Trial Outcomes & Findings for Effects of Doravirine (MK-1439) on Methadone Pharmacokinetics in Methadone-Maintained Participants (MK-1439-045) (NCT NCT02715700)

NCT ID: NCT02715700

Last Updated: 2019-06-25

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

14 participants

Primary outcome timeframe

Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Results posted on

2019-06-25

Participant Flow

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

Participant milestones

Participant milestones
Measure	Maintenance Methadone + Doravirine 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 Study STARTED	14
Overall Study COMPLETED	14
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Maintenance Methadone + Doravirine n=14 Participants 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.
Age, Continuous	36.7 Years STANDARD_DEVIATION 10.7 • n=5 Participants
Sex: Female, Male Female	7 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
Area Under the Concentration-Time Curve From Zero to 24 Hours After Dosing (AUC0-24) of R-Methadone	55.8 ng*hr/mL/mg Interval 46.4 to 67.1	53.2 ng*hr/mL/mg Interval 44.6 to 63.5

PRIMARY outcome

Timeframe: 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
Plasma Concentration at 24 Hours After Dosing (C24) of R-Methadone	1.91 ng/mL/mg Interval 1.56 to 2.34	1.82 ng/mL/mg Interval 1.45 to 2.27

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
Maximum Plasma Concentration (Cmax) of R-Methadone	3.41 ng/mL/mg Interval 2.89 to 4.01	3.33 ng/mL/mg Interval 2.83 to 3.91

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
Time to Maximum Plasma Concentration (Tmax) of R-Methadone	2.00 Hours Interval 1.0 to 6.0	2.01 Hours Interval 1.02 to 4.0

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
AUC0-24 of S-Methadone	52.0 ng*hr/mL/mg Interval 38.3 to 70.4	50.8 ng*hr/mL/mg Interval 37.5 to 68.8

PRIMARY outcome

Timeframe: 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
C24 of S-Methadone	1.51 ng/mL/mg Interval 1.03 to 2.22	1.47 ng/mL/mg Interval 0.974 to 2.21

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
Cmax of S-Methadone	3.77 ng/mL/mg Interval 2.95 to 4.82	3.67 ng/mL/mg Interval 2.87 to 4.68

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
Tmax of S-Methadone	1.99 Hours Interval 1.0 to 3.0	2.00 Hours Interval 1.02 to 4.0

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
AUC0-24 of Total Methadone	109 ng*hr/mL/mg Interval 86.0 to 137.0	105 ng*hr/mL/mg Interval 82.9 to 132.0

PRIMARY outcome

Timeframe: 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
C24 of Total Methadone	3.48 ng/mL/mg Interval 2.65 to 4.57	3.34 ng/mL/mg Interval 2.48 to 4.51

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
Cmax of Total Methadone	7.19 ng/mL/mg Interval 5.86 to 8.82	7.01 ng/mL/mg Interval 5.72 to 8.6

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 16, and 24 hours postdose on Day 1 and Day 6

Population: All treated participants are included.

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.

Outcome measures

Outcome measures
Measure	Maintenance Methadone n=14 Participants 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.	Maintenance Methadone + Doravirine n=14 Participants 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.
Tmax of Total Methadone	2.00 Hours Interval 1.0 to 6.0	2.01 Hours Interval 1.02 to 4.0

Adverse Events

Maintenance Methadone (Day 1)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Maintenance Methadone + Doravirine (Days 2 to 6)

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Maintenance Methadone (Day 7)

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Safety Follow-Up (Days 8 to 21)

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Maintenance Methadone (Day 1) n=14 participants at risk Participants received the methadone maintenance dose on Day 1.	Maintenance Methadone + Doravirine (Days 2 to 6) n=14 participants at risk Participants received the methadone maintenance dose and doravirine 100 mg on Days 2 to 6.	Maintenance Methadone (Day 7) n=14 participants at risk Participants received the maintenance methadone dose on Day 7.	Safety Follow-Up (Days 8 to 21) n=14 participants at risk Participants were monitored for safety for 14 days after the final dose of study treatment.
Gastrointestinal disorders Abdominal discomfort	0.00% 0/14 • Up to 21 days All treated participants are included.	7.1% 1/14 • Number of events 1 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.
General disorders Drug withdrawal syndrome	0.00% 0/14 • Up to 21 days All treated participants are included.	14.3% 2/14 • Number of events 2 • Up to 21 days All treated participants are included.	7.1% 1/14 • Number of events 1 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.
Investigations Blood urine present	0.00% 0/14 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.	7.1% 1/14 • Number of events 1 • Up to 21 days All treated participants are included.
Nervous system disorders Dizziness	0.00% 0/14 • Up to 21 days All treated participants are included.	7.1% 1/14 • Number of events 1 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.
Nervous system disorders Headache	0.00% 0/14 • Up to 21 days All treated participants are included.	14.3% 2/14 • Number of events 2 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.
Psychiatric disorders Euphoric mood	0.00% 0/14 • Up to 21 days All treated participants are included.	7.1% 1/14 • Number of events 1 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.
Respiratory, thoracic and mediastinal disorders Sinus congestion	0.00% 0/14 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.	7.1% 1/14 • Number of events 1 • Up to 21 days All treated participants are included.	0.00% 0/14 • Up to 21 days All treated participants are included.

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER