Effects of Doravirine (MK-1439) on Methadone Pharmacokinetics in Methadone-Maintained Participants (MK-1439-045)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02715700
• Collaborator: (none)
• Enrollment: 14
• Arm: 1
• Actual Duration (Months): 10.6

Study Details

Study Description

Brief Summary

This study will evaluate the effects of multiple doses of doravirine (MK-1439) on the pharmacokinetics of methadone in participants requiring methadone maintenance therapy. The primary hypothesis is that area under the plasma concentration-time curve to 24 hours postdose (AUC0-24) of (R)-methadone is similar when a maintenance regimen of methadone is administered with or without multiple daily doses of doravirine.

Condition or Disease	Intervention/Treatment	Phase
Human Immunodeficiency Virus (HIV) Infection	Drug: Methadone; Drug: Doravirine	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multiple-Dose Clinical Trial to Study the Effect of MK-1439 (Doravirine) on Methadone Pharmacokinetics
• Actual Study Start Date: Sep 28, 2015
• Actual Primary Completion Date: Jun 13, 2016
• Actual Study Completion Date: Aug 15, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Maintenance Methadone and MK-1439 Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 will continue to receive methadone maintenance once per day on Days 1 to 7. From Day 2 to 6, participants will also receive doravirine 100 mg once daily.	Drug: Methadone; Methadone 20 to 200 mg (10 mg/mL if oral solution concentrate) oral tablet once per day.; Drug: Doravirine; Doravirine 100 mg oral tablet once per day.; Other Names: MK-1439

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration-Time Curve From Zero to 24 Hours After Dosing (AUC0-24) of R-Methadone [Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6]

   The AUC0-24 of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by liquid chromatographic-tandem mass spectrometric (LC-MS/MS) detection. The lower limit of quantification (LLoQ) was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

2. Plasma Concentration at 24 Hours After Dosing (C24) of R-Methadone [24 hours postdose on Day 1 and Day 6]

   The C24 of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

3. Maximum Plasma Concentration (Cmax) of R-Methadone [Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6]

   The Cmax of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

4. Time to Maximum Plasma Concentration (Tmax) of R-Methadone [Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6]

   The Tmax of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

5. AUC0-24 of S-Methadone [Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6]

   The AUC0-24 of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

6. C24 of S-Methadone [24 hours postdose on Day 1 and Day 6]

   The C24 of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

7. Cmax of S-Methadone [Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6]

   The Cmax of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

8. Tmax of S-Methadone [Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6]

   The Tmax of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

9. AUC0-24 of Total Methadone [Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6]

   The AUC0-24 of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

10. C24 of Total Methadone [24 hours postdose on Day 1 and Day 6]

    The C24 of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

11. Cmax of Total Methadone [Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6]

    The Cmax of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

12. Tmax of Total Methadone [Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6]

    The Tmax of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• If female with reproductive potential: must demonstrate a serum β-human chorionic gonadotropin (β -hCG) level consistent with the nongravid state and agree to use (and/or have their partner use) two acceptable methods of birth control throughout the trial and until 2 weeks after the last dose of trial drug.

• If postmenopausal female: must be without menses for at least 1 year.

• If surgically sterile female: must have a status of post hysterectomy, oophorectomy or tubal ligation.

• Body Mass Index (BMI) of 18-35 kg/m^2 (inclusive).

• Able to comply with the smoking restrictions, including <=10 cigarettes per day while in the Clinical Research Unit, and no smoking from 2 hours predose to 2 hours postdose on Days 1 and 6.

• Reliably participating in a methadone maintenance program for at least two months prior to Day 1. Required to be on a documented stable dose of methadone for at least 14 days prior to Day 1.

• Agree not to change current maintenance methadone dose of 20-200 mg once daily (unless for safety reasons) from screening until the end of the study. Must agree to observation and documentation of daily methadone dose administration during the period of the study during which they are domiciled.

Exclusion Criteria:

• Mentally or legally incapacitated, have significant emotional problems at the time of pretrial (screening) visit or expected during the conduct of the trial or have a history of clinically significant psychiatric disorder of the last 5 years. Participants who have had situational depression may be enrolled in the trial at the discretion of the investigator.

• History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological (including stroke and chronic seizures) abnormalities or diseases. Participants with a history of uncomplicated kidney stones or childhood asthma may be enrolled in the trial at the discretion of the investigator.

• History of cancer (malignancy) - exceptions apply.

• History of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food.

• Positive for Human Immunodeficiency Virus (HIV).

• Major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pretrial (screening) visit.

• Participated in another investigational trial within 4 weeks prior to the pretrial (screening) visit.

• Nursing mother.

• Unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies beginning approximately 2 weeks prior to the first dose of the 14 day methadone maintenance phase prior to Day 1, throughout the trial, until the post-trial visit - exceptions apply.

• Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day - exceptions apply.

• Consumes excessive amounts of caffeine, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy-drinks, or other caffeinated beverages per day.

• Has a positive screen for drugs with a high potential for abuse such as cocaine, amphetamines, methylenedioxymethamphetamine (MDMA), barbiturates, benzodiazepines (exceptions apply), or opiates/opioids (apart from methadone as assigned maintenance therapy) on Day 1 that cannot be explained by concomitant medications, unless at the discretion of the principal investigator and the sponsor. Must have a negative Urine Drug Screen prior to randomization, with the exception of tetrahydrocannabinol (THC) and prescription benzodiazepines.

• Clinical Opiate Withdrawal Scale (COWS) score of >=5 prior to randomization.

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: NCT02715700
• Other Study ID Numbers: 1439-045; MK-1439-045
• First Posted: Mar 22, 2016
• Last Update Posted: Jun 25, 2019
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Methadone

Study Results

Participant Flow

Recruitment Details	Adult male and female participants on stable methadone maintenance therapy were recruited at 2 study sites in the United States.

Arm/Group Title	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Days 1 to 7 and doravirine 100 mg on Days 2 to 6.
Period Title: Overall Study
STARTED	14
COMPLETED	14
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Days 1 to 7 and doravirine 100 mg on Days 2 to 6.
Overall Participants	14
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	36.7 (10.7)
Sex: Female, Male (Count of Participants)
Female	7 50%
Male	7 50%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration-Time Curve From Zero to 24 Hours After Dosing (AUC0-24) of R-Methadone
Description	The AUC0-24 of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by liquid chromatographic-tandem mass spectrometric (LC-MS/MS) detection. The lower limit of quantification (LLoQ) was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng*hr/mL/mg]	55.8	53.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Methadone, Maintenance Methadone + Doravirine
	Comments
	Type of Statistical Test	Other
	Comments	Geometric mean ratio (GMR) of Methadone + Doravirine/Methadone Alone
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMR
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 90%; 0.90 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Plasma Concentration at 24 Hours After Dosing (C24) of R-Methadone
Description	The C24 of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng/mL/mg]	1.91	1.82

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Methadone, Maintenance Methadone + Doravirine
	Comments
	Type of Statistical Test	Other
	Comments	GMR of Methadone + Doravirine/Methadone Alone
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMR
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 90%; 0.88 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) of R-Methadone
Description	The Cmax of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng/mL/mg]	3.41	3.33

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Methadone, Maintenance Methadone + Doravirine
	Comments
	Type of Statistical Test	Other
	Comments	GMR of Methadone + Doravirine/Methadone Alone
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMR
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 90%; 0.93 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Time to Maximum Plasma Concentration (Tmax) of R-Methadone
Description	The Tmax of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Median (Full Range) [Hours]	2.00	2.01

5. Primary Outcome

Title	AUC0-24 of S-Methadone
Description	The AUC0-24 of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng*hr/mL/mg]	52.0	50.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Methadone, Maintenance Methadone + Doravirine
	Comments
	Type of Statistical Test	Other
	Comments	Geometric mean ratio (GMR) of Methadone + Doravirine/Methadone Alone
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMR
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 90%; 0.90 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	C24 of S-Methadone
Description	The C24 of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng/mL/mg]	1.51	1.47

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Methadone, Maintenance Methadone + Doravirine
	Comments
	Type of Statistical Test	Other
	Comments	GMR of Methadone + Doravirine/Methadone Alone
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMR
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 90%; 0.86 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Primary Outcome

Title	Cmax of S-Methadone
Description	The Cmax of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng/mL/mg]	3.77	3.67

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Methadone, Maintenance Methadone + Doravirine
	Comments
	Type of Statistical Test	Other
	Comments	GMR of Methadone + Doravirine/Methadone Alone
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMR
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 90%; 0.91 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Primary Outcome

Title	Tmax of S-Methadone
Description	The Tmax of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Median (Full Range) [Hours]	1.99	2.00

9. Primary Outcome

Title	AUC0-24 of Total Methadone
Description	The AUC0-24 of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng*hr/mL/mg]	109	105

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Methadone, Maintenance Methadone + Doravirine
	Comments
	Type of Statistical Test	Other
	Comments	Geometric mean ratio (GMR) of Methadone + Doravirine/Methadone Alone
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMR
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 90%; 0.90 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Primary Outcome

Title	C24 of Total Methadone
Description	The C24 of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng/mL/mg]	3.48	3.34

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Methadone, Maintenance Methadone + Doravirine
	Comments
	Type of Statistical Test	Other
	Comments	GMR of Methadone + Doravirine/Methadone Alone
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMR
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 90%; 0.87 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Primary Outcome

Title	Cmax of Total Methadone
Description	The Cmax of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [ng/mL/mg]	7.19	7.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Methadone, Maintenance Methadone + Doravirine
	Comments
	Type of Statistical Test	Other
	Comments	GMR of Methadone + Doravirine/Methadone Alone
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GMR
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 90%; 0.92 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Primary Outcome

Title	Tmax of Total Methadone
Description	The Tmax of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Time Frame	Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Outcome Measure Data

Analysis Population Description

All treated participants are included.

Arm/Group Title	Maintenance Methadone	Maintenance Methadone + Doravirine
Arm/Group Description	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose on Day 1.	Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 received the methadone maintenance dose + doravirine 100 mg once daily on Days 2 to 6.
Measure Participants	14	14
Median (Full Range) [Hours]	2.00	2.01

Adverse Events

Time Frame	Up to 21 days
Adverse Event Reporting Description	All treated participants are included.
Arm/Group Title	Maintenance Methadone (Day 1)		Maintenance Methadone + Doravirine (Days 2 to 6)		Maintenance Methadone (Day 7)		Safety Follow-Up (Days 8 to 21)
Arm/Group Description	Participants received the methadone maintenance dose on Day 1.		Participants received the methadone maintenance dose and doravirine 100 mg on Days 2 to 6.		Participants received the maintenance methadone dose on Day 7.		Participants were monitored for safety for 14 days after the final dose of study treatment.
All Cause Mortality
	Maintenance Methadone (Day 1)		Maintenance Methadone + Doravirine (Days 2 to 6)		Maintenance Methadone (Day 7)		Safety Follow-Up (Days 8 to 21)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Serious Adverse Events
	Maintenance Methadone (Day 1)		Maintenance Methadone + Doravirine (Days 2 to 6)		Maintenance Methadone (Day 7)		Safety Follow-Up (Days 8 to 21)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)		0/14 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Maintenance Methadone (Day 1)		Maintenance Methadone + Doravirine (Days 2 to 6)		Maintenance Methadone (Day 7)		Safety Follow-Up (Days 8 to 21)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		7/14 (50%)		2/14 (14.3%)		1/14 (7.1%)
Gastrointestinal disorders
Abdominal discomfort	0/14 (0%)	0	1/14 (7.1%)	1	0/14 (0%)	0	0/14 (0%)	0
General disorders
Drug withdrawal syndrome	0/14 (0%)	0	2/14 (14.3%)	2	1/14 (7.1%)	1	0/14 (0%)	0
Investigations
Blood urine present	0/14 (0%)	0	0/14 (0%)	0	0/14 (0%)	0	1/14 (7.1%)	1
Nervous system disorders
Dizziness	0/14 (0%)	0	1/14 (7.1%)	1	0/14 (0%)	0	0/14 (0%)	0
Headache	0/14 (0%)	0	2/14 (14.3%)	2	0/14 (0%)	0	0/14 (0%)	0
Psychiatric disorders
Euphoric mood	0/14 (0%)	0	1/14 (7.1%)	1	0/14 (0%)	0	0/14 (0%)	0
Respiratory, thoracic and mediastinal disorders
Sinus congestion	0/14 (0%)	0	0/14 (0%)	0	1/14 (7.1%)	1	0/14 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation.