A Phase I, Open-Label, Single-Sequence Drug-Drug Interaction Trial in Subjects On Stable Methadone Maintenance Therapy, to Investigate the Potential Pharmacokinetic Interaction Between TMC435 and Methadone, at Steady-State
Overview
- Phase
- Phase 1
- Intervention
- TMC435
- Conditions
- Hepatitis C
- Sponsor
- Tibotec Pharmaceuticals, Ireland
- Enrollment
- 13
- Primary Endpoint
- Maximum plasma concentration of S-methadone
- Status
- Completed
- Last Updated
- 12 years ago
Overview
Brief Summary
The purpose of this study is to evaluate the effect of steady-state (constant concentration of medication in the blood) TMC435 (150 mg, once a day) on the steady state pharmacokinetics (what the body does to the medication) of R- and S-methadone.
Detailed Description
This is an open label (all people know the identity of the intervention) drug-drug interaction (TMC435 versus methadone) study. Approximately 12 hepatitis C virus-negative opioid-dependent participants on stable maintenance therapy (for at least 30 days before screening) will be enrolled in the study. The study will consist of 3 phases: 1) Run-in phase: during this phase, participants will take individualized (dose of methadone will be adjusted for each participant between a range of 30 and 150 mg daily) dose of methadone from Day -14 (14 days before the first intake of TMC435) till Day -1 (1 day before the first intake of TMC435), which will be supervised by the medical staff. 2) 7 days treatment phase: during this phase, the participants will take 150 mg dose of TMC435 once daily from Day 1 to Day 7 orally (by mouth) plus the individualized dose of methadone which will be supervised by the medical staff. 3) Follow-up phase: during this phase, the participants will continue to take only the individualized dose of methadone for 30-32 days. Safety evaluations will include assessment of adverse events, clinical laboratory tests, cardiovascular safety, physical examination and alcohol breath test. The total study duration will be of 22 days excluding screening and follow-up phase.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Receiving once daily oral methadone maintenance therapy at a stable individualized dose of 30 to 130 mg once daily for at least 30 days prior to screening
- •Agreeing not to change the current methadone dose from screening until Day7 included and to have a daily observed and documented methadone intake from Day-14 until Day8 and to have a daily observed and documented TMC435 intake from Day1 until Day 7
- •Having obtained approval from his/her addiction physician for participation in the trial and addiction physician agrees to provide medical care for the volunteer after discharge from the testing facility
Exclusion Criteria
- •No female of childbearing potential, except if using effective birth control methods during the trial and for at least 30 days after the end of the treatment period
- •No positive testing for drugs of abuse
- •No positive testing for Hepatitis A, B and C and for HIV1 and 2
- •Impaired liver disease or other clinically relevant diseases
Arms & Interventions
TMC435 + methadone
Supervised intake of individualized methadone dose (range, 30 to 150 mg once daily) from Day -14 to Day -1; followed by addition of 150 mg dose of TMC435 once daily from Day 1 to Day 7 along with methadone; and later followed by continued intake of individualized methadone 30 to 32 days follow-up.
Intervention: TMC435
TMC435 + methadone
Supervised intake of individualized methadone dose (range, 30 to 150 mg once daily) from Day -14 to Day -1; followed by addition of 150 mg dose of TMC435 once daily from Day 1 to Day 7 along with methadone; and later followed by continued intake of individualized methadone 30 to 32 days follow-up.
Intervention: Methadone
Outcomes
Primary Outcomes
Maximum plasma concentration of S-methadone
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Area under the curve from time of administration up to 24 hours post dosing of S-methadone
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Predose plasma concentration of S-methadone
Time Frame: Day -4 to Day 6
Minimum plasma concentration between 0 hour and dosing interval of S-methadone
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Maximum plasma concentration of R-methadone
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Average steady-state plasma concentration of R-methadone
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Time to reach the maximum plasma concentration of R-methadone
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Area under the curve from time of administration up to 24 hours post dosing of TMC435
Time Frame: On Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose and on Day 8 at 24 hour postdose
Fluctuation index of TMC435, ie, percentage fluctuation (variation between maximum and minimum concentration at steady-state)
Time Frame: On Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose and on Day 8 at 24 hour postdose
Average steady-state plasma concentration of S-methadone
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Time to reach the maximum plasma concentration of S-methadone
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Fluctuation index of S-methadone, ie, percentage fluctuation (variation between maximum and minimum concentration at steady-state)
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Predose plasma concentration of R-methadone
Time Frame: Day -4 to Day 7
Minimum plasma concentration between 0 hour and dosing interval of R- and S-methadone
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Area under the curve from time of administration up to 24 hours post dosing of R-methadone
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Fluctuation index of R-methadone, ie, percentage fluctuation (variation between maximum and minimum concentration at steady-state)
Time Frame: On Day -1 and Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose
Predose plasma concentration of TMC435
Time Frame: Day 4 to Day 6
Maximum plasma concentration of TMC435
Time Frame: On Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose and on Day 8 at 24 hour postdose
Minimum plasma concentration between 0 hour and dosing interval of TMC435
Time Frame: On Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose and on Day 8 at 24 hour postdose
Average steady-state plasma concentration of TMC435
Time Frame: On Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose and on Day 8 at 24 hour postdose
Time to reach the maximum plasma concentration of TMC435
Time Frame: On Day 7 at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours postdose and on Day 8 at 24 hour postdose
Secondary Outcomes
- Short Opiate Withdrawal Scale Scores(On Day-1 and Day 7 at 2 hour and 4 hour predose; on Day-7, Day-2, and Day 1 to Day 6 at predose)
- Desires for Drugs Questionnaire(On Day-1 and Day 7 at 2 hour and 4 hour predose; on Day-7, Day-2, and Day 1 to Day 6 at predose)
- Resting pupil diameter(On Day-1 and Day 7 at 2 hour and 4 hour predose; on Day-7, Day-2, and Day 1 to Day 6 at predose)
- Number of participants with adverse events as a measure of safety and tolerability(Up to 30 to 32 days after the last medication dose)