RT Journal Article
SR Electronic
T1 A Population Pharmacokinetic Meta-analysis of Sunitinib Malate (SU11248) and Its Primary Metabolite (SU12662) in Healthy Volunteers and Oncology Patients
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 2497
OP 2506
DO 10.1158/1078-0432.CCR-08-1893
VO 15
IS 7
A1 Houk, Brett E.
A1 Bello, Carlo L.
A1 Kang, Dongwoo
A1 Amantea, Michael
YR 2009
UL http://clincancerres.aacrjournals.org/content/15/7/2497.abstract
AB Purpose: Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumor. Following administration, sunitinib is metabolized by cytochrome P450 3A4 to an active metabolite (SU12662). The objective of this analysis was to assess sunitinib and SU12662 pharmacokinetics and to identify covariates that might explain variability in exposure following oral administration. Experimental Design: Data from 590 subjects (73 volunteers and 517 patients) in 14 studies were analyzed. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling to estimate population pharmacokinetic parameters, as well as relationships between these parameters and gender, race, age, weight, creatinine clearance, Eastern Cooperative Oncology Group score, and tumor type. Simulations were done to determine the predicted effect of these covariates on exposure. Results: Separate models were developed for sunitinib and SU12662 (each a two-compartment model with first-order absorption and elimination). Sunitinib parameters were estimated as CL/F, 51.8 L/h and Vd/Fcentral, 2,030 liters. SU12662 parameters were estimated as CL/F, 29.6 L/h and Vd/Fcentral, 3,080 liters. Tumor type (except acute myeloid leukemia), Asian race, gender, body weight, and elevated Eastern Cooperative Oncology Group score described a portion of the variability in CL/F for sunitinib and metabolite; gender and body weight explained some of the variability in Vd/Fcentral for sunitinib and metabolite. Among patients, the predicted changes in sunitinib and metabolite AUC and Cmax as a result of the individual covariates ranged up to 17%. Conclusion: The magnitude of the predicted changes in exposure with the covariates studied minimizes the necessity for dose adjustment in any of these subpopulations.