Pharmacokinetic Interaction Between Telaprevir and Methadone
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Study Design
This was a single-sequence study in 18 (15 evaluable) HCV-negative volunteers who were on a stable, individualized maintenance dose (40-120mg) of methadone. The administration of methadone was observed from day -14 through the end of the study (morning of day 8). Volunteers stayed in the testing facility from day -2 until the end of the study. Telaprevir was administered as 750mg by mouth every 8 hours for 7 days, beginning on day 1. The sampling for the complete pharmacokinetic (PK) profile of telaprevir took place on day 7, pre-dose concentrations of R-methadone were obtained from day -4 to day 7, and complete PK sampling for R- and S-methadone took place on day -1 and day 7.
Study Results
The pharmacokinetic (PK) parameters of telaprevir during co-administration of methadone where comparable to telaprevir PK parameters seen in a previous study of healthy volunteers receiving 750mg every 8 hours. The telaprevir PK parameters (SD) measured on day 7 were Cmax 3376ng/mL (+/- 1260), Cmin 1894 (+/- 905), and AUC8h 20480 (+/- 7628). R-methadone and S-methadone levels were measured in this study. Notable, the R-isomer is primarily responsible for the opioid effect. Co-administration with telaprevir caused a decrease in the AUC24h of R-methadone and S-methadone by 29% and 36%, respectively, and a decrease in the total Cmin of R-methadone and total S-methadone by 31% and 40%, respectively. Protein displacement caused the free-fraction of R-methadone to increase by 26%, but there was no change in the unbound (effective) concentration. The Short Opioid Withdrawal Scale did not show withdrawal during co-administration, the Desires for Drugs Questionnaire had the same outcome during both phases of the study, and pupillometry did not show an increase in withdrawal symptoms at almost every time point during co-administration.
Study Conclusions
The manufacturer recommends to not adjust the methadone dose when initiating telaprevir, but to monitor the patient during therapy because the dose of methadone may need to be adjusted in some patients.
References
van Heeswijk R, Verboven P, Vandervoorde A. Pharmacokinetic interaction between telaprevir and methadone. Antimicrobial Agents And Chemotherapy . 2013; 5: 2304-2309.
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