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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

Abstract

Purpose

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 m2 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.

Keywords

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

Notes

Acknowledgments

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)

References

  1. 1.
    van Erp NP, Eechoute K, van der Veldt AA, Haanen JB, Reyners AK, Mathijssen RH, Boven E, van der Straaten T, Baak-Pablo RF, Wessels JA, Guchelaar HJ, Gelderblom H (2009) Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol 27(26):4406–4412. doi: 10.1200/JCO.2008.21.7679 CrossRefPubMedGoogle Scholar
  2. 2.
    Garcia-Donas J, Esteban E, Leandro-Garcia LJ, Castellano DE, del Alba AG, Climent MA, Arranz JA, Gallardo E, Puente J, Bellmunt J, Mellado B, Martinez E, Moreno F, Font A, Robledo M, Rodriguez-Antona C (2011) Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol 12(12):1143–1150. doi: 10.1016/S1470-2045(11)70266-2 CrossRefPubMedGoogle Scholar
  3. 3.
    van der Veldt AA, Eechoute K, Gelderblom H, Gietema J, Guchelaar HJ, van Erp NP, van den Eertwegh AJ, Haanen JB, Mathijssen RH, Wessels JA (2011) Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res 17(3):620–629. doi: 10.1158/1078-0432.CCR-10-1828 CrossRefPubMedGoogle Scholar
  4. 4.
    Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, Bello C, Deprimo S, Brega N, Massimini G, Armand JP, Scigalla P, Raymond E (2006) Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24(1):25–35. doi: 10.1200/JCO.2005.02.2194 CrossRefPubMedGoogle Scholar
  5. 5.
    Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, Bergsland E, Stuart K, Tye L, Huang X, Li JZ, Baum CM, Fuchs CS (2008) Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26(20):3403–3410. doi: 10.1200/JCO.2007.15.9020 CrossRefPubMedGoogle Scholar
  6. 6.
    Houk BE, Bello CL, Kang D, Amantea M (2009) A population pharmacokinetic meta-analysis of sunitinib malate (SU11248) and its primary metabolite (SU12662) in healthy volunteers and oncology patients. Clin Cancer Res 15(7):2497–2506. doi: 10.1158/1078-0432.CCR-08-1893 CrossRefPubMedGoogle Scholar
  7. 7.
    Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, Booth BP, Verbois SL, Morse DE, Liang CY, Chidambaram N, Jiang JX, Tang S, Mahjoob K, Justice R, Pazdur R (2007) Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 13(5):1367–1373. doi: 10.1158/1078-0432.CCR-06-2328 CrossRefPubMedGoogle Scholar
  8. 8.
    Yu H, Steeghs N, Nijenhuis CM, Schellens JH, Beijnen JH, Huitema AD (2014) Practical guidelines for therapeutic drug monitoring of anticancer tyrosine kinase inhibitors: focus on the pharmacokinetic targets. Clin Pharmacokinet 53(4):305–325. doi: 10.1007/s40262-014-0137-2 CrossRefPubMedGoogle Scholar
  9. 9.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356(2):115–124. doi: 10.1056/NEJMoa065044 CrossRefPubMedGoogle Scholar
  10. 10.
    Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schoffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R (2009) Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 10(8):757–763. doi: 10.1016/S1470-2045(09)70162-7 CrossRefPubMedGoogle Scholar
  11. 11.
    Yoo C, Kim JE, Lee JL, Ahn JH, Lee DH, Lee JS, Na S, Kim CS, Hong JH, Hong B, Song C, Ahn H (2010) The efficacy and safety of sunitinib in korean patients with advanced renal cell carcinoma: high incidence of toxicity leads to frequent dose reduction. Jpn J Clin Oncol 40(10):980–985. doi: 10.1093/jjco/hyq073 CrossRefPubMedGoogle Scholar
  12. 12.
    Lee SH, Bang YJ, Mainwaring P, Ng C, Chang JW, Kwong P, Li RK, Sriuranpong V, Toh CK, Yuan J, Pitman Lowenthal S, Chung HC (2014) Sunitinib in metastatic renal cell carcinoma: an ethnic Asian subpopulation analysis for safety and efficacy. Asia Pac J Clin Oncol 10(3):237–245. doi: 10.1111/ajco.12163 CrossRefPubMedGoogle Scholar
  13. 13.
    Tan HS, Li H, Hong YW, Toh CK, Wong A, Lopes G, Tay MH, Chan A, Yao X, Tang T, Ng QS, Kanesvaran R, Chau NM, Tan MH (2015) Efficacy and safety of an attenuated-dose sunitinib regimen in metastatic renal cell carcinoma: results from a prospective registry in Singapore. Clin Genitourin Cancer 13(4):e285–e295. doi: 10.1016/j.clgc.2014.11.004 CrossRefPubMedGoogle Scholar
  14. 14.
    Teo YL, Chue XP, Chau NM, Tan MH, Kanesvaran R, Wee HL, Ho HK, Chan A (2015) Association of drug exposure with toxicity and clinical response in metastatic renal cell carcinoma patients receiving an attenuated dosing regimen of sunitinib. Target Oncol 10(3):429–437. doi: 10.1007/s11523-014-0349-2 CrossRefPubMedGoogle Scholar
  15. 15.
    Kloth JS, Klumpen HJ, Yu H, Eechoute K, Samer CF, Kam BL, Huitema AD, Daali Y, Zwinderman AH, Balakrishnar B, Bennink RJ, Wong M, Schellens JH, Mathijssen RH, Gurney H (2014) Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib: the ClearSun study. Clin Pharmacokinet 53(3):261–269. doi: 10.1007/s40262-013-0111-4 CrossRefPubMedGoogle Scholar
  16. 16.
    Diekstra MH, Klumpen HJ, Lolkema MP, Yu H, Kloth JS, Gelderblom H, van Schaik RH, Gurney H, Swen JJ, Huitema AD, Steeghs N, Mathijssen RH (2014) Association analysis of genetic polymorphisms in genes related to sunitinib pharmacokinetics, specifically clearance of sunitinib and SU12662. Clin Pharmacol Ther 96(1):81–89. doi: 10.1038/clpt.2014.47 CrossRefPubMedGoogle Scholar
  17. 17.
    Teo YL, Chong XJ, Chue XP, Chau NM, Tan MH, Kanesvaran R, Wee HL, Ho HK, Chan A (2014) Role of sunitinib and SU12662 on dermatological toxicities in metastatic renal cell carcinoma patients: in vitro, in vivo, and outcomes investigation. Cancer Chemother Pharmacol 73(2):381–388. doi: 10.1007/s00280-013-2360-1 CrossRefPubMedGoogle Scholar
  18. 18.
    Etienne-Grimaldi MC, Renee N, Izzedine H, Milano G (2009) A routine feasible HPLC analysis for the anti-angiogenic tyrosine kinase inhibitor, sunitinib, and its main metabolite, SU12662, in plasma. J Chromatogr B Analyt Technol Biomed Life Sci 877(29):3757–3761. doi: 10.1016/j.jchromb.2009.09.011 CrossRefPubMedGoogle Scholar
  19. 19.
    Bruno R, Vivier N, Vergniol JC, De Phillips SL, Montay G, Sheiner LB (1996) A population pharmacokinetic model for docetaxel (Taxotere): model building and validation. J Pharmacokinet Biopharm 24(2):153–172CrossRefPubMedGoogle Scholar
  20. 20.
    Ette EI, Ludden TM (1995) Population pharmacokinetic modeling: the importance of informative graphics. Pharm Res 12(12):1845–1855CrossRefPubMedGoogle Scholar
  21. 21.
    Maitre PO, Buhrer M, Thomson D, Stanski DR (1991) A three-step approach combining Bayesian regression and NONMEM population analysis: application to midazolam. J Pharmacokinet Biopharm 19(4):377–384CrossRefPubMedGoogle Scholar
  22. 22.
    Mandema JW, Verotta D, Sheiner LB (1992) Building population pharmacokinetic–pharmacodynamic models. I. Models for covariate effects. J Pharmacokinet Biopharm 20(5):511–528CrossRefPubMedGoogle Scholar
  23. 23.
    Karlsson KE, Plan EL, Karlsson MO (2011) Performance of three estimation methods in repeated time-to-event modeling. AAPS J 13(1):83–91. doi: 10.1208/s12248-010-9248-3 CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Karlsson MO (2012) A full model approach based on the covariance matrix of parameters and covariates. In: Abstract, p 21Google Scholar
  25. 25.
    Hwi-yeol Y (2013) Evaluation of FREM and FFEM including use of model linearization. In: Abstract, p 22Google Scholar
  26. 26.
    Gastonguay M (2011) Full covariate models as an alternative to methods relying on statistical significance for inferences about covariate effects: a review of methodology and 42 case studies. In: Abstract, p 20Google Scholar
  27. 27.
    Lindauer A, Di Gion P, Kanefendt F, Tomalik-Scharte D, Kinzig M, Rodamer M, Dodos F, Sorgel F, Fuhr U, Jaehde U (2010) Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers. Clin Pharmacol Ther 87(5):601–608. doi: 10.1038/clpt.2010.20 CrossRefGoogle Scholar
  28. 28.
    Desar IM, Burger DM, Van Hoesel QG, Beijnen JH, Van Herpen CM, Van der Graaf WT (2009) Pharmacokinetics of sunitinib in an obese patient with a GIST. Ann Oncol 20(3):599–600. doi: 10.1093/annonc/mdn779 CrossRefPubMedGoogle Scholar
  29. 29.
    Lankheet NA, Kloth JS, Gadellaa-van Hooijdonk CG, Cirkel GA, Mathijssen RH, Lolkema MP, Schellens JH, Voest EE, Sleijfer S, de Jonge MJ, Haanen JB, Beijnen JH, Huitema AD, Steeghs N (2014) Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours. Br J Cancer 110(10):2441–2449. doi: 10.1038/bjc.2014.194 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Larson RA, Druker BJ, Guilhot F, O’Brien SG, Riviere GJ, Krahnke T, Gathmann I, Wang Y, Group IS (2008) Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111(8):4022–4028. doi: 10.1182/blood-2007-10-116475 CrossRefPubMedGoogle Scholar
  31. 31.
    Schmidli H, Peng B, Riviere GJ, Capdeville R, Hensley M, Gathmann I, Bolton AE, Racine-Poon A, Group IS (2005) Population pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia: results of a phase III study. Br J Clin Pharmacol 60(1):35–44. doi: 10.1111/j.1365-2125.2005.02372.x CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Guo F, Letrent SP, Sharma A (2007) Population pharmacokinetics of a HER2 tyrosine kinase inhibitor CP-724,714 in patients with advanced malignant HER2 positive solid tumors. Cancer Chemother Pharmacol 60(6):799–809. doi: 10.1007/s00280-007-0427-6 CrossRefPubMedGoogle Scholar
  33. 33.
    Sparreboom A, Wolff AC, Mathijssen RH, Chatelut E, Rowinsky EK, Verweij J, Baker SD (2007) Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol 25(30):4707–4713. doi: 10.1200/JCO.2007.11.2938 CrossRefPubMedGoogle Scholar
  34. 34.
    van Schinkel LD, Bakker LE, Jonker JT, de Roos A, Pijl H, Meinders AE, Jazet IM, Smit JW, Lamb HJ (2013) Functional and metabolic imaging of the cardiovascular system in young healthy South Asians and Caucasians unveils early differences. Diabetes Care 36(10):e178–e179. doi: 10.2337/dc13-0287 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Franken R, den Hartog AW, van de Riet L, Timmermans J, Scholte AJ, van den Berg MP, de Waard V, Zwinderman AH, Groenink M, Yip JW, Mulder BJM (2013) Clinical features differ substantially between caucasian and Asian populations of marfan syndrome. Circ J 77(11):2793–2798. doi: 10.1253/circj.CJ-13-0584 CrossRefPubMedGoogle Scholar
  36. 36.
    Uemura H, Shinohara N, Yuasa T, Tomita Y, Fujimoto H, Niwakawa M, Mugiya S, Miki T, Nonomura N, Takahashi M, Hasegawa Y, Agata N, Houk B, Naito S, Akaza H (2010) A phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma: insights into the treatment, efficacy and safety. Jpn J Clin Oncol 40(3):194–202. doi: 10.1093/jjco/hyp146 CrossRefPubMedGoogle Scholar
  37. 37.
    Hong MH, Kim HS, Kim C, Ahn JR, Chon HJ, Shin SJ, Ahn JB, Chung HC, Rha SY (2009) Treatment outcomes of sunitinib treatment in advanced renal cell carcinoma patients: a single cancer center experience in Korea. Cancer Res Treat 41(2):67–72. doi: 10.4143/crt.2009.41.2.67 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    FDA (2006) SUTENT (sunitinib malate) Clinical pharmacology and biopharmaceutics review. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021938_S000_Sutent_BioPharmR.pdf
  39. 39.
    Chowbay B, Li H, David M, Cheung YB, Lee EJ (2005) Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression. Br J Clin Pharmacol 60(2):159–171. doi: 10.1111/j.1365-2125.2005.02392.x CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hitzl M, Drescher S, van der Kuip H, Schaffeler E, Fischer J, Schwab M, Eichelbaum M, Fromm MF (2001) The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56 + natural killer cells. Pharmacogenetics 11(4):293–298CrossRefPubMedGoogle Scholar
  41. 41.
    Asano T, Takahashi KA, Fujioka M, Inoue S, Okamoto M, Sugioka N, Nishino H, Tanaka T, Hirota Y, Kubo T (2003) ABCB1 C3435T and G2677T/A polymorphism decreased the risk for steroid-induced osteonecrosis of the femoral head after kidney transplantation. Pharmacogenetics 13(11):675–682. doi: 10.1097/01.fpc.0000054135.14659.65 CrossRefGoogle Scholar
  42. 42.
    Yates CR, Zhang W, Song P, Li S, Gaber AO, Kotb M, Honaker MR, Alloway RR, Meibohm B (2003) The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. J Clin Pharmacol 43(6):555–564CrossRefPubMedGoogle Scholar
  43. 43.
    Dey S (2006) Single nucleotide polymorphisms in human P-glycoprotein: its impact on drug delivery and disposition. Expert Opin Drug Deliv 3(1):23–35. doi: 10.1517/17425247.3.1.23 CrossRefPubMedGoogle Scholar
  44. 44.
    Bello CL, Sherman L, Zhou J, Verkh L, Smeraglia J, Mount J, Klamerus KJ (2006) Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anticancer Drugs 17(3):353–358CrossRefPubMedGoogle Scholar

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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