Dolutegravir (DTG, GSK1349572) is an integrase inhibitor that is currently in Phase 3 clinical development for the treatment of HIV infection. As HIV-infected subjects may also be receiving methadone for opioid dependence, an evaluation of the potential interaction between DTG and methadone is warranted. The primary objective of this study is to determine whether concomitant administration of DTG can affect the pharmacokinetics (PK) of methadone. As a secondary endpoint, the PK of DTG will be compared to historical data. This study will be open-label with subjects receiving DTG and stable doses of methadone. The study will be conducted at one center in Canada in adult male and female subjects.
The study is an open label methadone- doltegravir (DTG, GSK1349572) drug interaction study consist of 2 periods. Subjects must be opiate-dependent and are HIV sero-negative and are on stable dose of methadone 14 days prior to pre-screening. After meeting all eligible criterions, subjects will remain on their individual methadone dose for 3 days in period 1. In period 2, subjects will continue on their individual stable dose of methadone and will receive 50 mg DTG every 12 hours for 5 days. Pharmacokinetics will be collected on Day 3 of period 1 and Day 5 of period 2. Safety measurements will be routine chemistry, haematology and urinalysis. Pharmacodynamic parameters for pupillometry and opioid symptom questionnaire will be collected at the same timepoints as for the pharmacokinetics. Subjects will be discharged after the last PK sample has been collected. A follow-up visit will occur 7-14 days after the last dose of study drug. This study will be conducted at one centre in Canada.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Masking
NONE
Enrollment
11
Dolutegravir is an experimental drug in the integrase inhibitor class for the treatment of HIV. Dose of 50mg every 12 hours for 5 days.
Methadone is a synthetic opioid used in the treatment of opioid dependence. Subjects will be on individualize stabe dose for 8 days.
GSK Investigational Site
Toronto, Ontario, Canada
Composite of Methadone Pharmacokinetics
Steady state total and R-methadone PK measure: AUC (0-t), Cmax and Ct.
Time frame: Day 3 (Period 1) and Day 5 (Period 2) at pre-dose, 1, 2, 3, 4. 6, 8, 12, 16, and 24 hours post-dose.
Composite of Methadone and DTG Pharmacokinetics
Dolutegravir PK: AUC (0-t), Cmax, C0, Ct, Cmin, and CL/F; Steady state total and R-methadone: C0, Cmin and CL/F; Steady state plasma S-methadone: AUC (0-t), Cmax, C0, Ct, Cmin, CL/F; Ratio of S/R-methadone AUC (0-t); Ratio of S/R-methadone AUC (0-t); Steady state plasma unbound R-methadone plasma concentrations.
Time frame: Day 3 (Period 1) and Day 5 (Period 2) at pre-dose, 1, 2, 3, 4, 6, 8, 12, 16, and 24 hrs post-dose for methadone; pre-dose, 1, 2, 3, 4, 6, 8, and 12 hrs post-dose for DTG. Unbound R-methadone at 3 and 24 hours on Day 3 (Period 1) and Day 5 (Period 2).
Adverse Events -Number of participants with adverse events
Assessed by change from baseline in vital signs (BP and HR), number of subjects with adverse events and toxicity grading of clinical laboratory tests.
Time frame: Pre-screen visit, Day 1 and Day 5 (Period 2)
Composite of Methadone and DTG Pharmacodynamics
Change from baseline in the subject in the overall opiate agonist score and withdrawal score at post-dose and PK concentrations of methadone alone and in combination; Change in the pupillometry parameters from baseline (minimum pupil diameter \[CFBmin\], pupillometry area over the effect curve \[PAOE\] and scores at each time point) and PK concentrations of methadone alone and in combination.
Time frame: Day 3 (Period 1) and Day 5 (Period 2) at pre-dose, 1, 3, 6, 12, and 24 post-dose.
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