Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients.

Abstract

Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients. Pharmacokinetic data were available from 96 patients from three clinical studies. A multi-compartment model including (i) a complex absorption profile, (ii) the potential non-linear dose-concentration relationship and (iii) the potential long-term decrease in exposure was developed. A two-compartment model best described pazopanib pharmacokinetics. The absorption phase was modelled by two first-order processes: 36% (relative standard error [RSE] 34%) of the administered dose was absorbed with a relatively fast rate (0.4h-1 [RSE 31%]); after a lag time of 1.0h (RSE 6%), the remaining dose was absorbed at a slower rate (0.1h-1 [RSE 28%]). The relative bioavailability (rF) at a dose of 200mg was fixed to 1. With an increasing dose, the rF was strongly reduced, which was modelled with an E max (maximum effect) model (E max was fixed to 1, the dose at half of maximum effect was estimated as 480mg [RSE 23%]). Interestingly, the plasma exposure to pazopanib also decreased over time, modelled on rF with a maximum magnitude of 50% (RSE 27%) and a first-order decay constant of 0.15day-1 (RSE 43%). The inter-patient and intra-patient variability on rF were estimated as 36% (RSE 16%) and 75% (RSE 22%), respectively. A popPK model for pazopanib was developed that illustrated the complex absorption process, the non-linear dose-concentration relationship, the high inter-patient and intra-patient variability, and the first-order decay of pazopanib concentration over time. The developed popPK model can be used in clinical practice to screen covariates and guide therapeutic drug monitoring.