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Effect of Fosamprenavir/Ritonavir on the Pharmacokinetics of the Integrase Inhibitor, Dolutegravir, in Healthy Subjects
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Reported by Jules Levin
51stAnnual Interscience Conference on Antimicrobial Agents and Chemotherapy, 17-20 September 2011, Chicago, IL, USA
SONG, J. BORLAND, S. CHEN, A. PEPPERCORN, T. WAJIMA, S. PISCITELLIGlaxoSmithKline, RTP, NC, USA, and Shionogi & Co., Ltd., Osaka, Japan
ABSTRACT
Background: Dolutegravir (DTG, S/GSK1349572) is a once daily, unboosted, next generation integrase inhibitor with activity against viruses resistant to raltegravir. As DTG is primarily metabolized by UGT1A1 with CYP3A as the minor route and fosamprenavir/ ritonavir (FPV/RTV) are inducer/inhibitors of these enzymes, the effect of concomitant FPV/RTV on DTG pharmacokinetics was evaluated.
Methods: This was a single-center, open-label, single-sequence study in healthy adult subjects. Subjects received DTG 50 mg q24h for 5 days followed by DTG 50 mg q24h in combination with FPV/RTV 700/100 mg q12h for 10 days. All doses were administered in the fasting state. Serial PK samples for DTG and amprenavir (APV) and safety assessments were obtained throughout the study. Non-compartmental PK analysis was performed and geometric least squares (GLS) mean ratios and 90% confidence intervals (CI) were generated by the mixed effect model for within-subject treatment comparison.
Results: Twelve subjects were enrolled and completed the study. There were no grade 2, 3, or 4 adverse events (AEs), serious adverse events, or withdrawals due to AEs. No clinically significant trends in laboratory values, vital signs or ECGs were observed. Co-administration of FPV/RTV decreased DTG plasma exposures: AUC(0-),Cmax, and Cwere reduced by 35%, 24%, and 49%, respectively. APV PK parameters were similar to historical values.
Conclusion: The combination of DTG and FPV/RTV was well tolerated.Co-administration of FPV/RTV decreased DTG plasma exposures. Despite these reductions, DTG concentrations remain well above the protein adjusted-IC90 for wild type HIV viruses. No dose adjustment is needed when DTG is co-administered with FPV/RTV in integrase inhibitor-naïve subjects.
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