Population pharmacokinetic and exposure simulation analysis for cediranib (AZD2171) in pooled Phase I/II studies in patients with cancer.

Abstract

A population pharmacokinetic (PK) model was developed for cediranib to simulate cediranib exposure for different doses, including comedication with strong uridine glucuronosyl transferase/P-glycoprotein inducers such as rifampicin, in cancer patients. Plasma concentrations and covariates from 625 cancer patients after single or multiple oral cediranib administrations ranging from 0.5 to 90 mg in 19 Phase I and II studies were included in the analysis. Stepwise covariate modelling was used to develop the population PK model. The final model was used to simulate cediranib exposure in cancer patients to evaluate cediranib target coverage and the need for dose adjustment for covariates or coadministration with rifampicin. A two-compartment model with sequential zero- and first-order absorption and first-order elimination adequately described the cediranib concentration-time courses. Body weight and age were identified as having statistically significant impact on cediranib PK, but only <21% impact on AUC and maximum concentrations. Simulated lower bounds of 90% prediction interval or median of unbound cediranib concentrations after cediranib 15 or 20 mg exceeded the IC50 for vascular endothelial growth factor receptors-1, -2 and -3. Exposures of cediranib 20 or 30 mg with coadministration of rifampicin were comparable to those of 15 or 20 mg, respectively, without coadministration. No covariate was identified to require dose adjustment for cediranib. Cediranib exposure following 15 or 20 mg daily dose administration is adequate overall for inhibition of in vitro estimated vascular endothelial growth factor receptor-1, -2 and -3 activities. An increase in cediranib dose may be needed for cediranib coadministered with strong uridine glucuronosyl transferase/P-glycoprotein inducers such as rifampicin.