Skip to main content
SpringerLink
Log in

PKPD Modeling and Dosing Considerations in Advanced Ovarian Cancer Patients Treated with Cisplatin-Based Intraoperative Intraperitoneal Chemotherapy

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Intraperitoneal chemoperfusion (IPEC) of cisplatin is a popular treatment for advanced ovarian cancer, typically under hyperthermia (HIPEC). The use of cisplatin under (H)IPEC is off-label, and the role of hyperthermia is unknown. The aim of this study was to characterize the pharmacokinetic/pharmacodynamic (PKPD) properties of cisplatin under (H)IPEC and to predict the optimal treatment regimen. Using a randomized design, data on intact cisplatin perfusate and plasma concentrations, leukocyte counts—a hematotoxicity marker—and serum creatinine—a nephrotoxicity marker—were collected from 50 patients treated with a combination of cytoreductive surgery (CRS) and either normothermic or hyperthermic IPEC of cisplatin dosed at 75, 100, and 120 mg/m2. The non-linear mixed effects modeling technique was used to construct the PKPD models. The PK of intact cisplatin was characterized by a two-compartment model. A semi-physiological myelosuppression model for the leukopenia was modified to account for the CRS-induced leukocytosis and the residual myelosuppression effect of neoadjuvant chemotherapy. The incidence and severity of nephrotoxicity were described by a discrete-time Markov model. Hyperthermia increased the absorption rate of cisplatin by 16.3% but did not show a clinically relevant impact on the investigated toxicities compared with normothermia. Leukopenia was not severe, but nephrotoxicity can become severe or life-threatening and was affected by the dose and IPEC duration. The model predicted that nephrotoxicity is minimal at a cisplatin dose of 75 mg/m2 with an IPEC duration of 1–2 h and an 1-h duration is favored for doses between 100 and 120 mg/m2.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  Google Scholar 

  2. de Bree E, Helm CW. Hyperthermic intraperitoneal chemotherapy in ovarian cancer: rationale and clinical data. Expert Rev Anticancer Ther. 2012;12(7):895–911.

    PubMed  Google Scholar 

  3. Tummala MK, Alagarsamy S, McGuire WP. Intraperitoneal chemotherapy: standard of care for patients with minimal residual stage III ovarian cancer? Expert Rev Anticancer Ther. 2008;8(7):1135–47.

    CAS  PubMed  Google Scholar 

  4. Polom K, Roviello G, Generali D, Marano L, Petrioli R, Marsili S, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for treatment of ovarian cancer. Int J Hyperth. 2016;32(3):298–310.

    CAS  Google Scholar 

  5. Van Driel WJ, Koole SN, Sikorska K, Schagen van Leeuwen JH, Schreuder HW, Hermans RH, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med. 2018;378(3):230–40.

    PubMed  Google Scholar 

  6. Van Driel WJ, Lok CA, Verwaal V, Sonke GS. The role of hyperthermic intraperitoneal intraoperative chemotherapy in ovarian cancer. Curr Treat Options in Oncol. 2015;16(4):14.

    Google Scholar 

  7. Ceelen WP, Van Nieuwenhove Y, Van Belle S, Denys H, Pattyn P. Cytoreduction and hyperthermic intraperitoneal chemoperfusion in women with heavily pretreated recurrent ovarian cancer. Ann Surg Oncol. 2012;19(7):2352–9.

    PubMed  Google Scholar 

  8. Cowan RA, O’Cearbhaill RE, Zivanovic O, Chi DS. Current status and future prospects of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) clinical trials in ovarian cancer. Int J Hyperth. 2017;33(5):548–53.

    Google Scholar 

  9. de Bree E, Theodoropoulos PA, Rosing H, Michalakis J, Romanos J, Beijnen JH, et al. Treatment of ovarian cancer using intraperitoneal chemotherapy with taxanes: from laboratory bench to bedside. Cancer Treat Rev. 2006;32(6):471–82.

    PubMed  Google Scholar 

  10. Fujiwara K, Armstrong D, Morgan M, Markman M. Principles and practice of intraperitoneal chemotherapy for ovarian cancer. Int J Gynecol Cancer. 2007;17(1):1–20.

    CAS  PubMed  Google Scholar 

  11. Hettinga J, Konings A, Kampinga H. Reduction of cellular cisplatin resistance by hyperthermia—a review. Int J Hyperth. 1997;13(5):439–57.

    CAS  Google Scholar 

  12. Takemoto M, Kuroda M, Urano M, Nishimura Y, Kawasaki S, Kato H, et al. The effect of various chemotherapeutic agents given with mild hyperthermia on different types of tumours. Int J Hyperth. 2003;19(2):193–203.

    CAS  Google Scholar 

  13. Sugarbaker PH. Peritonectomy procedures. Surg Oncol Clin N Am. 2003;12(3):703–27.

    PubMed  Google Scholar 

  14. Hanada K, Nishijima K, Ogata H, Atagi S, Kawahara M. Population pharmacokinetic analysis of cisplatin and its metabolites in cancer patients: possible misinterpretation of covariates for pharmacokinetic parameters calculated from the concentrations of unchanged cisplatin, ultrafiltered platinum and total platinum. Jpn J Clin Oncol. 2001;31(5):179–84.

    CAS  PubMed  Google Scholar 

  15. Farris FF, King FG, Dedrick RL, Litterst CL. Physiological model for the pharmacokinetics ofcis-dichlorodiammineplatinum (II)(DDP) in the tumored rat. J Pharmacokinet Biopharm. 1985;13(1):13–39.

    CAS  PubMed  Google Scholar 

  16. Alderden RA, Hall MD, Hambley TW. The discovery and development of cisplatin. J Chem Educ. 2006;83(5):728.

    CAS  Google Scholar 

  17. Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci. 2007;334(2):115–24.

    PubMed  Google Scholar 

  18. Barabas K, Milner R, Lurie D, Adin C. Cisplatin: a review of toxicities and therapeutic applications. Vet Comp Oncol. 2008;6(1):1–18.

    CAS  PubMed  Google Scholar 

  19. Reichman TW, Cracchiolo B, Sama J, Bryan M, Harrison J, Pliner L, et al. Cytoreductive surgery and intraoperative hyperthermic chemoperfusion for advanced ovarian carcinoma. J Surg Oncol. 2005;90(2):51–6.

    PubMed  Google Scholar 

  20. Königsrainer I, Horvath P, Struller F, Grischke EM, Wallwiener D, Königsrainer A, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in recurrent epithelial ovarian cancer with peritoneal metastases: a single centre experience. Langenbeck's Arch Surg. 2014;399(5):589–94.

    Google Scholar 

  21. Batista TP, Badiglian Filho L, Leão CS. Exploring flow rate selection in HIPEC procedures. Rev Col Bras Cir. 2016;43(6):476–9.

    PubMed  Google Scholar 

  22. Campbell AB, Kalman SM, Jacobs C. Plasma platinum levels: relationship to cisplatin dose and nephrotoxicity. Cancer Treat Rep. 1983;67(2):169–72.

    CAS  PubMed  Google Scholar 

  23. Reece PA, Stafford I, Russell J, Khan M, Gill P. Creatinine clearance as a predictor of ultrafilterable platinum disposition in cancer patients treated with cisplatin: relationship between peak ultrafilterable platinum plasma levels and nephrotoxicity. J Clin Oncol. 1987;5(2):304–9.

    CAS  PubMed  Google Scholar 

  24. Klaver YL, Hendriks T, Lomme RM, Rutten HJ, Bleichrodt RP, de Hingh IH. Hyperthermia and intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis: an experimental study. Ann Surg. 2011;254(1):125–30.

    PubMed  Google Scholar 

  25. Carlier C, Laforce B, Van Malderen SJ, Gremonprez F, Tucoulou R, Villanova J, et al. Nanoscopic tumor tissue distribution of platinum after intraperitoneal administration in a xenograft model of ovarian cancer. J Pharm Biomed Anal. 2016;131:256–62.

    CAS  PubMed  Google Scholar 

  26. Alvovsky I, Bespalov V, Kireeva G. Cisplatin in NIPEC or HIPEC? Ann Surg. 2018;29(suppl_8):mdy268.020.

    Google Scholar 

  27. Xie F, Colin P, Van Bocxlaer J. Zwitterionic hydrophilic interaction liquid chromatography-tandem mass spectrometry with HybridSPE-precipitation for the determination of intact cisplatin in human plasma. Talanta. 2017;174:171–8.

    CAS  PubMed  Google Scholar 

  28. Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002;20(24):4713–21.

    PubMed  Google Scholar 

  29. Summers C, Rankin SM, Condliffe AM, Singh N, Peters AM, Chilvers ER. Neutrophil kinetics in health and disease. Trends Immunol. 2010;31(8):318–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Pérez-Ruixo C, Valenzuela B, Peris JE, Bretcha-Boix P, Escudero-Ortiz V, Farré-Alegre J, et al. Neutrophil dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery and hyperthermic intraperitoneal oxaliplatin. Clin Pharmacokinet. 2013;52(12):1111–25.

    PubMed  Google Scholar 

  31. Cotte E, Colomban O, Guitton J, Tranchand B, Bakrin N, Gilly FN, et al. Population pharmacokinetics and pharmacodynamics of cisplatinum during hyperthermic intraperitoneal chemotherapy using a closed abdominal procedure. J Clin Pharmacol. 2011;51(1):9–18.

    CAS  PubMed  Google Scholar 

  32. Royer B, Jullien V, Guardiola E, Heyd B, Chauffert B, Kantelip JP, et al. Population pharmacokinetics and dosing recommendations for cisplatin during intraperitoneal peroperative administration: development of a limited sampling strategy for toxicity risk assessment. Clin Pharmacokinet. 2009;48(3):169–80.

    CAS  PubMed  Google Scholar 

  33. Royer B, Kalbacher E, Onteniente S, Jullien V, Montange D, Piedoux S, et al. Intraperitoneal clearance as a potential biomarker of cisplatin after intraperitoneal perioperative chemotherapy: a population pharmacokinetic study. Br J Cancer. 2012;106(3):460–7.

    CAS  PubMed  Google Scholar 

  34. Cashin PH, Ehrsson H, Wallin I, Nygren P, Mahteme H. Pharmacokinetics of cisplatin during hyperthermic intraperitoneal treatment of peritoneal carcinomatosis. Eur J Clin Pharmacol. 2013;69(3):533–40.

    CAS  PubMed  Google Scholar 

  35. Urien S, Lokiec F. Population pharmacokinetics of total and unbound plasma cisplatin in adult patients. Br J Clin Pharmacol. 2004;57(6):756–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Royer B, Guardiola E, Polycarpe E, Hoizey G, Delroeux D, Combe M, et al. Serum and intraperitoneal pharmacokinetics of cisplatin within intraoperative intraperitoneal chemotherapy: influence of protein binding. Anti-Cancer Drugs. 2005;16(9):1009–16.

    CAS  PubMed  Google Scholar 

  37. O'dwyer PJ, Stevenson JP, Johnson SW. Clinical pharmacokinetics and administration of established platinum drugs. Drugs. 2000;59(4):19–27.

    CAS  PubMed  Google Scholar 

  38. Borbás E, Sinkó B, Tsinman O, Tsinman K, Ev K, Démuth B, et al. Investigation and mathematical description of the real driving force of passive transport of drug molecules from supersaturated solutions. Mol Pharm. 2016;13(11):3816–26.

    PubMed  Google Scholar 

  39. Specenier PM, Ciuleanu T, Latz JE, Musib LC, Darstein CL, Vermorken JB. Pharmacokinetic evaluation of platinum derived from cisplatin administered alone and with pemetrexed in head and neck cancer patients. Cancer Chemother Pharmacol. 2009;64(2):233–41.

    CAS  PubMed  Google Scholar 

  40. Burdon PC, Martin C, Rankin SM. Migration across the sinusoidal endothelium regulates neutrophil mobilization in response to ELR+ CXC chemokines. Br J Haematol. 2008;142(1):100–8.

    CAS  PubMed  Google Scholar 

  41. Evans ND, Cheung SA, Yates JW. Structural identifiability for mathematical pharmacology: models of myelosuppression. J Pharmacokinet Pharmacodyn. 2018;45(1):79–90.

    CAS  PubMed  Google Scholar 

  42. Joerger M, Huitema AD, Richel DJ, Dittrich C, Pavlidis N, Briasoulis E, et al. Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group. Clin Cancer Res. 2007;13(21):6410–8.

    CAS  PubMed  Google Scholar 

  43. Hénin E, You B, VanCutsem E, Hoff P, Cassidy J, Twelves C, et al. A dynamic model of hand-and-foot syndrome in patients receiving capecitabine. Clin Pharmacol Ther. 2009;85(4):418–25.

    PubMed  Google Scholar 

  44. Schindler E, Karlsson MO. A minimal continuous-time Markov pharmacometric model. AAPS J. 2017;19(5):1424–35.

    CAS  PubMed  Google Scholar 

  45. Sheiner LB. A new approach to the analysis of analgesic drug trials, illustrated with bromfenac data. Clin Pharmacol Ther. 1994;56(3):309–22.

    CAS  PubMed  Google Scholar 

  46. Zingmark P-H, Kågedal M, Karlsson MO. Modelling a spontaneously reported side effect by use of a Markov mixed-effects model. J Pharmacokinet Pharmacodyn. 2005;32(2):261–81.

    PubMed  Google Scholar 

  47. Nagai N, Kinoshita M, Ogata H, Tsujino D, Wada Y, Someya K, et al. Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients. Cancer Chemother Pharmacol. 1996;39(1–2):131–7.

    CAS  PubMed  Google Scholar 

  48. Nagai N, Ogata H. Quantitative relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity in rats: importance of area under the concentration-time curve (AUC) as the major toxicodynamic determinant in vivo. Cancer Chemother Pharmacol. 1997;40(1):11–8.

    CAS  PubMed  Google Scholar 

  49. Hanada K, Asano K, Nishimura T, Chimata T, Matsuo Y, Tsuchiya M, et al. Use of a toxicity factor to explain differences in nephrotoxicity and myelosuppression among the platinum antitumour derivatives cisplatin, carboplatin and nedaplatin in rats. J Pharm Pharmacol. 2008;60(3):317–22.

    CAS  PubMed  Google Scholar 

  50. Le Saux O, Decullier E, Freyer G, Glehen O, Bakrin N. Long-term survival in patients with epithelial ovarian cancer following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Int J Hyperth. 2018;35(1):652–7.

    Google Scholar 

Download references

Acknowledgments

The authors thank all study participants and their families. We also thank the clinical study team members at the different study sites.

Funding

This work was supported by the Fund for Scientific Research – Flanders (FWO) (project number: G016915N).

Author information

Authors and Affiliations

  1. Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo Road 172, Changsha, 410013, China

    Feifan Xie

  2. Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium

    Feifan Xie, Jan Van Bocxlaer, Pieter Colin & An Vermeulen

  3. Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands

    Pieter Colin

  4. Department of GI Surgery, Ghent University Hospital, 9000, Ghent, Belgium

    Charlotte Carlier, Wouter Willaert & Wim Ceelen

  5. Cancer Research Institute Ghent (CRIG), 9000, Ghent, Belgium

    Charlotte Carlier, Hannelore Denys & Wim Ceelen

  6. Department of Surgery, St. Lucas Andreas Hospital, 9000, Ghent, Belgium

    Olivier Van Kerschaver

  7. Department of Surgery, CHC, Liège, Belgium

    Joseph Weerts

  8. Department of Medical Oncology, Ghent University Hospital, 9000, Ghent, Belgium

    Hannelore Denys

  9. Department of Gynecology, Ghent University Hospital, 9000, Ghent, Belgium

    Philippe Tummers

Authors
  1. Feifan Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan Van Bocxlaer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pieter Colin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charlotte Carlier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Olivier Van Kerschaver
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joseph Weerts
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hannelore Denys
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Philippe Tummers
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wouter Willaert
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wim Ceelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. An Vermeulen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Feifan Xie.

Ethics declarations

Conflict of Interest

An Vermeulen is an employee of Johnson & Johnson and holds stock/stock options in the company. She is also a visiting Professor at Ghent University. Wim Ceelen is a senior clinical researcher from the Fund for Scientific Research – Flanders (FWO). The other authors have no competing interests to declare.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(DOCX 26 kb)

ESM 2

(DOCX 685 kb)

ESM 3

(DOCX 23 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xie, F., Van Bocxlaer, J., Colin, P. et al. PKPD Modeling and Dosing Considerations in Advanced Ovarian Cancer Patients Treated with Cisplatin-Based Intraoperative Intraperitoneal Chemotherapy. AAPS J 22, 96 (2020). https://doi.org/10.1208/s12248-020-00489-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12248-020-00489-2

KEY WORDS

Search

Navigation