A Study to Investigate the Influence of Hepatic Insufficiency on the Pharmacokinetics of Doravirine (MK-1439) (MK-1439-019)

A 2-Part, Open-Label, Singe-Dose Study to Investigate the Influence of Hepatic Insufficiency on the Pharmacokinetics of MK-1439

This study aimed to investigate the influence of hepatic insufficiency on the pharmacokinetics (PK) of doravirine (MK-1439). In Part 1, PK of doravirine in participants with moderate hepatic insufficiency was compared with that of healthy control subjects matched with regard to mean age and weight. If a clinically meaningful increase in exposure of doravirine was observed in participants with moderate hepatic insufficiency in Part 1, study Part 2 was to evaluate PK of doravirine in participants with mild hepatic insufficiency.

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Doravirine

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Body Mass Index (BMI) between 19 and 40 kg/m^2
• Continuous non-smoker or moderate smoker of <20 cigarettes or equivalent per day. Agrees to consume <=10 cigarettes or equivalent per day from the time of screening through the period of sample collection.
• In good health and with no clinically significant electrocardiogram abnormality
• Hepatic impairment participants: diagnosis of chronic (>6 months), stable hepatic insufficiency with features of cirrhosis due to any etiology. Part 1 only: score of 7 to 9 on the Child-Pugh scale. Part 2: score of 5 to 6 on the Child-Pugh scale.
• Females of childbearing potential: sexually inactive for >=14 days before study drug administration and throughout the study, or using 2 acceptable methods of barrier contraception from screening until 14 days after study drug administration.

Exclusion Criteria:

• Mentally or legally incapacitated or has significant emotional problems at the time of screening or expected during the study
• History or presence of clinically significant medical or psychiatric condition or disease
• History or presence of drug abuse within the past 2 years
• History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related compounds
• Female participant who is pregnant or lactating
• Positive results for breath alcohol or urine drug screen (unless due to prescription drug use and is approved by the investigator) at screening
• Positive for HIV at screening
• Unable to refrain from or anticipates the use of any drug known to be a significant inhibitor or inducer of cytochrome oxidase CYP3A or P-glycoprotein, or any medication or substance which cannot be discontinued at least 14 days before study drug administration and throughout the study.
• Donation of >500 mL of blood or had significant blood loss within 56 days before study drug administration
• Plasma donation within 7 days before study drug administration
• Dosed in another clinical trial within 28 days before study drug administration
• Healthy control participants only: positive for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) at screening;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Moderate Hepatic Insufficiency; Participants with moderate hepatic insufficiency receive a single oral dose of 100 mg doravirine on Day 1 of Part 1. All participants in this arm were to have moderate hepatic insufficiency based on the Child-Pugh scale.	Drug: Doravirine; Following an overnight fast, a single tablet of 100 mg doravirine was be administered orally; Other Names: MK-1439
Experimental: Part 1: Healthy Matched Control; Healthy participants matched for age and weight receive a single oral dose of 100 mg doravirine on Day 1 of Part 1.	Drug: Doravirine; Following an overnight fast, a single tablet of 100 mg doravirine was be administered orally; Other Names: MK-1439
Experimental: Part 2: Mild Hepatic Insufficiency; Participants with mild hepatic insufficiency receive a single oral dose of 100 mg doravirine on Day 1 of Part 1. All participants in this arm were to have mild hepatic insufficiency based on the Child-Pugh scale. This arm was to be enrolled and investigated only if a clinically meaningful increase in exposure of doravirine was observed in participants with moderate hepatic insufficiency in Part 1.	Drug: Doravirine; Following an overnight fast, a single tablet of 100 mg doravirine was be administered orally; Other Names: MK-1439

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) of Doravirine	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method	Predose and at 0.5, 1, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours postdose for all participants and at 96, 120, and 144 hours postdose for participants with hepatic insufficiency
Maximum Observed Plasma Concentration (Cmax) of Doravirine	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method	Predose and at 0.5, 1, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours postdose for all participants and at 96, 120, and 144 hours postdose for participants with hepatic insufficiency
Area Under the Plasma Concentration Versus Time Curve Form 0 to 24 Hours (AUC0-24) of Doravirine	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method	Predose and at 0.5, 1, 1.5, 2, 3, 6, 12, and 24 hours postdose
Plasma Concentration of Doravirine at 24 Hours (C24)	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method	24 hours postdose

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Khalilieh S, Yee KL, Liu R, Fan L, Sanchez RI, Auger P, Triantafyllou I, Stypinski D, Lasseter KC, Marbury T, Iwamoto M. Moderate Hepatic Impairment Does Not Affect Doravirine Pharmacokinetics. J Clin Pharmacol. 2017 Jun;57(6):777-783. doi: 10.1002/jcph.857. Epub 2016 Dec 27.

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2014
• Primary Completion (Actual): May 12, 2014
• Study Completion (Actual): May 12, 2014

Study Registration Dates

• First Submitted: March 14, 2014
• First Submitted That Met QC Criteria: March 14, 2014
• First Posted (Estimate): March 18, 2014

Study Record Updates

• Last Update Posted (Actual): December 28, 2018
• Last Update Submitted That Met QC Criteria: July 3, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency
• Other Study ID Numbers: 1439-019; MK-1439-019 (Other Identifier: Merck Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: http://www.merck.com/clinicaltrials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf