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Effect of Atazanavir and Atazanavir/Ritonavir on the Pharmacokinetics of the Next Generation Integrase Inhibitor, S/GSK1349572
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Reported by Jules Levin
17th CROI Feb 16-19 2010 SF
Ivy Song, Julie Borland, Shuguang Chen, Yu Lou, Amanda Peppercorn, Toshihiro Wajima, Sherene Min, Stephen Piscitelli
GlaxoSmithKline, RTP, NC, USA and Shionogi & Co., Ltd., Osaka, Japan
ABSTRACT
Background:S/GSK1349572 is an unboosted, oncedaily, next generation integrase inhibitor with potent antiviralactivity, low PK variability, and a novel resistance profile. As the primary route of metabolism is via glucuronidation, the effects of concomitant atazanavir (ATV, an UGT1A1 inhibitor) and atazanavir/ritonavir (ATV/RTV) on S/GSK1349572PK were evaluated.
Methods: The design was a randomized, open-label, two-period, two-cohort cross over study in healthy adult subjects. Twenty-four subjects received S/GSK134957230 mg every 24 hours (q24h) for 5 days. Subjects then were administered S/GSK1349572 30 mg q24h in combination with either ATV/RTV 300/100 mg q24h (n=12) or ATV 400 mg q24h (n=12) for 14days. There was no washout between periods. All doses were administered with a moderate fat meal. Serial PK samples 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: The combination of S/GSK1349572 with ATV/RTV or ATV was generally well tolerated. No clinically significant trends in laboratory values, vital signs, or ECGs were observed during study drug dosing. All AEs were mild or moderate and no subject withdrew from the study due to an AE. The most common drug related AE observed during S/GSK1349572 alone was nausea (2/24,8%). The most common AE during co-administration with ATV or ATV/RTV was ocular icterus (11/24,46%). Increased bilirubin was only observed during concomitant ATV dosing. Co-administration with ATV or ATV/RTV increased plasma S/GSK1349572 exposure as shown with a more prominent effect from ATV alone.
Conclusions: Co-administration of ATV/RTV and ATV produced a modest, non-clinically significant increase in S/GSK1349572 exposure. No dose adjustment is necessary when S/GSK1349572 is co-administered with ATV/RTV or ATV.
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