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Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the next‐generation HIV integrase inhibitor, S/GSK1349572
Author(s) -
Song Ivy,
Borland Julie,
Chen Shuguang,
Lou Yu,
Peppercorn Amanda,
Wajima Toshihiro,
Min Sherene,
Piscitelli Stephen C.
Publication year - 2011
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2011.03947.x
Subject(s) - atazanavir , ritonavir , pharmacokinetics , pharmacology , glucuronidation , medicine , integrase inhibitor , bioequivalence , integrase , chemistry , human immunodeficiency virus (hiv) , virology , viral load , microsome , enzyme , biochemistry , antiretroviral therapy
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • S/GSK1349572, an investigational HIV integrase inhibitor, is primarily metabolized via glucuronidation by UGT1A1, with a minor component by CYP3A4. As such, inhibitors of UGT1A1 have the potential to increase S/GSK1349572 concentrations. Because S/GSK1349572 and atazanavir (ATV) may be used in combination and because ATV is a potent inhibitor of UGT1A1, this study evaluated the effect of ATV and ritonavir‐boosted ATV (ATV/RTV) on the pharmacokinetics of S/GSK1349572. WHAT THIS STUDY ADDS • The effects of concomitant atazanavir (ATV, a UGT1A1 inhibitor) and S/GSK1349572 pharmacokinetics were previously unknown and were evaluated in this study. Co‐administration of ATV/RTV and ATV was generally well tolerated and produced a modest, non‐clinically significant increase in S/GSK1349572 exposure. No dose adjustment for S/GSK1349572 is necessary when it is co‐administered with ATV and ATV/RTV. AIMS S/GSK1349572 is an unboosted, once daily, next generation integrase inhibitor with potent activity, low pharmacokinetic (PK) variability and a novel resistance profile. As the primary route of metabolism is via glucuronidation, the effects of atazanavir (ATV, a UGT1A1 inhibitor) and atazanavir/ritonavir (ATV/RTV) on S/GSK1349572 PK were evaluated. METHODS A randomized, open label, two period, crossover study was conducted in healthy adult subjects. Twenty‐four subjects received S/GSK1349572 30 mg every 24 h for 5 days. Subjects then were administered S/GSK1349572 30 mg every 24 h in combination with either ATV/RTV 300/100 mg every 24 h ( n = 12) or ATV 400 mg every 24 h ( n = 12) for 14 days. Serial PK samples and safety assessments were obtained throughout the study. RESULTS The combination of S/GSK1349572 with ATV/RTV or ATV was generally well tolerated. All adverse events were mild or moderate, and no subject withdrew because of an adverse event. The AE of highest frequency was ocular icterus, observed only during combination of S/GSK1349572 and ATV or ATV/RTV. Co‐administration with ATV/RTV resulted in increased plasma S/GSK1349572 area under the concentration–time curve during a dosing interval (AUC(0,τ)), observed maximal concentration ( C max ), and concentration at the end of dosing interval at steady state ( C τ ) by 62%, 34% and 121%, respectively. Co‐administration with ATV resulted in increased plasma S/GSK1349572 AUC(0,τ), C max , and C τ by 91%, 50% and 180%, respectively. CONCLUSIONS Co‐administration of ATV/RTV and ATV was generally well tolerated and produced a modest, non‐clinically significant increase in S/GSK1349572 exposure. No dose adjustment for S/GSK1349572 is necessary when co‐administered with ATV and ATV/RTV.