HIV-1 Infection
Conditions
Brief summary
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.
Interventions
DRUGDoravirine
Following an overnight fast, a single tablet of 100 mg doravirine was be administered orally
Sponsors
Merck Sharp & Dohme LLC
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 (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;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) of Doravirine | 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 | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method |
| Maximum Observed Plasma Concentration (Cmax) of Doravirine | 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 | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method |
| Area Under the Plasma Concentration Versus Time Curve Form 0 to 24 Hours (AUC0-24) of Doravirine | Predose and at 0.5, 1, 1.5, 2, 3, 6, 12, and 24 hours postdose | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method |
| Plasma Concentration of Doravirine at 24 Hours (C24) | 24 hours postdose | Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method |
Participant flow
Recruitment details
Part 2 of the study was to enroll participants only if a clinically meaningful increase in exposure of doravirine was observed in participants with moderate hepatic insufficiency in Part 1. Because this was not observed, no participants were enrolled in Part 2 of the study.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Participants With Moderate Hepatic Insufficiency Participants with moderate hepatic insufficiency received 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. | 8 |
| Part 1: Healthy Control Participants Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine on Day 1 of Part 1. | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | Part 1: Participants With Moderate Hepatic Insufficiency | Part 1: Healthy Control Participants | Total |
|---|---|---|---|
| Age, Continuous | 59 Years | 56 Years | 57 Years |
| Child-Pugh Total Score Total Score = 7 | 2 Participants | 0 Participants | 2 Participants |
| Child-Pugh Total Score Total Score = 8 | 4 Participants | 0 Participants | 4 Participants |
| Child-Pugh Total Score Total Score = 9 | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
| Weight | 82.0 kg | 79.8 kg | 80.9 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 4 / 8 | 3 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
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
Time frame: Predose and at 0.5, 1, 1.5, 2, 3, 6, 12, and 24 hours postdose
Population: The analysis population consisted of the subset of participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1: Participants With Moderate Hepatic Insufficiency | Area Under the Plasma Concentration Versus Time Curve Form 0 to 24 Hours (AUC0-24) of Doravirine | 28.5 µM*hr |
| Part 1: Healthy Control Participants | Area Under the Plasma Concentration Versus Time Curve Form 0 to 24 Hours (AUC0-24) of Doravirine | 30.6 µM*hr |
90% CI: [0.74, 1.18]
Primary
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
Time frame: 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
Population: The analysis population consisted of the subset of participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1: Participants With Moderate Hepatic Insufficiency | Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) of Doravirine | 53.9 µM*hr |
| Part 1: Healthy Control Participants | Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) of Doravirine | 54.6 µM*hr |
90% CI: [0.72, 1.35]
Primary
Maximum Observed Plasma Concentration (Cmax) of Doravirine
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method
Time frame: 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
Population: The analysis population consisted of the subset of participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1: Participants With Moderate Hepatic Insufficiency | Maximum Observed Plasma Concentration (Cmax) of Doravirine | 1850 nM |
| Part 1: Healthy Control Participants | Maximum Observed Plasma Concentration (Cmax) of Doravirine | 2050 nM |
90% CI: [0.66, 1.24]
Primary
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
Time frame: 24 hours postdose
Population: The analysis population consisted of the subset of participants who complied with the protocol sufficiently to ensure that generated data were likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1: Participants With Moderate Hepatic Insufficiency | Plasma Concentration of Doravirine at 24 Hours (C24) | 842 nM |
| Part 1: Healthy Control Participants | Plasma Concentration of Doravirine at 24 Hours (C24) | 847 nM |
90% CI: [0.74, 1.33]