Dolutegravir does not affect methadone pharmacokinetics in opioid-dependent, HIV-seronegative subjects.
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Study Design
This was an open-label, 2-period study in adult opiate-dependent, HIV-negative subjects. Period 1: individualized pre-study methadone doses once daily (QD) for 3 days. Period 2: Dolutegravir (DTG) 50mg twice daily (BID) for 5 days with stable methadone therapy. Serial PK samples for R- and S-methadone were collected on Period 1 day 3 and Period 2 day 5. Serial PK samples were also collected for DTG.
PD was assessed by pupillometry and overall opiate agonist and withdrawal scores.
Study Results
The PK of methadone was not altered by concomitant DTG. The ratio of the geometric least-squares means for all of the PK parameters calculated for total, R-methadone and S-methadone were not changed by more than 6% (all 90% CI were within 0.8 and 1.25) by coadministration with DTG. These values included AUC0-t, Cmax, C0, Ct, Cmin, CL/F, and the R-/S-methadone AUC ratio.
Geometic mean PK parameters of DTG were compared to historical data, with fairly similar results. DTG geometric mean (coefficient of variation) for AUC0-t was 44.3 (37)ug h/mL and 51.6 (36)ug h/mL for this study and historical data (subjects also received para-aminohippurate and iohexol infusions twice during DTG dosing), respectivly.
There were no clinically relevant changes to PD measures. The overall opiate agonist and withdrawl scores did not show a significant difference (P>0.10) when comparing subjects receiving methadone alone or those also receiving DTG in change from baseline. As well, there was no significant difference in change from baseline in pupillometry scores between subjects receiving methadone alone compared with those also receiving DTG.
There were no clinically significant changes in lab values, vital signs, or ECG observed.
Study Conclusions
DTG 50mg BID was used in this study because it is the highest clinically used dose, to increase the chance of creating an interaction.
***Caution should still be excercised if this combination is to be coadminitered, because although no PK changes were noted, the duration of the study was short and methadone can have a long half-life, so steady state may not have been reached during this study. That fact that there is no interaction cannot be stated with complete confidence.
References
Song I, Mark S, Chen S. Dolutegravir does not affect methadone pharmacokinetics in opioid-dependent, hiv-seronegative subjects. Drug And Alcohol Dependence. 2013; : 781-784.
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