A Study Evaluating the Pharmacokinetics of Doravirine (MK-1439) in Participants With Severe Renal Impairment (MK-1439-051)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02641067
• Collaborator: (none)
• Enrollment: 16
• Arms: 2
• Actual Duration (Months): 3.9

Study Details

Study Description

Brief Summary

This study will evaluate the effect of severe renal impairment on the pharmacokinetics of doravirine.

Condition or Disease	Intervention/Treatment	Phase
Renal Impairment	Drug: Doravirine	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of MK-1439 (Doravirine) in Subjects With Severe Renal Impairment
• Actual Study Start Date: Jan 26, 2016
• Actual Primary Completion Date: May 14, 2016
• Actual Study Completion Date: May 25, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Severe Renal Impairment Participants with severe renal impairment receive a single oral dose of 100 mg doravirine	Drug: Doravirine; Following an overnight fast, a single coated tablet of 100 mg doravirine will be administered orally; Other Names: MK-1439, PIFELTRO
Experimental: Healthy Matched Control Healthy participants matched for age and weight receive a single oral dose of 100 mg doravirine	Drug: Doravirine; Following an overnight fast, a single coated tablet of 100 mg doravirine will be administered orally; Other Names: MK-1439, PIFELTRO

Outcome Measures

Primary Outcome Measures

1. Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) of Doravirine [Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment]

   Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.

2. Plasma Concentration of Doravirine at 24 Hours Postdose (C24) [24 hours postdose]

   Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.

3. Maximum Observed Plasma Concentration (Cmax) of Doravirine [Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment]

   Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.

4. Area Under the Plasma Concentration Versus Time Curve From 0 Hours to the Time of Last Quantifiable Sample of Doravirine (AUC 0-last) [Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment]

   Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.

5. Time to Maximum Observed Plasma Concentration (Tmax) of Doravirine [Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment]

   Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.

6. Apparent Terminal Half-life (t1/2) of Plasma Doravirine [Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment]

   Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.

7. Apparent Clearance of Plasma Doravirine After Extravascular Administration (CL/F) [Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment]

   Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.

8. Apparent Volume of Distribution of Plasma Doravirine During the Terminal Phase (Vz/F) [Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment]

   Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• is a non-smoker or moderate smoker

• has a body mass index (BMI) ≥ 18.5 and ≤ 40.0 kg/m^2

• other than renal impairment, participant is judged to be in good health based on medical history, physical examination, vital signs, and laboratory safety tests

• female informed of the risks of pregnancy, agree not to become pregnant while participating in this study. Female of childbearing potential must either be sexually inactive for 14 days prior to dosing and throughout the study, or uses one acceptable birth control method

• female of non-childbearing potential must have undergone sterilization procedures at least 6 months prior to dosing.

• Participants with severe renal impairment only: has baseline estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m^2

Exclusion Criteria:

• is mentally or legally incapacitated or has significant emotional problems

• has a history or presence of clinically significant medical or psychiatric condition or disease

• has history or presence of alcoholism or drug abuse within the past 2 years

• has history or presence of hypersensitivity or idiosyncratic reaction to the study drug, any inactive ingredients, or related compounds

• has history or presence of renal artery stenosis

• has had a renal transplant or nephrectomy

• has rapidly fluctuating renal function as determined by historical measurements

• female is pregnant or lactating

• has positive results for the urine or saliva drug and urine or breath alcohol screen at screening or check-in

• has positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV)

• is unable to refrain from or anticipates the use of any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements beginning 14 days prior to dosing and throughout the study. Certain medications including those to treat kidney disease will be permitted. Other medications may be permitted following consultation with the Sponsor Clinical Monitor.

• is unable to refrain from or anticipates the use of inducers of cytochrome P450 3A (CYP3A) or permeability glycoprotein (P-gp) transporters for at least 28 days prior to dosing and throughout the study.

• has been on a diet incompatible with the on-study diet, within 28 days prior to dosing, and throughout the study

• has donated blood or had significant blood loss within 56 days prior to dosing

• has donated plasma within 7 days prior to dosing

• has participated in another clinical trial within 28 days prior to dosing

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02641067
• Other Study ID Numbers: 1439-051; MK-1439-051
• First Posted: Dec 29, 2015
• Last Update Posted: Feb 8, 2019
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Renal Insufficiency

Study Results

Participant Flow

Arm/Group Title	Severe Renal Impairment	Healthy Matched Controls
Arm/Group Description	Participants with severe renal impairment received a single oral dose of 100 mg doravirine	Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine
Period Title: Overall Study
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Severe Renal Impairment	Healthy Matched Controls	Total
Arm/Group Description	Participants with severe renal impairment received a single oral dose of 100 mg doravirine	Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine	Total of all reporting groups
Overall Participants	8	8	16
Age, Customized (Count of Participants)
19 to 49 years	0 0%	0 0%	0 0%
50 to 59 years	4 50%	4 50%	8 50%
60 to 69 years	4 50%	4 50%	8 50%
Sex: Female, Male (Count of Participants)
Female	2 25%	3 37.5%	5 31.3%
Male	6 75%	5 62.5%	11 68.8%
Body Weight (Kilogram) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilogram]	90.86 (17.409)	90.93 (6.086)	90.89 (12.599)

Outcome Measures

1. Primary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve From 0 Hours to Infinity (AUC0-∞) of Doravirine
Description	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time Frame	Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment

Outcome Measure Data

Analysis Population Description

All 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/Group Title	Severe Renal Impairment	Healthy Matched Controls
Arm/Group Description	Participants with severe renal impairment received a single oral dose of 100 mg doravirine	Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine
Measure Participants	8	8
Geometric Mean (95% Confidence Interval) [μM•hr]	64.5	45.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Renal Impairment, Healthy Matched Controls
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 90%; 1.00 to 2.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Plasma Concentration of Doravirine at 24 Hours Postdose (C24)
Description	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time Frame	24 hours postdose

Outcome Measure Data

Analysis Population Description

All 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/Group Title	Severe Renal Impairment	Healthy Matched Controls
Arm/Group Description	Participants with severe renal impairment received a single oral dose of 100 mg doravirine	Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine
Measure Participants	8	8
Geometric Mean (95% Confidence Interval) [nM]	943	684

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Renal Impairment, Healthy Matched Controls
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 90%; 0.99 to 1.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Doravirine
Description	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time Frame	Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment

Outcome Measure Data

Analysis Population Description

All 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/Group Title	Severe Renal Impairment	Healthy Matched Controls
Arm/Group Description	Participants with severe renal impairment received a single oral dose of 100 mg doravirine	Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine
Measure Participants	8	8
Geometric Mean (90% Confidence Interval) [nM]	1580	1900

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Severe Renal Impairment, Healthy Matched Controls
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 90%; 0.61 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve From 0 Hours to the Time of Last Quantifiable Sample of Doravirine (AUC 0-last)
Description	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time Frame	Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment

Outcome Measure Data

Analysis Population Description

All 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/Group Title	Severe Renal Impairment	Healthy Matched Controls
Arm/Group Description	Participants with severe renal impairment received a single oral dose of 100 mg doravirine	Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine
Measure Participants	8	8
Geometric Mean (Geometric Coefficient of Variation) [μM•hr]	60.5 (56.3)	41.0 (29.9)

5. Primary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) of Doravirine
Description	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time Frame	Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment

Outcome Measure Data

Analysis Population Description

All 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/Group Title	Severe Renal Impairment	Healthy Matched Controls
Arm/Group Description	Participants with severe renal impairment received a single oral dose of 100 mg doravirine	Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine
Measure Participants	8	8
Median (Full Range) [Hours]	2.00	1.50

6. Primary Outcome

Title	Apparent Terminal Half-life (t1/2) of Plasma Doravirine
Description	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time Frame	Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment

Outcome Measure Data

Analysis Population Description

All 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/Group Title	Severe Renal Impairment	Healthy Matched Controls
Arm/Group Description	Participants with severe renal impairment received a single oral dose of 100 mg doravirine	Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine
Measure Participants	8	8
Geometric Mean (Geometric Coefficient of Variation) [Hours]	25.02 (36.4)	16.69 (26.1)

7. Primary Outcome

Title	Apparent Clearance of Plasma Doravirine After Extravascular Administration (CL/F)
Description	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time Frame	Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment

Outcome Measure Data

Analysis Population Description

All 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/Group Title	Severe Renal Impairment	Healthy Matched Controls
Arm/Group Description	Participants with severe renal impairment received a single oral dose of 100 mg doravirine	Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine
Measure Participants	8	8
Geometric Mean (Geometric Coefficient of Variation) [Liter/hour]	3.53 (63.9)	5.38 (32.8)

8. Primary Outcome

Title	Apparent Volume of Distribution of Plasma Doravirine During the Terminal Phase (Vz/F)
Description	Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Time Frame	Pre-dose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72 hours post-dose for all participants; and 96 hours post-dose for participants with severe renal impairment

Outcome Measure Data

Analysis Population Description

All 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/Group Title	Severe Renal Impairment	Healthy Matched Controls
Arm/Group Description	Participants with severe renal impairment received a single oral dose of 100 mg doravirine	Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine
Measure Participants	8	8
Geometric Mean (Geometric Coefficient of Variation) [Liters]	127 (40.9)	129 (28.3)

Adverse Events

Time Frame	Up to 14 days after drug administration
Adverse Event Reporting Description	The population analyzed consisted of all participants who received at least 1 dose of study treatment.
Arm/Group Title	Severe Renal Impairment		Healthy Matched Control
Arm/Group Description	Participants with severe renal impairment received a single oral dose of 100 mg doravirine		Healthy participants matched for age and weight received a single oral dose of 100 mg doravirine
All Cause Mortality
	Severe Renal Impairment		Healthy Matched Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Serious Adverse Events
	Severe Renal Impairment		Healthy Matched Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Severe Renal Impairment		Healthy Matched Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/8 (25%)		1/8 (12.5%)
Gastrointestinal disorders
Nausea	1/8 (12.5%)	1	0/8 (0%)	0
Infections and infestations
Conjunctivitis	1/8 (12.5%)	1	0/8 (0%)	0
Vascular disorders
Phlebitis	0/8 (0%)	0	1/8 (12.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor's policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript.