Evaluation of the effect of food and ketoconazole on the pharmacokinetics of the smoothened inhibitor PF-04449913 in healthy volunteers

To evaluate the effect of a potent cytochrome P450 3A4 (CYP3A4) inhibitor, ketoconazole, and separately the effect of food on PF-04449913 pharmacokinetics in healthy volunteers. This was an open-label, two-sequence, three-period, three-treatment, single-dose, crossover study. Subjects were randomized to receive single doses of 200 mg PF-04449913 after an overnight fast or after consuming a high-fat meal during Period 1 or 2, with a washout period of at least 8 days. In Period 3, all subjects received ketoconazole (400 mg/day) (days 1-7) and a co-administered single 200-mg PF-04449913 dose (day 4). Geometric mean ratio of PF-04449913 in the presence of ketoconazole versus PF-04449913 alone was 2.40 [90 % confidence interval (CI) 2.15, 2.68] for area under the plasma concentration-time curve from time zero to infinity (AUC(0-inf)) and 1.40 (90 % CI 1.24, 1.58) for peak plasma concentration (C (max)). The geometric mean ratio for fed state compared with fasted state for AUC(0-inf) was 0.87 (90 % CI 0.78, 0.97) and for C (max) was 0.66 (90 % CI 0.56, 0.78). PF-04449913 was well tolerated, and all adverse events were mild to moderate. PF-04449913 plasma exposures and peak concentrations were increased following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for expected PF-04449913 exposures after co-administration of a strong CYP3A4 inhibitor in patients with cancer who routinely receive antifungal azoles. While a high-fat meal decreased PF-04449913 exposure, the differences in plasma exposure under the two conditions were not considered clinically meaningful.