Population Pharmacokinetics of Sunitinib and its Active Metabolite SU012662 in Pediatric Patients with Gastrointestinal Stromal Tumors or Other Solid Tumors

Abstract

Background and objective: Population pharmacokinetic analysis explored the pharmacokinetics of sunitinib and its primary active metabolite, SU012662, in children and evaluated the sunitinib dose(s) that produce comparable plasma exposures to adults receiving the approved daily dose.

Methods: Data were from 65 children with gastrointestinal stromal tumors (GIST) or solid tumors. Pharmacokinetic models of sunitinib and SU012662 were developed using a systematic multi-step approach employing nonlinear mixed-effects modeling. The effect of predefined covariates on pharmacokinetic parameters was assessed. Final models were validated using visual predictive check and statistical techniques.

Results: The final dataset comprised 439 sunitinib and 417 SU012662 post-baseline plasma observations. Base models were characterized by two-compartment models with first-order absorption and lag time. Body surface area (BSA) was the only covariate that affected (P < 0.001) pharmacokinetic parameters for sunitinib and SU012662 and was incorporated into the final models. Bootstrap results indicated that the final models represented the final dataset adequately. Based on the final models, a sunitinib dose of ~ 20mg/m2/day in children with GIST aged 6-17 years would be expected to lead to similar total plasma exposures of sunitinib and SU012661 as a dose of 50 mg/day in an adult with GIST on schedule 4/2.

Conclusions: In children with GIST or solid tumors receiving sunitinib, population pharmacokinetic analysis identified BSA as the only covariate that affected pharmacokinetic parameters and predicted a dose of ~ 20 mg/m2/day as achieving equivalent exposure to 50 mg/day in adults with GIST on schedule 4/2.

Trial registration: ClinicalTrials.gov identifiers (date registered): NCT01396148 (July 2011); NCT01462695 (October 2011); NCT00387920 (October 2006).

Conflict of interest statement

EW and RK are employees of Pfizer and hold stock or stock options with Pfizer. SGD has received travel expenses from Roche, Salarius, and Loxo Oncology, and consulting fees from Bayer and Loxo Oncology. CW has received research support and prior travel expenses from Eli Lilly & Co, and is an employee Exelixis Inc and holds stock or stock options with Exelixis Inc. ACV is a consultant for Pfizer.

Figures

Fig. 1

Goodness-of-fit diagnostic plots for plasma sunitinib (a) and SU012662 (b) concentrations from the final model.

Fig. 2

Visual predictive check plots for sunitinib (a) and SU012662 (b) in the first 12 h post-dose and for sunitinib (c) and SU012662 (d) up to 3000 h post-dose. Blue circles represent the observed data, and the red lines represent the median (solid line) and 2.5th and 97.5th percentiles (dashed lines) of the observed data. The solid black line and dashed black lines represent the median and 2.5th and 97.5th percentiles of the simulated data. The 95% confidence intervals for the simulated median and each percentile are shown by the pink and blue shaded areas, respectively. Sunitinib was administered at a dose of 15 mg/m2 once daily on a schedule of 4 weeks on treatment followed by 2 weeks off treatment (schedule 4/2)

Fig. 3

Effect of BSA on sunitinib (a) and SU012662 (b) AUC following multiple dosing of sunitinib 20 mg/m2 for different age groups, based on the final model. Effects are presented as probability density plots on a relative scale to indicate proportional size and precision relative to the adult reference patient. The plots represent distributions of 1000 nonparametric bootstrap estimates, with the heights of the plots representing probability. The reference is the geometric mean steady-state 24 h sunitinib and SU012662 AUCs of 1233 and 551 ng • h/ml, respectively, in an adult patient with GIST receiving a sunitinib dose of 50 mg. The green shaded areas represent the 0.75–1.25 ratio range. AUC area under the curve, BSA body surface area, GIST gastrointestinal stromal tumor