Pharmacokinetic Boosting of VX-950, an Inhibitor of HCV Protease, By Co-Dosing With Ritonavir:
Background HCV protease inhibitors (PIs) are a promising new class of small-molecule, peptidomimetric HCV antivirals. In initial clinical studies, antiviral activity has been associated with HCV PI plasma trough concentrations. However, modest pharmocokinetics and the need for frequent dosing may limit their efficacy. (emphasis being added) CO-DOSING WITH RITONAIVIR (RTV), A POTENT INHIBITOR OF CYP3A, HAS PROVEN USEFUL FOR PHARMACOKINETIC ENHANCEMENT OF PETIDOMIMETRIC HIV PIs, WHICH ARE METABOLIZED BY THIS ENZYME. We investigated the in vitro and in vivo interaction of the HCV PI VX-950 with RTV.
Methods: Metabolism rates (disappearance of parent compound) were measured in pooled human (HLM) and rat (RLM) liver microsomes at an initial concentration of 1.0 uM PI and 0.5 mg/ml microsomes. Inhibition by 0.4 and 4 uM RTV was assessed. Sprague-Dawley rates were dosed with VX-950 at 5 mg/kg orally by gavage, alone or with 5 mg/kg of RTV.
Results: In HLM and RLM, 70% and 75% of VX-950 was consumed within 30 minutes (estimated in vitro t1/2 17 and 16 min, respectively). In the presence of 4 uM RTV, metabolism of VX-950 in both HLM and RLM was >98% inhibited. At 0.4 uM RTV, >70% inhibition was observed. In rats, PLASMA EXPOSURE OF VX-950 INCREASED BY >8-FOLD WITH RTV CO-DOSING. PLASMA LEVELS 8 HOURS AFTER DOSING INCREASED BY >50-FOLD.
Conclusions: The metabolism of VX-950 is strongly inhibited by concentrations of RTV achieved with boosting doses. CO-DOSING OF VX-950 WITH RTV IN HUMANS IS EXPECTED TO SUBSTANTIALLY INCREASE VX-950 PLASMA EXPOSURE AND TROUGH LEVELS, AND SHOULD BE STUDIED.
Bad news huh? You have no credibility, you use what little knowledge you have to decieve. How pathetic.