The effect of ABCG2 genotype on the population pharmacokinetics of sunitinib in patients with renal cell carcinoma.
BACKGROUND
Sunitinib, a multitargeted tyrosine kinase inhibitor, offers favorable therapeutic outcomes to patients with advanced renal cell carcinoma. However, to maximize the clinical benefits, an effective therapeutic management strategy with dose optimization is essential. The objectives of this analysis were to describe the pharmacokinetics (PK) of sunitinib by a population PK approach and to quantitatively evaluate the effect of potential predictive factors including ABCG2 genotype on the PK of sunitinib.


METHODS
Plasma concentration-time profiles at 3 consecutive days including a total of 245 sunitinib plasma concentrations were available from 19 Japanese patients with renal cell carcinoma. Blood samples were collected on days 2, 8, and 15 after the start of the therapy. Population PK analysis was performed using NONMEM 7.2. Body weight, gender, and genotype of ABCG2 421C>A were evaluated as potential covariates. Interoccasion variability (IOV) among the 3 sampling days was also assessed as a random effect parameter.


RESULTS
The sunitinib PK profiles were best described by a 1-compartment model with first-order absorption. The ABCG2 421C>A genotype was identified as a significant covariate for the prediction of oral clearance (CL/F). No significant improvement in model fit was observed by including body weight and/or gender. A systematic difference in estimated population CL/F was observed between days 2 and 8, which was quantified as approximately 30% decrease over time. This difference was described as a covariate for CL/F in the model. IOV included as a random effect parameter significantly improved the model fit.


CONCLUSIONS
This analysis provides a population PK model of sunitinib with the ABCG2 421C>A genotype as a predictive covariate for CL/F. It also suggests that IOV and change of CL/F over time need to be considered to predict the sunitinib PK more accurately. These findings will be implemented to optimize the pharmacotherapy of sunitinib.
*Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Japan; †Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center; ‡Department of Pediatrics, College of Medicine, University of Cincinnati, Ohio; and §Department of Urology, Graduate School of Medicine, Kyoto University, Japan. Dr Terada is now with the Department of Pharmacy, Shiga University of Medical Science Hospital, Japan; Dr Katsura is now with the College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan; and Dr Inui is now with the Kyoto Pharmaceutical University, Japan.
Tomoyuki
T
Mizuno
Masahide
M
Fukudo
Tsuyoshi
T
Fukuda
Tomohiro
T
Terada
Min
M
Dong
Tomomi
T
Kamba
Toshinari
T
Yamasaki
Osamu
O
Ogawa
Toshiya
T
Katsura
Ken-Ichi
K
Inui
Alexander A
AA
Vinks
Kazuo
K
Matsubara
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000652:urine; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D005260:Female; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007564:Japan; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics*; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077210:Sunitinib
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007211:Indoles; D009363:Neoplasm Proteins; D011758:Pyrroles; D000077210:Sunitinib