Skip to main content

Chemotherapeutic dosing implicated by pharmacodynamic modeling of in vitro cytotoxic data: a case study of paclitaxel

Abstract

Conventional maximum tolerated doses (MTD) in chemotherapy are recently challenged by an alternative dosing method with low doses and high dosing frequency (LDHF). Still, it remains unclear which chemotherapies would potentially benefit from LDHF. The pharmacokinetic (PK) differences between MTD and LDHF are drug exposure magnitude (concentration) and exposure duration (time), two fundamental PK elements that are associated with the pharmacodynamics (PD) of chemotherapies. Here we hypothesized that quantitatively analyzing the contribution of each PK element to the overall cytotoxic effects would provide insights to the selection of the preferred chemotherapeutic dosing. Based on in vitro cytotoxic data, we developed a cellular PD model, which assumed that tumor cells were generally comprised of two subpopulations that were susceptible to either concentration- or time-dependent cytotoxicity. The developed PD model exhibited high flexibility to describe diverse patterns of cell survival curves. Integrated with a PK model, the cellular PD model was further extended to predict and compare the anti-tumor effect of paclitaxel in two dosing regimens: multiple MTD bolus and continuous constant infusion (an extreme LDHF). Our simulations of paclitaxel in treatment of three types of cancers were consistent with clinical observations that LDHF yielded higher patient efficacy than MTD. Our further analysis suggested that the ratio between drug steady-state concentrations and its cytotoxic sensitivity (C ss /KC 50 ) was a critical factor that largely determines favored dosing regimen. LDHF would produce higher efficacy when the ratio C ss /KC 50 is greater than 1. Otherwise MTD was favored. The developed PD model presented an approach simply based on in vitro cytotoxic data to predict the potentially favored chemotherapeutic dosing between MTD and LDHF.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Kamen BA, Rubin E, Aisner J, Glatstein E (2000) High-time chemotherapy or high time for low dose. J Clin Oncol 18(16):2935–2937. doi:10.1200/jco.2000.18.16.2935

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Weitman SD, Glatstein E, Kamen BA (1993) Back to the basics: the importance of concentration x time in oncology. J Clin Oncol 11(5):820–821

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Hanahan D, Bergers G, Bergsland E (2000) Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105(8):1045–1047

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Romiti A, Cox MC, Sarcina I, Di Rocco R, D’Antonio C, Barucca V, Marchetti P (2013) Metronomic chemotherapy for cancer treatment: a decade of clinical studies. Cancer Chemother Pharmacol 72(1):13–33. doi:10.1007/s00280-013-2125-x

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Klingebiel T, Boos J, Beske F, Hallmen E, Int-Veen C, Dantonello T, Treuner J, Gadner H, Marky I, Kazanowska B, Koscielniak E (2008) Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: report of the HD CWS-96 trial. Pediatr Blood Cancer 50(4):739–745. doi:10.1002/pbc.21494

    Article  PubMed  Google Scholar 

  6. 6.

    Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L (2003) Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21(8):1431–1439

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Munzone E, Colleoni M (2015) Clinical overview of metronomic chemotherapy in breast cancer. Nat Rev Clin Oncol 12(11):631–644. doi:10.1038/nrclinonc

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, de Jongh FE, Erdkamp FL, Erjavec Z, van der Torren AM, Tol J, Braun HJ, Nieboer P, van der Hoeven JJ, Haasjes JG, Jansen RL, Wals J, Cats A, Derleyn VA, Honkoop AH, Mol L, Punt CJ, Koopman M (2015) Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 385(9980):1843–1852. doi:10.1016/S0140-6736(14)62004-3

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Jang JW, Park ST, Kwon JH, You CR, Choi JY, Jung CK, Bae SH, Yoon SK (2011) Suppression of hepatic tumor growth and metastasis by metronomic therapy in a rat model of hepatocellular carcinoma. Exp Mol Med 43(5):305–312. doi:10.3858/emm.2011.43.5.033

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Au JL, Li D, Gan Y, Gao X, Johnson AL, Johnston J, Millenbaugh NJ, Jang SH, Kuh HJ, Chen CT, Wientjes MG (1998) Pharmacodynamics of immediate and delayed effects of paclitaxel: role of slow apoptosis and intracellular drug retention. Cancer Res 58(10):2141–2148

    CAS  PubMed  Google Scholar 

  11. 11.

    Barbolosi D, Ciccolini J, Lacarelle B, Barlési F, André N (2016) Computational oncology–mathematical modelling of drug regimens for precision medicine. Nat Rev Clin Oncol. 13(4):242–254. doi:10.1038/nrclinonc.2015.204

    Article  PubMed  Google Scholar 

  12. 12.

    Levasseur LM, Slocum HK, Rustum YM, Greco WR (1998) Modeling of the time-dependency of in vitro drug cytotoxicity and resistance. Cancer Res 58(24):5749–5761

    CAS  PubMed  Google Scholar 

  13. 13.

    El-Kareh AW, Labes RE, Secomb TW (2008) Cell cycle checkpoint models for cellular pharmacology of paclitaxel and platinum drugs. AAPS J 10(1):15–34. doi:10.1208/s12248-007-9003-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Millenbaugh NJ, Wientjes MG, Au JL (2000) A pharmacodynamic analysis method to determine the relative importance of drug concentration and treatment time on effect. Cancer Chemother Pharmacol 45(4):265–272

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Gardner SN (2000) A mechanistic, predictive model of dose-response curves for cell cycle phase-specific and -nonspecific drugs. Cancer Res 60(5):1417–1425

    CAS  PubMed  Google Scholar 

  16. 16.

    Lobo ED, Balthasar JP (2002) Pharmacodynamic modeling of chemotherapeutic effects: application of a transit compartment model to characterize methotrexate effects in vitro. AAPS PharmSci 4(4):E42

    Article  PubMed  Google Scholar 

  17. 17.

    El-Kareh AW, Secomb TW (2005) Two-mechanism peak concentration model for cellular pharmacodynamics of Doxorubicin. Neoplasia 7(7):705–713

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Jusko W (1973) A pharmacodynamic model for cell-cycle-specific chemotherapeutic agents. J Pharmacokin Biopharm 1(3):175–200

    CAS  Article  Google Scholar 

  19. 19.

    Roux J, Hafner M, Bandara S, Sims JJ, Hudson H, Chai D, Sorger PK (2015) Fractional killing arises from cell-to-cell variability in overcoming a caspase activity threshold. Mol Syst Biol 11(5):803. doi:10.15252/msb.20145584

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Spencer SL, Gaudet S, Albeck JG, Burke JM, Sorger PK (2009) Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459(7245):428–432. doi:10.1038/nature08012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Marusyk A, Polyak K (2010) Tumor heterogeneity: causes and consequences. Biochim Biophys Acta 1805(1):105–117. doi:10.1016/j.bbcan.2009.11.002

    CAS  PubMed  Google Scholar 

  22. 22.

    Brown JM, Attardi LD (2005) The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 5(3):231–237. doi:10.1038/nrc1560

    CAS  PubMed  Google Scholar 

  23. 23.

    Roos WP, Kaina B (2013) DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett 332(2):237–248. doi:10.1016/j.canlet.2012.01.007

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Matsushima Y, Kanzawa F, Hoshi A, Shimizu E, Nomori H, Sasaki Y, Saijo N (1985) Time-schedule dependency of the inhibiting activity of various anticancer drugs in the clonogenic assay. Cancer Chemother Pharmacol 14(2):104–107

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Henkels KM, Turchi JJ (1999) Cisplatin-induced apoptosis proceeds by caspase-3-dependent and -independent pathways in cisplatin-resistant and -sensitive human ovarian cancer cell lines. Cancer Res 59(13):3077–3083

    CAS  PubMed  Google Scholar 

  26. 26.

    Rodionov N. Graph digitizer version 1.9. 2000 http://www.geocities.com/graphdigitizer

  27. 27.

    Nokihara H, Yamamoto N, Ohe Y, Hiraoka M, Tamura T (2016) Pharmacokinetics of weekly paclitaxel and feasibility of dexamethasone taper in Japanese patients with advanced non-small cell lung cancer. Clin Ther 38(2):338–347. doi:10.1016/j.clinthera.2015.12.009

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Yoo TK, Min JW, Kim MK, Lee E, Kim J, Lee HB, Kang YJ, Kim YG, Moon HG, Moon WK, Cho N, Noh DY, Han W (2015) In vivo tumor growth rate measured by US in preoperative period and long term disease outcome in breast cancer patients. PLoS ONE 10(12):e0144144. doi:10.1371/journal.pone.0144144

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Sutherland RL, Hall RE, Taylor IW (1983) Cell proliferation kinetics of MCF-7 human mammary carcinoma cells in culture and effects of tamoxifen on exponentially growing and plateau-phase cells. Cancer Res 43(9):3998–4006

    CAS  PubMed  Google Scholar 

  30. 30.

    Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE (2008) Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358(16):1663–1671. doi:10.1056/NEJMoa0707056

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Chan JK, Brady MF, Penson RT, Huang H, Birrer MJ, Walker JL, DiSilvestro PA, Rubin SC, Martin LP, Davidson SA, Huh WK, O’Malley DM, Boente MP, Michael H, Monk BJ (2016) Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer. N Engl J Med 374(8):738–748. doi:10.1056/NEJMoa1505067

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Vaughn DJ, Brown AW Jr, Harker WG, Huh S, Miller L, Rinaldi D, Kabbinavar F (2004) Multicenter Phase II study of estramustine phosphate plus weekly paclitaxel in patients with androgen-independent prostate carcinoma. Cancer 100(4):746–750. doi:10.1002/cncr.11956

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Bocci G, Kerbel RS (2016) Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect. Nat Rev Clin Oncol 13(11):659–973. doi:10.1038/nrclinonc.2016.64

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Choi SY, Lin D, Gout PW, Collins CC, Xu Y, Wang Y (2014) Lessons from patient-derived xenografts for better in vitro modeling of human cancer. Adv Drug Deliv Rev 79–80:222–237. doi:10.1016/j.addr.2014.09.009

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants from NIH (R35 GM119661).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yanguang Cao.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 3488 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

He, H., Cao, Y. Chemotherapeutic dosing implicated by pharmacodynamic modeling of in vitro cytotoxic data: a case study of paclitaxel. J Pharmacokinet Pharmacodyn 44, 491–501 (2017). https://doi.org/10.1007/s10928-017-9540-2

Download citation

Keywords

  • Maximum tolerated dose
  • Low dose high frequency regimen
  • Cellular pharmacodynamics
  • Dosing regimen
  • In vitro cytotoxicity