Pharmacokinetics and Pharmacodynamics of GS-9350: A Novel Pharmacokinetic Enhancer Without Anti-HIV Activity

Abstract

GS-9350 is a new chemical entity under development as a potent, mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) isoforms. Its intended use is to increase the systemic exposure of coadministered agents that are metabolized by CYP3A enzymes. Unlike ritonavir, which is in current clinical use for this purpose, GS-9350 is devoid of anti-HIV activity. The pharmacokinetics of GS-9350 and its efficacy in increasing systemic exposure of the probe CYP3A substrate midazolam were examined in a study involving single- and multiple-dose escalations of GS-9350 from 50 to 400 mg. Single-dose escalation from 50 to 400 mg resulted in a 164-fold increase in GS-9350 exposure, whereas multiple-dose escalation in the dosage range of 50-300 mg resulted in a 47-fold increase in exposure. GS-9350 potently inhibited midazolam apparent clearance (95% reduction), similar in effect to ritonavir 100 mg. GS-9350 was generally well tolerated at all doses, and there was no evidence of dose-limiting toxicity. Establishing proof-of-concept, GS-9350 is currently under phase II development as a potential alternative to ritonavir for use with antiretroviral agents (including the HIV integrase inhibitor elvitegravir) that are often prescribed along with a "booster" drug.

Combination Drug Products for HIV–A Word of Caution for the Transplant Clinician

“…The dosing administration was similar to that seen in ritonavir-treated kidney and liver recipients, in which dose reductions of up to 99% have been reported (13)(14)(15). This finding is also consistent with pharmacokinetic data demonstrating similar inhibition of midazolam (a CYP3A substrate) clearance when compared to ritonavir (16). Of note, cobicistat may decrease estimated creatinine clearance due to inhibition of tubular secretion While many studies report little to no clinically relevant interaction between EFV and calcineurin inhibitors, a large study evaluating drug-drug interactions (DDI) in human immunodeficiency virus (HIV)-positive transplant recipients found an almost twofold increase in cyclosporine dosage requirements (8-10).…”

Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer

“…Compound 3 also showed dose nonlinear and time-dependent PKs, consistent with it being a mechanism-based inhibitor. 25 CYP3A enzymes are known to display substrate dependence in their susceptibility to inhibition. To confirm that compound 3 also retains broad substrate specificity similar to that of RTV in inhibiting CYP3A, we compared the abilities of RTV and 3 to inhibit metabolism of a diverse set of substrates using assay protocols based on current industry and regulatory guidelines.…”

“…13,25 When used as a component of the integrase FDR Quad, 3 (150 mg once daily) enhanced the PK of elvitegravir to similar levels (C trough ) as boosted with 100 mg of once daily RTV. 13,25 Additionally, 3 boosted plasma concentrations of ATV to levels that were bioequivalent to those obtained when coadministered with 100 mg of once daily RTV. 31 Compound 3 is currently being evaluated in phase II studies in HIV-1-infected subjects, both as a component of Quad and as a pharmacoenhancer for ATV.…”

Impact and differential clinical utility of cobicistat-boosted darunavir in HIV/AIDS

“…Potent inhibition of CYP3A activity has also been demonstrated with Cobi in a Phase I study in healthy volunteers (n#60). 12 Upon coadministration, oral Cobi at doses of 100 and 200 mg increased the median half-life of oral midazolam 2.1-and 3.7-fold and reduced its mean apparent clearance by 93% and 95%, respectively. Similarly, RTV 100 mg increased the midazolam half-life 4.9-fold and reduced the midazolam clearance by 96%.…”