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

Phase 1

Completed

• Conditions: Hepatitis C
• Interventions: Drug: MK-3682B

• Registration Number: NCT02661126
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2016-01-19
• Study First Submitted: 2016-01-19
• Study First Submitted QC: 2016-01-19
• Study First Posted: 2016-01-22
• Primary Completion: 2016-08-26
• Study Completion: 2016-08-26
• Results First Submitted: 2018-05-17
• Status Verified: 2018-12
• Results First Submitted QC: 2018-12-12
• Results First Posted: 2018-12-14
• Last Update Submitted: 2018-12-18
• Last Update Posted: 2019-01-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Moderate RI Participants	MK-3682B	Participants with an estimated glomerular filtration rate (eGFR) of ≥30 mL/min/1.73m\^2 to \<60 mL/min/1.73m\^2 take 2 MK-3682B FDC tablets on Day 1 after fasting for 10 hours.
Severe RI Participants	MK-3682B	Participants with an eGFR of ≥15 mL/min/1.73m\^2 to \<30 mL/min/1.73m\^2 take 2 MK-3682B FDC tablets on Day 1 after fasting for 10 hours.
Healthy Participants	MK-3682B	Healthy participants (creatinine clearance \[CLcr\] ≥80 mL/min) take 2 MK-362B FDC tablets on Day 1 after fasting for 10 hours. Healthy participants are matched to RI participants based on mean age, body mass index (BMI) and gender.

Primary Outcome Measures

Name	Time	Method
AUC From Dosing to 24 Hours Post-dose (AUC0-24) of Uprifosbuvir	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose	AUC0-24 is a measure of total exposure to uprifosbuvir in plasma from dosing to 24 hours following oral administration of MK-3682B.
Plasma Concentration 24 Hours Post-dose (C24) of Uprifosbuvir	24 hours post-dose	C24 is the plasma concentration of uprifosbuvir 24 hours following oral administration of MK-3682B.
Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Time of Last Measurable Concentration (AUC0-last) of Uprifosbuvir (MK-3682)	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 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.
AUC From Dosing to Infinity (AUC0-∞) of Uprifosbuvir	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-∞ is a measure of total exposure to uprifosbuvir in plasma from the start of dosing to infinity following oral administration of MK-3682B.
Maximum Plasma Concentration (Cmax) of Uprifosbuvir	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	Cmax is the maximum amount of uprifosbuvir in plasma following oral administration of MK-3682B.
AUC0-24 of Uprifosbuvir Metabolite M6	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose	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 to Reach Maximum Plasma Concentration (Tmax) of Uprifosbuvir	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	Tmax is the time required to reach the maximum post-dose plasma concentration of uprifosbuvir following oral administration of MK-3682B.
Apparent Total Body Clearance (CL/F) of Uprifosbuvir	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 is the apparent total body clearance of uprifosbuvir following oral administration of MK-3682B.
Apparent Volume of Distribution (Vz/F) of Uprifosbuvir	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 is the apparent volume of distribution of uprifosbuvir following oral administration of MK-3682B.
C24 of Uprifosbuvir Metabolite M5	24 hours post-dose	C24 is the plasma concentration of uprifosbuvir metabolite M5 24 hours following oral administration of MK-3682B.
AUC0-∞ of Uprifosbuvir Metabolite M6	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-∞ 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.
Cmax of Uprifosbuvir Metabolite M6	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	Cmax is the maximum amount of uprifosbuvir metabolite M6 in plasma following oral administration of MK-3682B.
C24 of Uprifosbuvir Metabolite M6	24 hours post-dose	C24 is the plasma concentration of uprifosbuvir metabolite M6 24 hours following oral administration of MK-3682B.
Apparent Terminal Half-life in Plasma (t½) of Uprifosbuvir	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	t1/2 is the amount of time required to clear 50% of uprifosbuvir from plasma following oral administration of MK-3682B.
Cmax of Uprifosbuvir Metabolite M5	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	Cmax is the maximum amount of uprifosbuvir metabolite M5 in plasma following oral administration of MK-3682B.
Lag Time (Tlag) of Uprifosbuvir Metabolite M5	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	Tlag is the time from dosing to first appearance in plasma of uprifosbuvir metabolite M5 following oral administration of MK-3682B.
AUC0-last of Uprifosbuvir Metabolite M5	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 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.
AUC0-∞ of Uprifosbuvir Metabolite M5	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-∞ 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.
AUC0-24 of Uprifosbuvir Metabolite M5	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose	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.
Tmax of Uprifosbuvir Metabolite M5	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	Tmax is the time required to reach the maximum post-dose plasma concentration of uprifosbuvir metabolite M5 following oral administration of MK-3682B.
t½ of Uprifosbuvir Metabolite M5	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	t1/2 is the amount of time required to clear 50% of uprifosbuvir metabolite M5 from plasma following oral administration of MK-3682B.
AUC0-last of Uprifosbuvir Metabolite M6	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 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.
Tmax of Uprifosbuvir Metabolite M6	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	Tmax is the time required to reach the maximum post-dose plasma concentration of uprifosbuvir metabolite M6 following oral administration of MK-3682B.
t½ of Uprifosbuvir Metabolite M6	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	t1/2 is the amount of time required to clear 50% of uprifosbuvir metabolite M6 from plasma following oral administration of MK-3682B.
AUC0-last of Grazoprevir (MK-5172)	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 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.
AUC0-∞ of Grazoprevir	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-∞ is a measure of total exposure to grazoprevir in plasma from the start of dosing to infinity following oral administration of MK-3682B.
AUC0-24 of Grazoprevir	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose	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.
Cmax of Grazoprevir	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	Cmax is the maximum amount of grazoprevir in plasma following oral administration of MK-3682B.
C24 of Grazoprevir	24 hours post-dose	C24 is the plasma concentration of grazoprevir 24 hours following oral administration of MK-3682B.
Tmax of Grazoprevir	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	Tmax is the time required to reach the maximum post-dose plasma concentration of grazoprevir following oral administration of MK-3682B.
CL/F of Grazoprevir	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 is the apparent total body clearance of grazoprevir following oral administration of MK-3682B.
Vz/F of Grazoprevir	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 is the apparent volume of distribution of grazoprevir following oral administration of MK-3682B.
t½ of Grazoprevir	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	t1/2 is the amount of time required to clear 50% of grazoprevir from plasma following oral administration of MK-3682B.
AUC0-last of Ruzasvir (MK-8408)	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 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.
AUC0-∞ of Ruzasvir	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-∞ is a measure of total exposure to ruzasvir in plasma from the start of dosing to infinity following oral administration of MK-3682B.
AUC0-24 of Ruzasvir	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose	AUC0-24 is a measure of total exposure to ruzasvir in plasma from dosing to 24 hours following oral administration of MK-3682B.
Cmax of Ruzasvir	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	Cmax is the maximum amount of ruzasvir in plasma following oral administration of MK-3682B.
C24 of Ruzasvir	24 hours post-dose	C24 is the plasma concentration of ruzasvir 24 hours following oral administration of MK-3682B.
Tmax of Ruzasvir	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	Tmax is the time required to reach the maximum post-dose plasma concentration of ruzasvir following oral administration of MK-3682B.
CL/F of Ruzasvir	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 is the apparent total body clearance of ruzasvir following oral administration of MK-3682B.
Vz/F of Ruzasvir	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 is the apparent volume of distribution of ruzasvir following oral administration of MK-3682B.
t½ of Ruzasvir	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	t1/2 is the amount of time required to clear 50% of ruzasvir from plasma following oral administration of MK-3682B.