1. Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics
Chetan Lathia, John Lettieri, Frank Cihon, Martha Gallentine, Martin Radtke, Pavur Sundaresan. Cancer Chemother Pharmacol (2006) 57: 685–692
On day 1 of period 1, all subjects received a single oral dose of sorafenib tosylate 50 mg tablet (calculated as free base sorafenib). After at least a 10-day washout, 400 mg ketoconazole (Nizoral, Janssen Pharmaceutica, Titusville, NJ; Batch 91P0982E) was administered for three consecutive days in period 2. On day 4 in period 2, a single dose of sorafenib tosylate 50 mg tablet (calculated as free base sorafenib) from the same batch as in period 1 was co-administered with 400 mg ketoconazole. Sorafenib doses were administered in the fasted state with 240 ml of water. Ketoconazole was administered for three additional days in period 2 (days 5, 6 and 7) to maintain CYP3A inhibition for the duration of blood sampling. Blood samples (5 ml) for the determination of sorafenib and its metabolite concentrations in plasma were collected before and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, 120, and 168 h after drug administration. Samples were prepared by centrifugation to obtain plasma, which was frozen at -20 ℃ until analysis.