from the first dose until 90 days after dosing * Males must agree not to donate sperm from dosing until 90 days after dosing Moderate and Severe RI Participants: * Baseline health is judged to be stable based on medical history, physical examination, laboratory profiles, vital signs, or electrocardiograms (ECGs), as deemed by the Investigator * Has had no clinically significant change in renal status at least 1 month prior to dosing and is not currently or has not previously been on hemodialysis * Moderate RI: has baseline eGFR ≥ 30 mL/min/1.73m\^2 and \< 60 mL/min/1.73m\^2, based on the Modification of Diet in Renal Disease (MDRD) equation at screening * Severe RI: has baseline eGFR ≥ 15 mL/min/1.73m\^2 and \< 30 mL/min/1.73m\^2, based on the MDRD equation at screening Healthy Participants: * Is within ± 10 years of the mean age of moderate and severe RI arms * BMI is within 10% of the mean BMI of participants with moderate and severe RI arms * Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs, or ECGs, as deemed by the Investigator * Baseline CLcr ≥ 80 mL/min based on Cockcroft-Gault equation at screening Exclusion Criteria: * Is mentally or legally incapacitated or has significant emotional problems at the time of the screening * History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the Investigator * History of any illness that, in the opinion of the Investigator, might confound the results of the study or poses an additional risk by participating in the study * Is female and pregnant or lactating * Positive results for the urine or saliva drug screen or urine or breath alcohol screen at screening or check-in unless the positive drug screen is due to prescription drug use that is approved by the Investigator and Sponsor * Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) * Seated heart rate is equal to or lower than 44 beats per minute (bpm) or higher than 100 bpm at screening * Has had a renal transplant or has had nephrectomy * Donation of blood or had significant blood loss within 56 days prior to dosing of study drug, or donation of plasma within 7 days prior to dosing * Has participated in another clinical trial within 28 days prior to dosing of study drug

Outcomes

Primary Outcomes

Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Time of Last Measurable Concentration (AUC0-last) of Uprifosbuvir (MK-3682)

AUC0-last is a measure of total exposure to uprifosbuvir in plasma from the start of dosing to the time of the last quantifiable (\< lower limit of quantification \[LLOQ\]) sample following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC From Dosing to Infinity (AUC0-∞) of Uprifosbuvir

AUC0-∞ is a measure of total exposure to uprifosbuvir in plasma from the start of dosing to infinity following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC From Dosing to 24 Hours Post-dose (AUC0-24) of Uprifosbuvir

AUC0-24 is a measure of total exposure to uprifosbuvir in plasma from dosing to 24 hours following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

Maximum Plasma Concentration (Cmax) of Uprifosbuvir

Cmax is the maximum amount of uprifosbuvir in plasma following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Plasma Concentration 24 Hours Post-dose (C24) of Uprifosbuvir

C24 is the plasma concentration of uprifosbuvir 24 hours following oral administration of MK-3682B.

Time frame: 24 hours post-dose

Time to Reach Maximum Plasma Concentration (Tmax) of Uprifosbuvir

Tmax is the time required to reach the maximum post-dose plasma concentration of uprifosbuvir following oral administration of MK-3682B.

Data from ClinicalTrials.gov

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Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Apparent Total Body Clearance (CL/F) of Uprifosbuvir

CL/F is the apparent total body clearance of uprifosbuvir following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Apparent Volume of Distribution (Vz/F) of Uprifosbuvir

Vz/F is the apparent volume of distribution of uprifosbuvir following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Apparent Terminal Half-life in Plasma (t½) of Uprifosbuvir

t1/2 is the amount of time required to clear 50% of uprifosbuvir from plasma following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-last of Uprifosbuvir Metabolite M5

AUC0-last is a measure of total exposure to uprifosbuvir metabolite M5 in plasma from the start of dosing to the time of the last quantifiable (\<LLOQ) sample following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-∞ of Uprifosbuvir Metabolite M5

AUC0-∞ is a measure of total exposure to uprifosbuvir metabolite M5 in plasma from the start of dosing to infinity following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-24 of Uprifosbuvir Metabolite M5

AUC0-24 is a measure of total exposure to uprifosbuvir metabolite M5 in plasma from dosing to 24 hours following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

Cmax of Uprifosbuvir Metabolite M5

Cmax is the maximum amount of uprifosbuvir metabolite M5 in plasma following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

C24 of Uprifosbuvir Metabolite M5

C24 is the plasma concentration of uprifosbuvir metabolite M5 24 hours following oral administration of MK-3682B.

Time frame: 24 hours post-dose

Tmax of Uprifosbuvir Metabolite M5

Tmax is the time required to reach the maximum post-dose plasma concentration of uprifosbuvir metabolite M5 following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Lag Time (Tlag) of Uprifosbuvir Metabolite M5

Tlag is the time from dosing to first appearance in plasma of uprifosbuvir metabolite M5 following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

t½ of Uprifosbuvir Metabolite M5

t1/2 is the amount of time required to clear 50% of uprifosbuvir metabolite M5 from plasma following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-last of Uprifosbuvir Metabolite M6

AUC0-last is a measure of total exposure to uprifosbuvir metabolite M6 in plasma from the start of dosing to the time of the last quantifiable (\<LLOQ) sample following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-∞ of Uprifosbuvir Metabolite M6

AUC0-∞ is a measure of total exposure to uprifosbuvir metabolite M6 in plasma from the start of dosing to infinity following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-24 of Uprifosbuvir Metabolite M6

AUC0-24 is a measure of total exposure to uprifosbuvir metabolite M6 in plasma from dosing to 24 hours following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

Cmax of Uprifosbuvir Metabolite M6

Cmax is the maximum amount of uprifosbuvir metabolite M6 in plasma following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

C24 of Uprifosbuvir Metabolite M6

C24 is the plasma concentration of uprifosbuvir metabolite M6 24 hours following oral administration of MK-3682B.

Time frame: 24 hours post-dose

Tmax of Uprifosbuvir Metabolite M6

Tmax is the time required to reach the maximum post-dose plasma concentration of uprifosbuvir metabolite M6 following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

t½ of Uprifosbuvir Metabolite M6

t1/2 is the amount of time required to clear 50% of uprifosbuvir metabolite M6 from plasma following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-last of Grazoprevir (MK-5172)

AUC0-last is a measure of total exposure to grazoprevir in plasma from the start of dosing to the time of the last quantifiable (\<LLOQ) sample following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-∞ of Grazoprevir

AUC0-∞ is a measure of total exposure to grazoprevir in plasma from the start of dosing to infinity following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-24 of Grazoprevir

AUC0-24 is a measure of total exposure to grazoprevir in plasma from the start of dosing to 24 hours post-dose following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

Cmax of Grazoprevir

Cmax is the maximum amount of grazoprevir in plasma following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

C24 of Grazoprevir

C24 is the plasma concentration of grazoprevir 24 hours following oral administration of MK-3682B.

Time frame: 24 hours post-dose

Tmax of Grazoprevir

Tmax is the time required to reach the maximum post-dose plasma concentration of grazoprevir following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

CL/F of Grazoprevir

CL/F is the apparent total body clearance of grazoprevir following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Vz/F of Grazoprevir

Vz/F is the apparent volume of distribution of grazoprevir following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

t½ of Grazoprevir

t1/2 is the amount of time required to clear 50% of grazoprevir from plasma following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-last of Ruzasvir (MK-8408)

AUC0-last is a measure of total exposure to ruzasvir in plasma from the start of dosing to the time of the last quantifiable (\<LLOQ) sample following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-∞ of Ruzasvir

AUC0-∞ is a measure of total exposure to ruzasvir in plasma from the start of dosing to infinity following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

AUC0-24 of Ruzasvir

AUC0-24 is a measure of total exposure to ruzasvir in plasma from dosing to 24 hours following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

Cmax of Ruzasvir

Cmax is the maximum amount of ruzasvir in plasma following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

C24 of Ruzasvir

C24 is the plasma concentration of ruzasvir 24 hours following oral administration of MK-3682B.

Time frame: 24 hours post-dose

Tmax of Ruzasvir

Tmax is the time required to reach the maximum post-dose plasma concentration of ruzasvir following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

CL/F of Ruzasvir

CL/F is the apparent total body clearance of ruzasvir following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Vz/F of Ruzasvir

Vz/F is the apparent volume of distribution of ruzasvir following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

t½ of Ruzasvir

t1/2 is the amount of time required to clear 50% of ruzasvir from plasma following oral administration of MK-3682B.

Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose