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

Hepatitis C Clinical Trial

Official title:

A Two-Part, Open-Label Study to Investigate the Single-Dose Pharmacokinetics of MK-3682B (MK-3682/MK-5172/MK-8408 Fixed Dose Combination) When Administered to Subjects With Moderate and Severe Renal Insufficiency

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02661126
• Other study ID #: 3682B-030
• Secondary ID: MK-3682B-030CA16
• Status: Completed
• Phase: Phase 1
• Start date: January 19, 2016
• Est. completion date: August 26, 2016

Study information

• Verified date: December 2018
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: August 26, 2016
• Est. primary completion date: August 26, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Hepatitis C
• Renal Insufficiency

Intervention

Drug:
• MK-3682B
FDC oral tablet containing 225 mg uprifosbuvir + 50 mg grazoprevir + 30 mg ruzasvir.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	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
Primary	AUC From Dosing to Infinity (AUC0-8) of Uprifosbuvir	AUC0-8 is a measure of total exposure to uprifosbuvir in plasma from the start of dosing to infinity following oral administration of MK-3682B.	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
Primary	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.	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose
Primary	Maximum Plasma Concentration (Cmax) of Uprifosbuvir	Cmax is the maximum amount of uprifosbuvir in plasma following oral administration of MK-3682B.	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
Primary	Plasma Concentration 24 Hours Post-dose (C24) of Uprifosbuvir	C24 is the plasma concentration of uprifosbuvir 24 hours following oral administration of MK-3682B.	24 hours post-dose
Primary	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.	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
Primary	Apparent Total Body Clearance (CL/F) of Uprifosbuvir	CL/F is the apparent total body clearance of uprifosbuvir following oral administration of MK-3682B.	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
Primary	Apparent Volume of Distribution (Vz/F) of Uprifosbuvir	Vz/F is the apparent volume of distribution of uprifosbuvir following oral administration of MK-3682B.	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
Primary	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.	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
Primary	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 (	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
Primary	AUC0-8 of Uprifosbuvir Metabolite M5	AUC0-8 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.	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
Primary	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.	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose
Primary	Cmax of Uprifosbuvir Metabolite M5	Cmax is the maximum amount of uprifosbuvir metabolite M5 in plasma following oral administration of MK-3682B.	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
Primary	C24 of Uprifosbuvir Metabolite M5	C24 is the plasma concentration of uprifosbuvir metabolite M5 24 hours following oral administration of MK-3682B.	24 hours post-dose
Primary	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.	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
Primary	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.	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
Primary	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.	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
Primary	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 (	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
Primary	AUC0-8 of Uprifosbuvir Metabolite M6	AUC0-8 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.	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
Primary	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.	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose
Primary	Cmax of Uprifosbuvir Metabolite M6	Cmax is the maximum amount of uprifosbuvir metabolite M6 in plasma following oral administration of MK-3682B.	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
Primary	C24 of Uprifosbuvir Metabolite M6	C24 is the plasma concentration of uprifosbuvir metabolite M6 24 hours following oral administration of MK-3682B.	24 hours post-dose
Primary	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.	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
Primary	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.	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
Primary	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 (	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
Primary	AUC0-8 of Grazoprevir	AUC0-8 is a measure of total exposure to grazoprevir in plasma from the start of dosing to infinity following oral administration of MK-3682B.	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
Primary	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.	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose
Primary	Cmax of Grazoprevir	Cmax is the maximum amount of grazoprevir in plasma following oral administration of MK-3682B.	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
Primary	C24 of Grazoprevir	C24 is the plasma concentration of grazoprevir 24 hours following oral administration of MK-3682B.	24 hours post-dose
Primary	Tmax of Grazoprevir	Tmax is the time required to reach the maximum post-dose plasma concentration of grazoprevir following oral administration of MK-3682B.	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
Primary	CL/F of Grazoprevir	CL/F is the apparent total body clearance of grazoprevir following oral administration of MK-3682B.	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
Primary	Vz/F of Grazoprevir	Vz/F is the apparent volume of distribution of grazoprevir following oral administration of MK-3682B.	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
Primary	t½ of Grazoprevir	t1/2 is the amount of time required to clear 50% of grazoprevir from plasma following oral administration of MK-3682B.	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
Primary	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 (	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
Primary	AUC0-8 of Ruzasvir	AUC0-8 is a measure of total exposure to ruzasvir in plasma from the start of dosing to infinity following oral administration of MK-3682B.	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
Primary	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.	0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose
Primary	Cmax of Ruzasvir	Cmax is the maximum amount of ruzasvir in plasma following oral administration of MK-3682B.	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
Primary	C24 of Ruzasvir	C24 is the plasma concentration of ruzasvir 24 hours following oral administration of MK-3682B.	24 hours post-dose
Primary	Tmax of Ruzasvir	Tmax is the time required to reach the maximum post-dose plasma concentration of ruzasvir following oral administration of MK-3682B.	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
Primary	CL/F of Ruzasvir	CL/F is the apparent total body clearance of ruzasvir following oral administration of MK-3682B.	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
Primary	Vz/F of Ruzasvir	Vz/F is the apparent volume of distribution of ruzasvir following oral administration of MK-3682B.	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
Primary	t½ of Ruzasvir	t1/2 is the amount of time required to clear 50% of ruzasvir from plasma following oral administration of MK-3682B.	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