Sunitinib (SU) pharmacokinetic (PK)–pharmacodynamic (PD) modeling with respect to safety and efficacy endpoints in Asian patients (pts) with gastrointestinal stromal tumor (GIST) or renal cell carcinoma (RCC) in pursuit of a therapeutic window.

Abstract

e15128 Background: SU is an oral multitargeted tyrosine kinase inhibitor, approved multinationally for the treatment of advanced RCC, imatinib-resistant or -intolerant GIST, and well-differentiated pancreatic neuroendocrine tumor. We explored SU PK–PD relationships with respect to safety and efficacy endpoints to determine a therapeutic window for SU in Asian pts with GIST and RCC. Methods: We analyzed pooled PK–PD data from two Japanese phase II studies in pts with GIST and RCC (N=81 combined) using NONMEM V7.0. We initially built a PK model (2-compartments with 1st order absorption and elimination) to describe SU PK data. Subsequently, different sequential semi-mechanistic or mechanism-based (i.e., transit compartments with feedback loop [TCF] or indirect response [IDR] with Emax or sigmoid Emax drug effect) PK–PD models were built and compared for selection of a PK–PD model to describe each PD endpoint; these models were internally validated by Visual Predictive Check using PsN and Xpose. Results: Key PK–PD model characteristics or parameter estimates are shown in the table below. There appeared to be great inter-pt variability in, and overlap between, the exposure-response curves for safety endpoints and that of the efficacy endpoint. Conclusions: We could not identify a therapeutic window for SU in Asian pts with GIST and RCC. SU dose modification based on individual pt safety/tolerability appears to be the best approach to ensure maximum SU plasma exposure and efficacy, consistent with the SU label recommendation. PD endpoint PK–PD model EC50 Mean (CV) ng/mL (%) γ Mean Safety Absolute neutrophil count TCF 6.91 (146) 1(F) Platelet count TCF 55.7 (27) 5.22 Lymphocyte count IDR 98.6 (NE) 3.09 LVEF IDR 1050 (180) 1(F) Diastolic blood pressure IDR 318 (44) 1(F) AST TCF 74.7 (NE) 4.66 Efficacy SLD IDR 80.1 (248) 1(F) Abbreviations: CV, coefficient of variation; EC50, SU concentration at which 50% of the maximum effect is achieved; F, fixed; γ (gamma), Hill coefficient; LVEF, left ventricular ejection fraction; NE, not estimable; SLD, sum of the largest diameters of target tumors.