Population pharmacokinetics of sunitinib in Japanese and Western healthy volunteers, solid tumor, metastatic renal cell carcinoma (MRCC) and imatinib-resistant or -intolerant gastrointestinal stromal tumors (GIST) patients

Abstract

2522 Background: Sunitinib, an oral multi-targeted tyrosine kinase inhibitor, is approved internationally to treat advanced MRCC and imatinib-resistant or -intolerant GIST. Sunitinib is metabolized via CYP3A4 to an active metabolite, SU012662 (SU). Methods: Merged data from 12 Western and 2 Japanese studies in healthy volunteers (HV; n=73), GIST (n=241), MRCC (n=153), solid tumors (ST, n=95) and acute myelogenous leukemia (AML; n=29) patients were analyzed. The impact of tumor type, gender, performance status, creatinine clearance (CrCL), body weight (BW) and race on sunitinib and SU012662 clearance (CL/F) and volume of distribution (Vd/F) were assessed by nonlinear mixed effects modeling at p<0.01. Simulations with final parameter calculations estimated the impact of demographic and clinical factors on steady-state area under the curve (AUC) and maximum plasma concentrations (Cmax) of SU and total drug (SU + SU012662). Results: The terminal half-lives of sunitinib and SU012662 in HV were estimated to be 69 and 80 h, respectively. Inter- individual variability was estimated to be 38 % for CL/F and 43 % for Vd/F. Although tumor presence had the greatest impact on CL/F for SU and SU012662 vs HV, the magnitude of the decrease (26–29%) was similar across tumor types, except AML. Performance status and CrCL did not affect sunitinib or SU012662 CL/F. In Asians vs other races, CL/F decreased 13 % for sunitinib and 12 % for SU012662. CL/F was lower in females relative to males for sunitinib by 9 % and SU012662 by 26 %. BW correlated to sunitinib Vd/F, and to SU012662 CL/F and Vd/F. The lower CL/F in Asians predicted a 15% increase in AUC and Cmax for SU and total drug. In females, a 9–10% increase in AUC and a 17% increase in Cmax was predicted. Changes in total-drug AUC and Cmax were all <5% in low (40 kg) and high (100 kg) BW subjects. Conclusions: ST contributed the largest PK effect on sunitinib and SU012662. Asian race, gender, BW (metabolite only) and ECOG score had less impact. Predicted change are relatively small vs inter-individual variability. No dose adjustments are recommended for sunitinib based on the magnitude of predicted changes due to any covariate studied. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Inc Pfizer Inc