Single-Dose Pharmacokinetics of MK-3866 in Participants With Hepatic Impairment (MK-3866-006)

Phase 1

Terminated

• Conditions: Hepatic Insufficiency; Antibacterial Agents
• Interventions: Drug: MK-3866

• Registration Number: NCT03295266
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

This is an open-label, single-dose, Phase 1 study to evaluate the pharmacokinetics (PK) of intravenous (IV) MK-3866 in participants with moderate and severe hepatic impairment (HI) compared to that of matched healthy participants. The primary purpose of this study is to understand the effect of HI on the plasma PK of MK-3866 in order to guide dosing recommendations for participants with HI. This study will also evaluate the safety and tolerability of MK-3866 in participants with moderate and severe HI.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-09-25
• Study First Submitted QC: 2017-09-25
• Study First Posted: 2017-09-27
• Study Start: 2017-12-19
• Primary Completion: 2018-03-15
• Study Completion: 2018-03-15
• Status Verified: 2019-10
• Results First Submitted: 2019-10-22
• Results First Submitted QC: 2019-10-22
• Last Update Submitted: 2019-10-22
• Results First Posted: 2019-11-13
• Last Update Posted: 2019-11-13

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 9

Inclusion Criteria

• Body mass index ≥19 & ≤40 kg/m^2
• Continuous non-smoker prior to screening & enrollment
• HI Participants: Baseline health judged to be stable based on medical history (except for the HI condition), physical examination, vital signs, electrocardiograms, & laboratory safety tests
• Healthy control participants: Is medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs, or electrocardiograms
• HI Participants: Diagnosis of chronic (>6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) HI with features of cirrhosis
• HI Participants - Panel A (moderate HI) only: score on the Child-Pugh scale from 7 to 9 (moderate HI). At least 3 participants must have a score of 2 or higher on at least one of the laboratory parameters (i.e., albumin, international normalized ratio, and/or bilirubin) on the Child-Pugh scale
• HI Participants - Panel B (severe HI) only: Score on the Child-Pugh scale from 10 to 15 (severe HI)
• Is completely informed of the unknown risks of pregnancy & agrees not to become pregnant or father a child during time in study
• For a female of childbearing potential: is either sexually inactive (abstinent) for 14 days prior to dosing & throughout the study or is using an acceptable birth control method
• Non-vasectomized male: Participants must agree to use a condom with spermicide or abstain from sexual intercourse from dosing until 90 days after dosing

Exclusion Criteria

• Mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study
• Has a history or presence of clinically significant medical or psychiatric condition or disease (other than HI - Panels A & B) that might confound the results of the study or poses an additional risk to the participant. Remote history of cholecystectomy that is not an active issue may be included.
• Panels A & B: Has a clinically significant history of cancer. Remote history with full cure or limited disease with complete resection (cure) may be included
• Has a history of drug/alcohol abuse within the past 6 months prior to dosing (Panels A & B) or within the past 2 years prior to dosing (Panel C [Healthy controls])
• Panels A & B: Consumes more than 3 glasses of alcoholic beverages (1 glass approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day, within 6 months of screening. Participants that consume 4 glasses of alcoholic beverages/day may be enrolled
• Panels A & B: Consumes excessive amounts, defined as more than 6 servings (1 serving approximately equivalent to 120 mg of caffeine), of coffee, tea, cola, energy-drinks, or other caffeinated beverages/day
• Panels A & B: Has a history of a liver transplant
• Has a history or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds
• Has moderate or severe renal insufficiency (estimated glomerular filtration rate of ≤60 mL/min/1.73 m2 for moderate HI or healthy control participants or ≤50 mL/min/1.73 m2 for severe HI participants)
• Panel C: Has positive macroscopic urine protein at screening (trace protein by dipstick allowed)
• Is a female participant who is pregnant or lactating
• Has positive results for the urine or breath alcohol screen and/or urine drug screen at screening
• Has positive results at screening for human immunodeficiency virus (HIV) (Panels A & B) or for HIV, HBsAg, or hepatitis C virus (HCV) (Panel C)
• Panels A & B: Participants with active HCV infection or hepatitis B virus (HBV) infection. Participants with prior/inactive HCV infection or past HBV infection may be enrolled.
• Is unable to refrain from or anticipates use of any medication or substance prohibited in study
• Has taken amiodarone at any time in their life

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Severe Hepatic Impairment (Panel B)	MK-3866	Participants with severe HI (eGFR of ≤50 mL/min/1.73m\^2) receive a single IV dose of MK-3866 (150 mg) on Day 1.
Moderate Hepatic Impairment (Panel A)	MK-3866	Participants with moderate HI (estimated glomerular filtration rate \[eGFR\] of ≤60mL/min/1.73m\^2) receive a single IV dose of MK-3866 (150 mg) on Day 1.
Healthy Matched Controls (Panel C)	MK-3866	Healthy participants receive a single IV dose of MK-3866 (150 mg) on Day 1.

Primary Outcome Measures

Name	Time	Method
Area Under the Concentration-time Curve of MK-3866 From Time 0 to 24 Hours (AUC0-24hr)	Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, and 24 hours postdose	AUC0-24 is determined for the period up to 24 hours post-single dose. AUC0-24 is an estimate of total daily plasma exposure from dosing to 24 hours postdose.
Area Under the Concentration-time Curve of MK-3866 From Time 0 to Infinity (AUC0-∞)	Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose	AUC0-∞ is determined for the period up to 72 hours post-single dose. AUC0-∞ is an estimate of total plasma exposure from dosing to (extrapolated) infinity.
Area Under the Concentration-time Curve of MK-3866 From Time 0 to Last Quantifiable Concentration (AUC0-last)	Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose	AUC0-last is determined for the period up to 72 hours post-single dose. AUC0-last is an estimate of total plasma exposure from dosing to the time of last measurable sample.
Time to Maximum Concentration (Tmax) of MK-3866	Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose	Tmax is the time at which the maximum plasma drug concentration is detected.
Apparent Terminal Half-life (t1/2) of MK-3866	Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose	Apparent t1/2 is the elimination half-life of MK-3866 from plasma.
Volume of Distribution (Vz) of MK-3866	Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose	Vz is the apparent volume of distribution during the terminal phase.
Concentration at the End of Infusion (Ceoi) of MK-3866	0.5 (end of infusion) hours postdose	The plasma sample collected at end-of-infusion (0.5 hours postdose) was used to determine Ceoi.
Clearance (CL) of MK-3866	Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose	CL is the volume of plasma from which the study drug is completely removed per unit time.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With at Least One Adverse Event (AE)	Up to 14 days	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Fraction of Dose of MK-3866 Excreted Unchanged in Urine (Fe)	Predose, then pooled in the following increments: 0-4, 4-8, 8-12, 12-24 hours postdose	Fe is the amount of drug excreted unchanged in urine. Urine samples were collected in 4-hour intervals up to 24 hours post-dose. The study terminated prior to analysis of urine samples and therefore no data are available.
Number of Participants Who Discontinued the Study Due to an AE	Up to 14 days	An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Renal Clearance (CLr) of MK-3866	Predose, then pooled in the following increments: 0-4, 4-8, 8-12, 12-24 hours postdose	CLr is the volume of plasma from which the study drug is completely removed per unit time by the kidney (i.e., excreted into the urine). Urine samples are collected in 4-hour intervals up to 24 hours post-dose. The study terminated prior to analysis of urine samples and therefore no data are available.

Trial Locations

Locations (2)

Clinical Pharmacology of Miami ( Site 0001); 🇺🇸 Hialeah, Florida, United States

Orlando Clinical Research Center ( Site 0002); 🇺🇸 Orlando, Florida, United States