The effect of food on the single dose pharmacokinetics of cediranib.
Jayson GC., Evans TR., Harris A., Mitchell CL., Kelly C., Middleton M., Fielding A., Laud P., Robertson J., Puchalski TA.
14533 Background: Cediranib (AZD2171) is an oral, highly potent and selective inhibitor of vascular endothelial growth factor (VEGF) signaling, with activity against VEGFR-1, -2 and -3. The effect of food on the pharmacokinetic (PK) profile of cediranib is not known. This study compared the single dose exposure PK parameters of cediranib following single oral doses to patients after a) a standard regulatory meal and b) an overnight fast. METHODS: In this randomized, open-label, two-period, crossover study, 34 patients with advanced solid tumors refractory to standard therapies, ECOG PS ≤2, with adequate hematologic, renal and liver function, received two single doses of cediranib 45 mg with ≥8 days washout period. Patients were randomized to receive treatment in either the fed then the fasted state (group 1) or the fasted then the fed state (group 2). In the fed period, patients ate a standard high-fat breakfast (as per FDA guidelines) prior to dosing with cediranib. In both groups, intensive PK sampling occurred over 168 hours post dosing on each occasion. The effect of food on the single dose PK of cediranib was assessed using the criteria for establishing bioequivalence based on the endpoints of AUC and Cmax. Food would be considered to have no effect on the PK of cediranib if confidence intervals (CI) for the food effect ratio for endpoints of AUC and Cmax fell within the acceptance range of 0.8-1.25. CI of 94% were used in order to allow for the 2-group sequential design of the study and obtain an overall 5% significance level. RESULTS: Both the AUC and Cmax of cediranib were lower in the presence of food by a mean of 24% and 33% respectively (94% CI: AUC, 12-34% and Cmax, 20-43%; Table 1 ). The CI for AUC crossed the lower equivalence boundary of 0.8 but the entirety of the CI was <1. The CI for Cmax was entirely outside the equivalence boundary, indicating a clear food effect. CONCLUSIONS: These data indicate that food reduces cediranib plasma exposure in terms of AUC and Cmax. It is recommended that cediranib be administered at least 1 hour before or 2 hours after food. [Table: see text] [Table: see text].