The authors concluded that the modest effects of atazanavir and ritonavir on the PK of BMS-955176 suggested a minor role of CYP3A4 and/or P-glycoprotein in the disposition of BMS-855176.
BMS-955176 vs atazanavir
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Study Design
Eighty patients were enrolled in this phase 1, randomized, placebo-controlled double blind, sequential single-ascending and multiple ascending dose study. In each arm, eight subjects were randomized 3:1 to receive BMS-955176 or placebo. In Part A, patients received a single dose of spray dried dispersion (SDD) BMS-955176 (10 mg, 20 mg, 40 mg or 120 mg) on day 1. On day eight one group received 40 mg SDD plus ritonavir (RTV) 100 mg. In Part B, patients received BMS-955176 (10 mg, 20 mg, or 80 mg) once daily for 14 days, BMS-955176 40 mg daily for 28 days, or BMS-955176 40 mg daily plus Atazanavir 400 mg daily for 14 days. Serial blood samples were collected and geometric means ratios were calculated.
Study Results
In total, 79/80 patients completed the study. In Part A, BMS-955176 exposures increased in a less than dose proportional manner. Slopes (90% confidence intervals) were 0.845 (0.73, 0.961) and 0.9 (0.79, 1.009) for Cmax and AUC respectively. Coadministration of single dose BMS-955176 40 mg with two ritonavir 100 mg doses given twelve hours apart increased the GMR Cmax and AUC of BMS-955176 by 11% and 48% respectively. After 14 days of BMS-955176 40 mg daily plus atazanavir 400 mg daily Ctau increased 26% versus BMS-955176 administered alone.
References
H Sevinsky, Y Gandhi, B Vakkalagadda, P Ravindran, A Schuster, M Stonier, et al. Pharmacokinetics and exploratory interactions of hiv maturation inhibitor bms-955176 in healthy subjects: single and multiple ascending dose studies. abstract p_63. 17thinternational Workshop On Clinical Pharmacology Of Hiv And Hepatitis Therapy. Washington DC, USA. ; 2016.
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