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Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts

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Abstract

The anticancer effects of combined gemcitabine and birinapant were demonstrated as synergistic in PANC-1 cells in vitro. In this study, pharmacokinetic information derived from experiments and the literature was utilized to develop full physiologically-based pharmacokinetic (PBPK) models that characterize individual drugs. The predicted intra-tumor drug concentrations were used as the driving force within a linked PBPK/PD model for treatment-mediated changes in tumor volume in a xenograft mouse model. The efficacy of the drug combination in vivo was evaluated mathematically as exhibiting additivity. The network model developed for drug effects in the in vitro cell cultures was applied successfully to link the in vivo tumor drug concentrations with tumor growth inhibition, incorporating more mechanistic features and accounting for disparate drug interaction outcomes in vitro and in vivo.

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References

  1. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30. https://doi.org/10.3322/caac.21332

    Article  PubMed  Google Scholar 

  2. Eli Lilly and Company, Indianapolis I (1996) GEMZAR

  3. Morgan MA, Parsels LA, Parsels JD, Mesiwala AK, Maybaum J, Lawrence TS (2005) Role of checkpoint kinase 1 in preventing premature mitosis in response to gemcitabine. Cancer Res 65:6835–6842. https://doi.org/10.1158/0008-5472.CAN-04-2246

    Article  CAS  PubMed  Google Scholar 

  4. Wong A, Soo RA, Yong W-P, Innocenti F (2009) Clinical pharmacology and pharmacogenetics of gemcitabine. Drug Metab Rev 41:77–88. https://doi.org/10.1080/03602530902741828

    Article  CAS  PubMed  Google Scholar 

  5. Shipley LA, Brown TJ, Cornpropst JD, Hamilton M, Daniels WD, Culp HW (2006) Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs. Drug Metab Dispos 20:849–855

    Google Scholar 

  6. Veltkamp SA, Pluim D, van Tellingen O, Beijnen JH, Schellens JHM (2008) Extensive metabolism and hepatic accumulation of gemcitabine after multiple oral and intravenous administration in mice. Drug Metab Dispos 36:1606–1615. https://doi.org/10.1124/dmd.108.021048

    Article  CAS  PubMed  Google Scholar 

  7. Benetatos CA, Mitsuuchi Y, Burns JM, Neiman EM, Condon SM, Yu G, Seipel ME, Kapoor GS, Laporte MG, Rippin SR, Deng Y, Hendi MS, Tirunahari PK, Lee Y-H, Haimowitz T, Alexander MD, Graham MA, Weng D, Shi Y, McKinlay MA, Chunduru SK (2014) Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-κB activation, and is active in patient-derived xenograft models. Mol Cancer Ther 13:867–879. https://doi.org/10.1158/1535-7163.MCT-13-0798

    Article  CAS  PubMed  Google Scholar 

  8. Bai L, Smith DC, Wang S (2014) Small-molecule SMAC mimetics as new cancer therapeutics. Pharmacol Ther 144:82–95. https://doi.org/10.1016/j.pharmthera.2014.05.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Infante JR, Dees EC, Olszanski AJ, Dhuria SV, Sen S, Cameron S, Cohen RB (2014) Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. J Clin Oncol 32:3103–3110. https://doi.org/10.1200/JCO.2013.52.3993

    Article  CAS  PubMed  Google Scholar 

  10. Tolcher A, Papadopoulos K, Patnaik A, Fairbrother W, Wong H, Budha N, Darbonne W, Peale F, Mamounas M, Royer-Joo S, Yu R, Portera C, Bendell J, Burris H, Tolcher JI, Papadopoulos K, Patnaik A, Fairbrother W, Wong H, Budha N, Darbonne W, Peale F, Mamounas M, Royer-Joo S, Yu R, Portera C, Bendell J, Burris H, Infante J (2013) Abstract 2503: phase I study of safety and pharmacokinetics (PK) of GDC-0917, an antagonist of inhibitor of apoptosis (IAP) proteins in patients with refractory solid tumors or lymphoma. 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, 31:2503

  11. Hurwitz HI, Smith DC, Pitot HC, Brill JM, Chugh R, Rouits E, Rubin J, Strickler J, Vuagniaux G, Sorensen JM, Zanna C (2015) Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study. Cancer Chemother Pharmacol 75:851–859. https://doi.org/10.1007/s00280-015-2709-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Amaravadi RK, Schilder RJ, Martin LP, Levin M, Graham MA, Weng DE, Adjei AA (2015) A phase 1 study of the SMAC-mimetic birinapant in adults with refractory solid tumors or lymphoma. Mol Cancer Ther. https://doi.org/10.1158/1535-7163.mct-15-0475

    Article  PubMed  Google Scholar 

  13. Zhu X, Straubinger RM, Jusko WJ (2015) Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells. J Pharmacokinet Pharmacodyn 42:477–496. https://doi.org/10.1007/s10928-015-9429-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhu X, Shen X, Qu J, Straubinger RM, Jusko WJ (2018) Multi-scale network model supported by proteomics for analysis of combined gemcitabine and birinapant effects in pancreatic cancer cells. CPT Pharmacometrics Syst Pharmacol (in press)

  15. Zhu X, Shen X, Qu J, Straubinger RM, Jusko WJ (2018) Proteomic analysis of combined gemcitabine and birinapant in pancreatic cancer cells. Front Pharmacol 9:84. https://doi.org/10.3389/fphar.2018.00084

    Article  PubMed  PubMed Central  Google Scholar 

  16. Trueman SA, Ma WW, Straubinger RM (2016) Optimization of stromal modulation and drug-transporter interactions of a dovitnib/gemcitabine combination regimen in pancreatic cancer models. In: American association for cancer research conference-engineering and physical sciences in oncology, Boston, MA, 25–26 June 2016

  17. Wang H, Li M, Rinehart JJ, Zhang R (2004) Pretreatment with dexamethasone increases antitumor activity of carboplatin and gemcitabine in mice bearing human cancer xenografts: in vivo activity, pharmacokinetics, and clinical implications for cancer chemotherapy. Clin Cancer Res 10:1633–1644. https://doi.org/10.1158/1078-0432.CCR-0829-3

    Article  CAS  PubMed  Google Scholar 

  18. Moore MM, Estrada VA, Nieves FE, Burns JM, Mitsuuchi Y, Chunduru SK, Graham MA, McKinlay MA, Tolcher AW, Wick MJ (2009) Abstract B163: pharmacokinetic analysis and preclinical evaluation of the SMAC mimetic TL32711 in an orthotopic human breast tumor xenograft model. Mol Cancer Ther 8:B163. https://doi.org/10.1158/1535-7163.TARG-09-B163

    Article  Google Scholar 

  19. Ma WW, Zhang H, Hylander B, LeVea C, Repasky E, Weng D, Burns J, Chunduru S, Graham M, Fetterly G, McKinlay M, Adjei A (2012) Abstract 1939: TL32711, a novel Smac mimetic, exerts significant antitumor efficacy in primary pancreatic adenocarcinoma model. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Ph. Cancer Res 72:1939. https://doi.org/10.1158/1538-7445.am2012-1939

    Article  Google Scholar 

  20. Baxter LT, Zhu H, Mackensen DG, Jain RK (1994) Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice. Cancer Res 54:1517–1528

    CAS  PubMed  Google Scholar 

  21. Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP (1997) Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13:407–484

    Article  CAS  PubMed  Google Scholar 

  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 71:1219–1229. https://doi.org/10.1007/s00280-013-2116-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 94:1259–1276. https://doi.org/10.1002/jps.20322

    Article  CAS  PubMed  Google Scholar 

  24. La H, Halladay JS, Shin Y, Wong S, Plise E, Chan OH, Flygare J, Fairbrother W, Wong. H (2010) Abstract P136: preclinical pharmacokinetic assessment of GDC-0152, a selective antagonist of the Inhibitor of Apoptosis (IAP) Proteins. 9th Int Soc Study Xenobiotics Meet Drug Discov Dev Istanbul, Turkey

  25. Zhang T, Li Y, Zou P, Yu J, McEachern D, Wang S, Sun D (2013) Physiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer. Biopharm Drug Dispos 34:348–359. https://doi.org/10.1002/bdd.1850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. D’Argenio DZ, Schumitzky A, Wang X (2009) ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software

  27. Amaravadi RK, Senzer NN, Martin LP, Schilder RJ, Lorusso P, Papadopoulos KP, Weng DE, Graham M, Adjei AA (2013) Abstract 2504: a phase I study of birinapant (TL32711) combined with multiple chemotherapies evaluating tolerability and clinical activity for solid tumor patients. J Clin Oncol 31:2504

    Google Scholar 

  28. Fetterly GJ, Liu B, Senzer NN, Amaravadi RK, Schilder RJ, Martin LP, Lorusso P, Papadopoulos KP, Adjei AA, Zagst PD, Mckinlay MA, Weng DE, Graham M, Park R, Cancer MC (2012) Abstract 3029: clinical pharmacokinetics of the smac-mimetic birinapant (TL32711) as a single agent and in combination with multiple chemotherapy regimens. J Clin Oncol 30:3029

    Article  Google Scholar 

  29. Nishikawa Y, Tsuji Y, Isoda H, Kodama Y, Chiba T (2014) Perfusion in the tissue surrounding pancreatic cancer and the patient’s prognosis. Biomed Res Int 2014:648021. https://doi.org/10.1155/2014/648021

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bouffard DY, Laliberté J, Momparler RL (1993) Kinetic studies on 2′,2′-difluorodeoxycytidine (Gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase. Biochem Pharmacol 45:1857–1861

    Article  CAS  PubMed  Google Scholar 

  31. Ebrahem Q, Mahfouz RZ, Ng KP, Saunthararajah Y (2012) High cytidine deaminase expression in the liver provides sanctuary for cancer cells from decitabine treatment effects. Oncotarget 3:1137–1145. https://doi.org/10.18632/oncotarget.597

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sugiyama E, Kaniwa N, Kim S-R, Hasegawa R, Saito Y, Ueno H, Okusaka T, Ikeda M, Morizane C, Kondo S, Yamamoto N, Tamura T, Furuse J, Ishii H, Yoshida T, Saijo N, Sawada J-I (2010) Population pharmacokinetics of gemcitabine and its metabolite in Japanese cancer patients: impact of genetic polymorphisms. Clin Pharmacokinet 49:549–558. https://doi.org/10.2165/11532970-000000000-00000

    Article  CAS  PubMed  Google Scholar 

  33. Zhang L, Sinha V, Forgue ST, Callies S, Ni L, Peck R, Allerheiligen SRB (2006) Model-based drug development: the road to quantitative pharmacology. J Pharmacokinet Pharmacodyn 33:369–393. https://doi.org/10.1007/s10928-006-9010-8

    Article  CAS  PubMed  Google Scholar 

  34. Kuenen BC, Rosen L, Smit EF, Parson MRN, Levi M, Ruijter R, Huisman H, Kedde MA, Noordhuis P, van der Vijgh WJF, Peters GJ, Cropp GF, Scigalla P, Hoekman K, Pinedo HM, Giaccone G (2002) Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 20:1657–1667

    Article  CAS  PubMed  Google Scholar 

  35. Kazmi F, Hensley T, Pope C, Funk RS, Loewen GJ, Buckley DB, Parkinson A (2013) Lysosomal sequestration (trapping) of lipophilic amine (cationic amphiphilic) drugs in immortalized human hepatocytes (Fa2N-4 cells). Drug Metab Dispos 41:897–905. https://doi.org/10.1124/dmd.112.050054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dovzhanskiy DI, Arnold SM, Hackert T, Oehme I, Witt O, Felix K, Giese N, Werner J (2012) Experimental in vivo and in vitro treatment with a new histone deacetylase inhibitor belinostat inhibits the growth of pancreatic cancer. BMC Cancer 12:226. https://doi.org/10.1186/1471-2407-12-226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nolan-Stevaux O, Tedesco D, Ragan S, Makhanov M, Chenchik A, Ruefli-Brasse A, Quon K, Kassner PD (2013) Measurement of cancer cell growth heterogeneity through lentiviral barcoding identifies clonal dominance as a characteristic of in vivo tumor engraftment. PLoS ONE. https://doi.org/10.1371/journal.pone.0067316

    Article  PubMed  PubMed Central  Google Scholar 

  38. Trédan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441–1454. https://doi.org/10.1093/jnci/djm135

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by National Institutes of Health Grants R01 GM24211 to WJJ and R01 CA198096 to RMS. We thank Tetralogic Pharmaceuticals Inc. for sharing the information for the tumor growth study.

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Correspondence to William J. Jusko.

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Zhu, X., Trueman, S., Straubinger, R.M. et al. Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts. J Pharmacokinet Pharmacodyn 45, 733–746 (2018). https://doi.org/10.1007/s10928-018-9603-z

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