Cancer Chemotherapy and Pharmacology

, Volume 77, Issue 5, pp 1039–1052 | Cite as

Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice

  • Andrea N. Edginton
  • Eric I. Zimmerman
  • Aksana Vasilyeva
  • Sharyn D. Baker
  • John C. PanettaEmail author
Original Article



This study used uncertainty and sensitivity analysis to evaluate a physiologically based pharmacokinetic (PBPK) model of the complex mechanisms of sorafenib and its two main metabolites, sorafenib glucuronide and sorafenib N-oxide in mice.


A PBPK model for sorafenib and its two main metabolites was developed to explain disposition in mice. It included relevant influx (Oatp) and efflux (Abcc2 and Abcc3) transporters, hepatic metabolic enzymes (CYP3A4 and UGT1A9), and intestinal β-glucuronidase. Parameterization of drug-specific processes was based on in vitro, ex vivo, and in silico data along with plasma and liver pharmacokinetic data from single and multiple transporter knockout mice.


Uncertainty analysis demonstrated that the model structure and parameter values could explain the observed variability in the pharmacokinetic data. Global sensitivity analysis demonstrated the global effects of metabolizing enzymes on sorafenib and metabolite disposition and the local effects of transporters on their respective substrate exposures. In addition, through hypothesis testing, the model supported that the influx transporter Oatp is a weak substrate for sorafenib and a strong substrate for sorafenib glucuronide and that the efflux transporter Abcc2 is not the only transporter affected in the Abcc2 knockout mouse.


Translation of the mouse model to humans for the purpose of explaining exceptionally high human pharmacokinetic variability and its relationship with exposure-dependent dose-limiting toxicities will require delineation of the importance of these processes on disposition.


Sorafenib Physiologically based pharmacokinetics Influx transporters Efflux transporters Sensitivity analysis 



This work was supported, in part, by the American Lebanese Syrian Associated Charities (ALSAC), USPHS Cancer Center Support Grant 3P30CA021765 (S.D. Baker), and NCI Grants 5R01CA138744 (S.D. Baker)

Author contributions

ANE, EIZ, AV, SDB, JCP wrote the manuscript. ANE, SDB, JCP designed the research. EIZ, AV performed experimental studies. ANE and JCP performed the research and analyzed the data.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

Supplementary material

280_2016_3018_MOESM1_ESM.docx (984 kb)
Supplementary material 1 (DOCX 985 kb)


  1. 1.
    Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23(3):329–336. doi: 10.1038/nbt1068 CrossRefPubMedGoogle Scholar
  2. 2.
    Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5(10):835–844. doi: 10.1038/nrd2130 CrossRefPubMedGoogle Scholar
  3. 3.
    Mori S, Cortes J, Kantarjian H, Zhang W, Andreef M, Ravandi F (2008) Potential role of sorafenib in the treatment of acute myeloid leukemia. Leuk Lymphoma 49(12):2246–2255. doi: 10.1080/10428190802510349 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Inaba H, Rubnitz JE, Coustan-Smith E, Li L, Furmanski BD, Mascara GP, Heym KM, Christensen R, Onciu M, Shurtleff SA, Pounds SB, Pui CH, Ribeiro RC, Campana D, Baker SD (2011) Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia. J Clin Oncol 29(24):3293–3300. doi: 10.1200/JCO.2011.34.7427 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Gadaleta-Caldarola G, Infusino S, Divella R, Ferraro E, Mazzocca A, De Rose F, Filippelli G, Abbate I, Brandi M (2015) Sorafenib: 10 years after the first pivotal trial. Future Oncol 11(13):1863–1880. doi: 10.2217/fon.15.85 CrossRefPubMedGoogle Scholar
  6. 6.
    Fukudo M, Ito T, Mizuno T, Shinsako K, Hatano E, Uemoto S, Kamba T, Yamasaki T, Ogawa O, Seno H, Chiba T, Matsubara K (2014) Exposure–toxicity relationship of sorafenib in Japanese patients with renal cell carcinoma and hepatocellular carcinoma. Clin Pharmacokinet 53(2):185–196. doi: 10.1007/s40262-013-0108-z CrossRefPubMedGoogle Scholar
  7. 7.
    Henin E, Blanchet B, Boudou-Rouquette P, Thomas-Schoemann A, Freyer G, Vidal M, Goldwasser F, Tod M (2014) Fractionation of daily dose increases the predicted risk of severe sorafenib-induced hand-foot syndrome (HFS). Cancer Chemother Pharmacol 73(2):287–297. doi: 10.1007/s00280-013-2352-1 CrossRefPubMedGoogle Scholar
  8. 8.
    Boudou-Rouquette P, Ropert S, Mir O, Coriat R, Billemont B, Tod M, Cabanes L, Franck N, Blanchet B, Goldwasser F (2012) Variability of sorafenib toxicity and exposure over time: a pharmacokinetic/pharmacodynamic analysis. Oncologist 17(9):1204–1212. doi: 10.1634/theoncologist.2011-0439 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Drenberg CD, Baker SD, Sparreboom A (2013) Integrating clinical pharmacology concepts in individualized therapy with tyrosine kinase inhibitors. Clin Pharmacol Ther 93(3):215–219. doi: 10.1038/clpt.2012.247 CrossRefPubMedGoogle Scholar
  10. 10.
    Saber-Mahloogi H, Morse DE (2005) Pharmacology review-Sorafenib. Center for Drug Evaluation and Research, RockvilleGoogle Scholar
  11. 11.
    Ghassabian S, Rawling T, Zhou F, Doddareddy MR, Tattam BN, Hibbs DE, Edwards RJ, Cui PH, Murray M (2012) Role of human CYP3A4 in the biotransformation of sorafenib to its major oxidized metabolites. Biochem Pharmacol 84(2):215–223. doi: 10.1016/j.bcp.2012.04.001 CrossRefPubMedGoogle Scholar
  12. 12.
    Lathia C, Lettieri J, Cihon F, Gallentine M, Radtke M, Sundaresan P (2006) Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol 57(5):685–692. doi: 10.1007/s00280-005-0068-6 CrossRefPubMedGoogle Scholar
  13. 13.
    Miller AA, Murry DJ, Owzar K, Hollis DR, Kennedy EB, Abou-Alfa G, Desai A, Hwang J, Villalona-Calero MA, Dees EC, Lewis LD, Fakih MG, Edelman MJ, Millard F, Frank RC, Hohl RJ, Ratain MJ (2009) Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 27(11):1800–1805. doi: 10.1200/JCO.2008.20.0931 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zaher H, Meyer zu Schwabedissen HE, Tirona RG, Cox ML, Obert LA, Agrawal N, Palandra J, Stock JL, Kim RB, Ware JA (2008) Targeted disruption of murine organic anion-transporting polypeptide 1b2 (Oatp1b2/Slco1b2) significantly alters disposition of prototypical drug substrates pravastatin and rifampin. Mol Pharmacol 74(2):320–329. doi: 10.1124/mol.108.046458 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chu XY, Strauss JR, Mariano MA, Li J, Newton DJ, Cai X, Wang RW, Yabut J, Hartley DP, Evans DC, Evers R (2006) Characterization of mice lacking the multidrug resistance protein MRP2 (ABCC2). J Pharmacol Exp Ther 317(2):579–589. doi: 10.1124/jpet.105.098665 CrossRefPubMedGoogle Scholar
  16. 16.
    Vlaming ML, Pala Z, van Esch A, Wagenaar E, van Tellingen O, de Waart DR, Oude Elferink RP, van de Wetering K, Schinkel AH (2008) Impact of Abcc2 (Mrp2) and Abcc3 (Mrp3) on the in vivo elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate. Clin Cancer Res 14(24):8152–8160. doi: 10.1158/1078-0432.CCR-08-1609 CrossRefPubMedGoogle Scholar
  17. 17.
    Zimmerman EI, Hu S, Roberts JL, Gibson AA, Orwick SJ, Li L, Sparreboom A, Baker SD (2013) Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res 19(6):1458–1466. doi: 10.1158/1078-0432.CCR-12-3306 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Swift B, Nebot N, Lee JK, Han T, Proctor WR, Thakker DR, Lang D, Radtke M, Gnoth MJ, Brouwer KL (2013) Sorafenib hepatobiliary disposition: mechanisms of hepatic uptake and disposition of generated metabolites. Drug Metab Dispos 41(6):1179–1186. doi: 10.1124/dmd.112.048181 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Vasilyeva A, Durmus S, Li L, Wagenaar E, Hu S, Gibson AA, Panetta JC, Mani S, Sparreboom A, Baker SD, Schinkel AH (2015) Hepatocellular shuttling and recirculation of sorafenib-glucuronide is dependent on Abcc2, Abcc3, and Oatp1a/1b. Cancer Res. doi: 10.1158/0008-5472.can-15-0280 Google Scholar
  20. 20.
    Jain L, Woo S, Gardner ER, Dahut WL, Kohn EC, Kummar S, Mould DR, Giaccone G, Yarchoan R, Venitz J, Figg WD (2011) Population pharmacokinetic analysis of sorafenib in patients with solid tumours. Br J Clin Pharmacol 72(2):294–305. doi: 10.1111/j.1365-2125.2011.03963.x CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Gallo JM (2013) Physiologically based pharmacokinetic models of tyrosine kinase inhibitors: a systems pharmacological approach to drug disposition. Clin Pharmacol Ther 93(3):236–238. doi: 10.1038/clpt.2012.244 CrossRefPubMedGoogle Scholar
  22. 22.
    Pawaskar DK, Straubinger RM, Fetterly GJ, Hylander BH, Repasky EA, Ma WW, Jusko WJ (2013) Physiologically based pharmacokinetic models for everolimus and sorafenib in mice. Cancer Chemother Pharmacol 71(5):1219–1229. doi: 10.1007/s00280-013-2116-y CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Rodgers T, Leahy D, Rowland M (2005) Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci 94(6):1259–1276. doi: 10.1002/jps.20322 CrossRefPubMedGoogle Scholar
  24. 24.
    Rodgers T, Rowland M (2006) Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci 95(6):1238–1257. doi: 10.1002/jps.20502 CrossRefPubMedGoogle Scholar
  25. 25.
    Zimmerman EI, Roberts JL, Li L, Finkelstein D, Gibson A, Chaudhry AS, Schuetz EG, Rubnitz JE, Inaba H, Baker SD (2012) Ontogeny and sorafenib metabolism. Clin Cancer Res 18(20):5788–5795. doi: 10.1158/1078-0432.CCR-12-1967 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Blower SM, Dowlatabadi H (1994) Sensitivity and uncertainty analysis of complex-models of disease transmission—an HIV model, as an example. Int Stat Rev 62(2):229–243. doi: 10.2307/1403510 CrossRefGoogle Scholar
  27. 27.
    Marino S, Hogue IB, Ray CJ, Kirschner DE (2008) A methodology for performing global uncertainty and sensitivity analysis in systems biology. J Theor Biol 254(1):178–196. doi: 10.1016/j.jtbi.2008.04.011 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD (2009) Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res 15(19):6062–6069. doi: 10.1158/1078-0432.CCR-09-0048 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wagner C, Pan Y, Hsu V, Sinha V, Zhao P (2015) Predicting the effect of CYP3A inducers on the pharmacokinetics of substrate drugs using physiologically based pharmacokinetic (PBPK) modeling: an analysis of PBPK submissions to the US FDA. Clin Pharmacokinet. doi: 10.1007/s40262-015-0330-y PubMedGoogle Scholar
  30. 30.
    Maharaj AR, Barrett JS, Edginton AN (2013) A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. AAPS J 15(2):455–464. doi: 10.1208/s12248-013-9451-0 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Andrea N. Edginton
    • 1
  • Eric I. Zimmerman
    • 2
  • Aksana Vasilyeva
    • 2
  • Sharyn D. Baker
    • 2
    • 3
  • John C. Panetta
    • 2
    Email author
  1. 1.School of PharmacyUniversity of WaterlooWaterlooCanada
  2. 2.Department of Pharmaceutical SciencesSt. Jude Children’s Research HospitalMemphisUSA
  3. 3.Division of Pharmaceutics, College of Pharmacy and Comprehensive Cancer CenterThe Ohio State UniversityColumbusUSA

Personalised recommendations