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

An Open-Label Study to Investigate the Single-Dose Pharmacokinetics of MK-3866 When Administered to Subjects With Moderate and Severe Hepatic Impairment

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03295266

Enrollment

Registered

2017-09-27

Start date

2017-12-19

Completion date

2018-03-15

Last updated

2019-11-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Antibacterial Agents, Hepatic Insufficiency

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.

Interventions

DRUGMK-3866

Single IV infusion of MK-3866 150 mg administered over 30 minutes at Hour 0 on Day 1 of treatment period.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Yes

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

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
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.
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.
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.

Secondary

Measure	Time frame	Description
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.
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.
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.
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.

Countries

United States

Participant flow

Recruitment details

The study terminated prior to enrollment of any healthy control participants.

Pre-assignment details

Participants with moderate or severe hepatic impairment (HI) based on estimated glomerular filtration rate (eGFR) were enrolled at 2 study centers in the US.

Participants by arm

Arm	Count
Moderate Hepatic Impairment (Panel A) Participants with moderate HI (eGFR of ≤60mL/min/1.73m\^2) received a single IV dose of MK-3866 (150 mg infused over 30 minutes) on Day 1.	5
Severe Hepatic Impairment (Panel B) Participants with severe HI (eGFR of ≤50 mL/min/1.73m\^2) received a single IV dose of MK-3866 (150 mg infused over 30 minutes) on Day 1.	4
Total	9

Baseline characteristics

Characteristic	Severe Hepatic Impairment (Panel B)	Total	Moderate Hepatic Impairment (Panel A)
Age, Continuous	56.0 Years STANDARD_DEVIATION 8.98	58.2 Years STANDARD_DEVIATION 7.24	60.0 Years STANDARD_DEVIATION 5.96
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	4 Participants	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants	5 Participants	3 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	7 Participants	4 Participants
Sex: Female, Male Female	1 Participants	2 Participants	1 Participants
Sex: Female, Male Male	3 Participants	7 Participants	4 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 5	0 / 4
other Total, other adverse events	2 / 5	1 / 4
serious Total, serious adverse events	0 / 5	0 / 4

Outcome results

Primary

Apparent Terminal Half-life (t1/2) of MK-3866

Apparent t1/2 is the elimination half-life of MK-3866 from plasma.

Time frame: 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