Population pharmacokinetics-pharmacodynamics of sunitinib in pediatric patients with solid tumors

Abstract

Purpose: The safety profile of sunitinib in children, including the impact of sunitinib exposure on safety endpoints, was assessed using population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) models.

Methods: Data were from two clinical studies in 59 children with solid tumors (age range 2-21 years, 28 male/31 female, body weight range 16.2-100 kg, body surface are [BSA] range 0.7-2.1 m2). Analysis of covariates that affected PK and PD parameters was conducted using a nonlinear mixed-effects model. Safety and tolerability endpoints were absolute neutrophil count, hepatic transaminases, diastolic blood pressure, hemoglobin, lymphocyte count, platelet count, white blood cell count, hand-foot syndrome, fatigue, nausea, intracranial hemorrhage, and vomiting.

Results: The models well described the time courses of concentrations of sunitinib and its primary active metabolite SU012662, as well as safety and tolerability endpoints. In PK models for sunitinib and SU012662, BSA was the only covariate that statistically significantly affected apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). Higher BSA was associated with greater CL/F and Vc/F. No statistically significant covariates were identified in the PK-PD models. For safety endpoints that had a sufficient number of adverse events, a higher probability of adverse events was associated with higher average plasma sunitinib concentrations.

Conclusion: In PK models, BSA was the only covariate that affected major PK parameters of sunitinib and SU012662. Based on analysis of safety and tolerability endpoints, the PK-PD relationships were mainly driven by sunitinib plasma exposures and were not affected by age, sex, respective baseline safety endpoint values, baseline Eastern Cooperative Oncology Group performance status, or body size.

Trial registration: ClinicalTrials.gov: NCT00387920 (registered October 13, 2006), NCT01462695 (registered October 31, 2011).

Keywords: Children; Pharmacodynamic; Pharmacokinetic; Safety; Solid tumor; Sunitinib.

Conflict of interest statement

Erjian Wang and Reza Khosravan are employees of Pfizer and hold stock or stock options with Pfizer. Steven G. DuBois has received prior travel expenses from Loxo Oncology, Roche and Salarius, and prior consulting fees from Loxo Oncology. Cynthia Wetmore has received research support and prior travel expenses from Eli Lilly & Co.

Figures

Fig. 1

Final model prediction and variance-corrected visual predictive check plots for sunitinib and SU012662 plasma concentrations, and safety and tolerability endpoints, up to 3000 h post-dose. Visual predictive check plots for a sunitinib, b SU012662, c ANC, d ALT, e AST, f diastolic BP, g hemoglobin, h lymphocyte count, i platelet count, and j WBC count. Blue circles represent the observed data. Red lines represent the median (solid line) and 2.5th and 97.5th percentiles (dashed lines) of the observed data. Black lines represent the median (solid line) and 2.5th and 97.5th percentiles (dashed lines) of the simulated data. The 95% CIs for simulated median and each percentile are shown by pink and blue shaded areas, respectively. ALT alanine transaminase, ANC absolute neutrophil count, AST aspartate transaminase, BP blood pressure, WBC white blood cell

Fig. 2

Observed and predicted probabilities of worst adverse event grades for the safety and tolerability endpoints. Probabilities of worst grade adverse events for a neutropenia (n = 23 patients), b increased ALT (n = 15), c increased AST (n = 13), d hypertension (n = 10), (E) lymphopenia (n = 16), f thrombocytopenia (n = 13), g leukopenia (n = 20), h fatigue (n = 24), i nausea (n = 7), and j vomiting (n = 7). ALT alanine transaminase, AST aspartate transaminase