Integrated semi-physiological pharmacokinetic model for both sunitinib and its active metabolite SU12662

Abstract

AIMS: Previously published pharmacokinetics (PK) models for sunitinib and its active metabolite SU12662 were based on a limited dataset or lacked important elements such us correlations between sunitinib and its metabolite. The current study was to develop an improved PK model that circumvented these limitations and to prove the utility of the PK model in treatment optimisation in clinical practice. METHODS: 1205 plasma samples from 70 cancer patients were collected from three PK studies with sunitinib and SU12662. A semi-physiological PK model for sunitinib and SU12662 was developed incorporating pre-systemic metabolism using nonlinear mixed-effects modelling (NONMEM). Allometric scaling based on body weight was applied. The final model was used for simulation of the PK of different treatment regimens. RESULTS: Sunitinib and SU12662 PK were best described by one and two compartment model, respectively. Introduction of pre-systemic formation of SU12662 strongly improved model fit, compared to solely systemic metabolism. The clearance of sunitinib and SU12662 was estimated at 35.7 (relative standard error (RSE) 5.7%) L·h(-1) and 17.1 (RSE 7.4%) L·h(-1) , respectively for 70 kg patients. Correlation coefficients were estimated between inter-individual variability of both clearances, both volume of distributions, and between clearance and volume of distribution of SU12662 as 0.53, 0.48 and 0.45, respectively. Simulation of the PK model predicted correctly the ratio of patients that not reaching proposed PK targets for efficacy. CONCLUSIONS: A semi-physiological PK model for sunitinib and SU12662 in cancer patients was presented including pre-systemic metabolism. The model was superior to previous PK models in multiple aspects.