Darunavir versus Methadone or Buprenorphine
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Study Design
phase I, open-label, add-on trials in volunteers on stable maintenance therapy (METH or BUP/NLX) and were designed to investigate the potential pharmacokinetic interaction between opi-oid maintenance therapy and DRV/r at steady state. Volunteers needed to be on stable individualized maintenance therapy, that is, METH tablets (60–200 mg once daily) or BUP/NLX sublingual tablets (max-imum dose 24/6 mg once daily) for at least 2 weeks prior to study start. Enrolled volunteers received DRV/r, 600/100 mg twice daily, on days 1 to 7 with their current opioid maintenance therapy. DRV and RTV were taken with approximately 200 mL of water between 7:30 and 9:30 a.m. and 7:30 and 9:30 p.m., within 10 minutes of a standardized breakfast or dinner. DRV was administered within 5 minutes after RTV adminis-tration. The maintenance therapy, at prestudy doses, was taken immediately after the morning intake of DRV/r. Full pharmacokinetic profiles of METH (R- and S-isomers), BUP, norBUP, and NLX were determined on days −1 and 7 up to 24 hours post dosing. To explore the pharmacokinetics of multiple doses of DRV/r in METH and in BUP/NLX users of each study, full pharmacokinetic profiles of DRV and RTV up to 12 hours post dosing were determined on day 7. Because the trials were to be conducted in volunteers who were already maintained on either METH or BUP/NLX treatment, a DRV/r-alone arm could not be studied in the same volunteers. Therefore, the pharmacokinetics of DRV and RTV in these trial volunteers (on METH or on BUP/NLX) were compared with those of historic controls.In the METH study, blood samples for METH analyses (R- and S-isomers) were collected on day −2 (prior to dosing), days −1 and 7 (prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, and 12 hours post dos-ing), and days 1, 5, 6, and 8 (prior to dosing). Samples for DRV an
Study Results
Twenty-two volunteers were screened: 6 did not ful-fill the inclusion/exclusion criteria, and 16 com-pleted the study. Fifteen (94%) volunteers were male, and the median age was 45 (range, 30–55 years. Most (75%) volunteers were Caucasian, and all were smokers. Volunteers received between 55 and 200 mg of METH once daily (mean dose, 86 mg; median dose, 75 mg).Full pharmacokinetic profiles (days −1 and 7) were available for the 16 volunteers. There were no major deviations (>10%) in sampling times. Steady-state conditions for the R- and S-isomers of METH were present (data not shown) prior to blood collection on days −1 and 7. The mean plasma-concentration pro-files demonstrated that METH coadministration with DRV/r resulted in lower systemic exposure to both isomers compared with METH alone. Coadministration of DRV/r with METH resulted in a greater decrease in S-isomer exposure than R-isomer exposure.
Study Conclusions
These results showed a decrease in METH pharmacokinetic parameters, with exposure to the S-isomer being more affected than the R-isomer (eg, 36% vs 15% decrease in AUC24h). METH dose adjust-ment is unlikely to be required during DRV/r coad-ministration because the R-isomer is the biologically active enantiomer, although monitoring withdrawal symptoms during initial combination treatment would be prudent
References
Sekar V, Tomaka F, Lefebvre E, Pauw M, Vangeneugden T, Brink W, Hoetelmans R. Pharmacokinetic interactions between darunavir/ritonavir and opioid maintenance therapy using methadone or buprenorphine/naloxone. The Journal Of Clinical Pharmacology. 2011; 2: 271-278.
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