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An Open-Label, Placebo-controlled Study to Evaluate the Effect of Dolutegravir (DTG, S/GSK1349572) on Iohexol and Para-aminohippurate Clearance in Healthy Subjects
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Reported by Jules Levin
ICAAC- 51stAnnual Interscience Conference on Antimicrobial Agents and Chemotherapy, 17-20 September 2011, Chicago, IL, USA
J.KOTEFF1, J. BORLAND2, S. CHEN2, I. SONG2, A. PEPPERCORN2, T. KOSHIBA3, C. CANNON4, H. MUSTER4, S. PISCITELLI21ViiV Healthcare, RTP, NC, 2GlaxoSmithKline, RTP, NC, USA and 3Shionogi & Co., Ltd., Osaka, Japan, 4DaVita Clinical Research, Minneapolis, MN, USA
ABSTRACT
Background: Dolutegravir (DTG, S/GSK1349572) is a once daily, unboosted, next generation integrase inhibitor. Small, reversible increases in serum creatinine have been observed in clinical trials; these changes are consistent with in-vitro data indicating that DTG is an inhibitor of the organic cation transporter 2 (OCT2), responsible for tubular secretion of creatinine. This study evaluated the effect of DTG on glomerular filtration rate (GFR), renal plasma flow, and serum creatinine clearance (CrCl).
Methods: An open-label, randomized, parallel, placebo-controlled study was conducted in 34 healthy subjects. Subjects received DTG 50mg (q12h or q24h) or placebo for 14 days. The primary endpoint was GFR measured by iohexol plasma clearance on day 14. Secondary endpoints were effective renal plasma flow, (ERPF) assessed by para-aminohippurate (PAH) and CrCl measured by 24-hour urine collection. A linear mixed-effect repeated measures analysis of variance (ANOVA) model was used to analyze the results.
Results: All treatments were generally well tolerated.
Conclusion: A modest decrease (10-14%) in CrCl was observed, consistent with observations from clinical studies. DTG at 50mg q24h and 50mg q12h had no significant effect on GFR or renal plasma flow compared to placebo over 14 days for healthy subjects. These data support the hypothesis that DTG increases serum creatinine by benign inhibition of OCT2.
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