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Monday 01 May 2006

Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics.

By: Lathia C, Lettieri J, Cihon F, Gallentine M, Radtke M, Sundaresan P.

Cancer Chemother Pharmacol 2006 May;57(5):685-92

Sorafenib is a novel, small-molecule anticancer compound that inhibits tumor cell proliferation by targeting Raf in the Raf/MEK/ERK signalling pathway, and inhibits angiogenesis by targeting tyrosine kinases such as vascular-endothelial growth factor receptor (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor (PDGFR). In vitro microsomal data indicate that sorafenib is metabolized by two pathways: phase I oxidation mediated by cytochrome P450 (CYP) 3A4; and phase II conjugation mediated by UGT1A9. Approximately 50% of an orally administered dose is recovered as unchanged drug in the feces, due to either biliary excretion or lack of absorption. The aim of this study was to evaluate the effect of CYP3A inhibition by ketoconazole on sorafenib pharmacokinetics. This was an open-label, non-randomized, 2-period, one-way crossover study in sixteen healthy male subjects. A single 50 mg dose of sorafenib was administered alone (period 1) and in combination with ketoconazole 400 mg once daily (period 2) (ketoconazole was given for 7 days, and a single 50 mg sorafenib dose was administered concomitantly on day 4). No clinically relevant change in pharmacokinetics of sorafenib and no clinically relevant adverse events or laboratory abnormalities were observed in this study upon co-administration of the two drugs. Plasma concentrations of the main CYP3A4 generated metabolite, sorafenib N-oxide, decreased considerably upon ketoconazole co-administration. This effect is in accordance with the in vitro finding that CYP3A4 is the primary enzyme for sorafenib N-oxide formation. Further, these data indicate that blocking sorafenib metabolism by the CYP3A4 pathway will not lead to an increase in sorafenib exposure. This is consistent with data from a clinical mass-balance study that showed 15% of the administered dose was eliminated by glucuronidation, compared to less than 5% eliminated as oxidative metabolites. Since there was no increase in sorafenib exposure following concomitant administration of the highly potent CYP3A4 inhibitor ketoconazole with low dose sorafenib, it is postulated that higher therapeutic doses of sorafenib may be safely co-administered with ketoconazole, as well as with other inhibitors of CYP3A.

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