title: BSA and ABCB1 polymorphism affect the pharmacokinetics of sunitinib and its active metabolite in Asian mRCC patients receiving an attenuated sunitinib dosing regimen.
abstract: OBJECTIVE
  An attenuated dosing (AD) sunitinib regimen of 37.5 mg daily has been suggested to reduce the toxicity reported with the standard dosing regimen to metastatic renal cell carcinoma (mRCC) patients. The aim of this study was to characterize the population pharmacokinetic (PK) properties of sunitinib and SU12662, the active metabolite, in patients receiving the AD regimen and to ascertain significant covariates influencing PK parameters.
  
  
  METHODS
  Thirty-one mRCC patients receiving AD sunitinib regimen were included. Plasma samples were collected on day 29 of each treatment cycle after the start of the therapy. Nonlinear mixed-effects modeling was applied to estimate the population PK properties of sunitinib and SU12662 as well as the effect of covariates on PK parameters. Monte Carlo simulation was also performed to predict the total trough level (TTL) of sunitinib and SU12662.
  
  
  RESULTS
  Sunitinib population means for CL/F and V d /F central were 13.8 L/h and 1720 L, respectively. SU12662 population means for CL/F and V d /F were 42.1 L/h and 1410 L, respectively. Body surface area (BSA) and ABCB1 polymorphism significantly influenced the CL/F variability of sunitinib: CL/F parent = 13.8 × exp((BSA - 1.75) × 2.08 + (ABCB1 genotype - 0.67) × 0.61), ABCB1-0: wild genotype, 1: mutant genotype. The effect size of ABCB1 mutant genotype and BSA greater than 1.75 m(2) in relation to sunitinib clearance was 31.14 % (p = 0.006) and 22.11 % (p = 0.011), respectively, relative to the reference group.
  
  
  CONCLUSIONS
  Adjusting doses of sunitinib according to BSA and ABCB1 polymorphism in Asian mRCC patients may be recommended for sufficient attainment of a target TTL of sunitinib and its metabolite.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, 305-764, Korea.|Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Block S4A, Singapore, 117543, Singapore.
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Chae
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Block S4A, Singapore, 117543, Singapore.
authors.forename: Yi Ling
authors.initials: YL
authors.lastname: Teo
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Block S4A, Singapore, 117543, Singapore.
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, 305-764, Korea.
authors.forename: Jaeyeon
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, 305-764, Korea.
authors.forename: Hyun-Moon
authors.initials: HM
authors.lastname: Back
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, 305-764, Korea.
authors.forename: Hwi-Yeol
authors.initials: HY
authors.lastname: Yun
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, 305-764, Korea. kwon@cnu.ac.kr.
authors.forename: Kwang-Il
authors.initials: KI
authors.lastname: Kwon
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Block S4A, Singapore, 117543, Singapore. phaac@nus.edu.sg.|Oncology Pharmacy, National Cancer Centre Singapore, Singapore, 169610, Singapore. phaac@nus.edu.sg.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D044466:Asian People; D001830:Body Surface Area; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D009362:Neoplasm Metastasis; D017711:Nonlinear Dynamics; D011110:Polymorphism, Genetic; D011758:Pyrroles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077210:Sunitinib
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C544393:SU 12662; D000077210:Sunitinib
keywords: ABCB1 polymorphism; Attenuated sunitinib dosing regimen; Body surface area; Metastatic renal cell carcinoma; Population pharmacokinetics; SU12662; Sunitinib