Cancer Chemotherapy and Pharmacology

, Volume 78, Issue 3, pp 623–632 | Cite as

BSA and ABCB1 polymorphism affect the pharmacokinetics of sunitinib and its active metabolite in Asian mRCC patients receiving an attenuated sunitinib dosing regimen

  • Jung-woo Chae
  • Yi Ling Teo
  • Han Kiat Ho
  • Jaeyeon Lee
  • Hyun-moon Back
  • Hwi-yeol Yun
  • Mats O. Karlsson
  • Kwang-il KwonEmail author
  • Alexandre ChanEmail author
Original Article



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.


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.


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 m2 in relation to sunitinib clearance was 31.14 % (p = 0.006) and 22.11 % (p = 0.011), respectively, relative to the reference group.


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.


Sunitinib SU12662 Population pharmacokinetics Metastatic renal cell carcinoma Attenuated sunitinib dosing regimen Body surface area ABCB1 polymorphism 



The authors would like to acknowledge the Singapore Cancer Society for the provision of grant support for this work. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2014R1A1A1006006). This work was supported by research fund of Chungnam National University.

Compliance with ethical standards

Conflict of interest

Chan serves as consultant for Merck Sharp and Dohme and Mundipharma. All remaining authors have declared no conflicts of interest.

Supplementary material

280_2016_3104_MOESM1_ESM.doc (34 kb)
Supplementary material 1 (DOC 34 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Jung-woo Chae
    • 1
    • 2
  • Yi Ling Teo
    • 2
  • Han Kiat Ho
    • 2
  • Jaeyeon Lee
    • 1
  • Hyun-moon Back
    • 1
  • Hwi-yeol Yun
    • 1
  • Mats O. Karlsson
    • 4
  • Kwang-il Kwon
    • 1
    Email author
  • Alexandre Chan
    • 2
    • 3
    Email author
  1. 1.College of PharmacyChungnam National UniversityDaejeonKorea
  2. 2.Department of Pharmacy, Faculty of ScienceNational University of SingaporeSingaporeSingapore
  3. 3.Oncology PharmacyNational Cancer Centre SingaporeSingaporeSingapore
  4. 4.Department of Pharmaceutical BiosciencesUppsala UniversityUppsalaSweden

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