Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 3, pp 571–582 | Cite as

Population pharmacokinetics of peritoneal, plasma ultrafiltrated and protein-bound oxaliplatin concentrations in patients with disseminated peritoneal cancer after intraperitoneal hyperthermic chemoperfusion of oxaliplatin following cytoreductive surgery: correlation between oxaliplatin exposure and thrombocytopenia

  • Quentin Chalret du Rieu
  • Mélanie White-Koning
  • Laetitia Picaud
  • Isabelle Lochon
  • Sabrina Marsili
  • Laurence Gladieff
  • Etienne ChatelutEmail author
  • Gwenaël Ferron
Original Article



First, to evaluate the peritoneal (IP), plasma ultrafiltrated (UF) and protein-bound (B) pharmacokinetics (PK) of oxaliplatin after intraperitoneal hyperthermic chemoperfusion (HIPEC) following cytoreductive surgery. Second, to evaluate the relationship between oxaliplatin exposure and observed toxicity.


IP, UF, and B concentrations from 75 patients treated by 30-min oxaliplatin-based HIPEC procedures were analysed according to a pharmacokinetic modelling approach using NONMEM. Oxaliplatin was administered in a 5 % dextrose solution (2 L/m2) at 360 (n = 58) or 460 mg/m2 (n = 17). The most frequently observed toxicities were related to the peritoneal, systemic exposures and to the parameters corresponding to the oxaliplatin absorption from peritoneal cavity into plasma.


IP (n = 536), UF (n = 669) and B (n = 661) concentrations were simultaneously described according to a five-compartment PK model with irreversible nonlinear binding from UF to B according to a Michaelis–Menten equation. The mean (±SD) maximum fraction of dose absorbed and elimination half-life from the peritoneum was 53.7 % (±8.5) and 0.49 h (±0.1), respectively. The mean (±SD) ratio AUCIP/AUCUF was 5.3 (±2) confirming the pharmacokinetic advantage of the procedure. Haemoperitoneum (22.7 %), neuropathy (18.7 %), grade 3/4 thrombocytopenia (13.3 %) were the most frequently reported toxicities. AUCUF accounts for approximately 12 % of the variation in the maximum percentage of platelet decrease (r = 0.35, p = 0.002). Thrombocytopenia was correlated with higher AUCUF, partly dependent on the extent and rate of oxaliplatin absorption.


Despite a common dose administered, variability in peritoneal and systemic oxaliplatin exposures are observed, leading to differences in haematological toxicity between patients.


Oxaliplatin HIPEC Population pharmacokinetic Thrombocytopenia NONMEM 



This work was integrated in a Ph.D. project (Quentin Chalret du Rieu), granted by Institut de Recherches Internationales Servier.

Conflict of interest



  1. 1.
    Cao C, Yan TD, Black D, Morris DL (2009) A systematic review and meta-analysis of cytoreductive surgery with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol 16:2152–2165PubMedCrossRefGoogle Scholar
  2. 2.
    Los G, Mutsaers PH, van der Vijgh WJ, Baldew GS, de Graaf PW, McVie JG (1989) Direct diffusion of cis-diamminedichloroplatinum(II) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy. Cancer Res 49:3380–3384PubMedGoogle Scholar
  3. 3.
    Elias DM, Ouellet JF (2001) Intraperitoneal chemohyperthermia: rationale, technique, indications, and results. Surg Oncol Clin N Am 10:915–33, xiGoogle Scholar
  4. 4.
    Glehen O, Gilly FN, Boutitie F, Bereder JM, Quenet F, Sideris L, Mansvelt B, Lorimier G, Msika S, Elias D (2010) Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy: a multi-institutional study of 1,290 patients. Cancer 116:5608–5618PubMedCrossRefGoogle Scholar
  5. 5.
    Elias D, Quenet F, Goere D (2012) Current status and future directions in the treatment of peritoneal dissemination from colorectal carcinoma. Surg Oncol Clin N Am 21:611–623PubMedCrossRefGoogle Scholar
  6. 6.
    Bakrin N, Bereder JM, Decullier E, Classe JM, Msika S, Lorimier G, Abboud K, Meeus P, Ferron G, Quenet F, Marchal F, Gouy S, Morice P, Pomel C, Pocard M, Guyon F, Porcheron J, Glehen O (2013) Peritoneal carcinomatosis treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced ovarian carcinoma: a French multicentre retrospective cohort study of 566 patients. Eur J Surg Oncol 39:1435–1443PubMedCrossRefGoogle Scholar
  7. 7.
    Fagotti A, Costantini B, Petrillo M, Vizzielli G, Fanfani F, Margariti PA, Turco LC, Piovano E, Scambia G (2012) Cytoreductive surgery plus HIPEC in platinum-sensitive recurrent ovarian cancer patients: a case–control study on survival in patients with 2 year follow-up. Gynecol Oncol 127:502–505PubMedCrossRefGoogle Scholar
  8. 8.
    Yang XJ, Huang CQ, Suo T, Mei LJ, Yang GL, Cheng FL, Zhou YF, Xiong B, Yonemura Y, Li Y (2011) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol 18:1575–1581PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Cho HK, Lush RM, Bartlett DL, Alexander HR, Wu PC, Libutti SK, Lee KB, Venzon DJ, Bauer KS, Reed E, Figg WD (1999) Pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) to patients with peritoneal carcinomatosis. J Clin Pharmacol 39:394–401PubMedCrossRefGoogle Scholar
  10. 10.
    Steller MA, Egorin MJ, Trimble EL, Bartlett DL, Zuhowski EG, Alexander HR, Dedrick RL (1999) A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small-volume residual ovarian cancer. Cancer Chemother Pharmacol 43:106–114PubMedCrossRefGoogle Scholar
  11. 11.
    de Bree E, Rosing H, Filis D, Romanos J, Melisssourgaki M, Daskalakis M, Pilatou M, Sanidas E, Taflampas P, Kalbakis K, Beijnen JH, Tsiftsis DD (2008) Cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy with paclitaxel: a clinical and pharmacokinetic study. Ann Surg Oncol 15:1183–1192PubMedCrossRefGoogle Scholar
  12. 12.
    Votanopoulos K, Ihemelandu C, Shen P, Stewart J, Russell G, Levine EA (2013) A comparison of hematologic toxicity profiles after heated intraperitoneal chemotherapy with oxaliplatin and mitomycin C. J Surg Res 179:e133–e139PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Jacquet P, Stuart OA, Chang D, Sugarbaker PH (1996) Effects of intra-abdominal pressure on pharmacokinetics and tissue distribution of doxorubicin after intraperitoneal administration. Anticancer Drugs 7:596–603PubMedCrossRefGoogle Scholar
  14. 14.
    Atallah D, Marsaud V, Radanyi C, Kornprobst M, Rouzier R, Elias D, Renoir JM (2004) Thermal enhancement of oxaliplatin-induced inhibition of cell proliferation and cell cycle progression in human carcinoma cell lines. Int J Hyperth 20:405–419CrossRefGoogle Scholar
  15. 15.
    Elias D, Bonnay M, Puizillou JM, Antoun S, Demirdjian S, El OA, Pignon JP, Drouard-Troalen L, Ouellet JF, Ducreux M (2002) Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution. Ann Oncol 13:267–272PubMedCrossRefGoogle Scholar
  16. 16.
    Culy CR, Clemett D, Wiseman LR (2000) Oxaliplatin: a review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs 60:895–924PubMedCrossRefGoogle Scholar
  17. 17.
    Elias D, Matsuhisa T, Sideris L, Liberale G, Drouard-Troalen L, Raynard B, Pocard M, Puizillou JM, Billard V, Bourget P, Ducreux M (2004) Heated intra-operative intraperitoneal oxaliplatin plus irinotecan after complete resection of peritoneal carcinomatosis: pharmacokinetics, tissue distribution and tolerance. Ann Oncol 15:1558–1565PubMedCrossRefGoogle Scholar
  18. 18.
    Ferron G, Dattez S, Gladieff L, Delord JP, Pierre S, Lafont T, Lochon I, Chatelut E (2008) Pharmacokinetics of heated intraperitoneal oxaliplatin. Cancer Chemother Pharmacol 62:679–683PubMedCrossRefGoogle Scholar
  19. 19.
    Perez-Ruixo C, Valenzuela B, Peris JE, Bretcha-Boix P, Escudero-Ortiz V, Farre-Alegre J, Perez-Ruixo JJ (2013) Population pharmacokinetics of hyperthermic intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis after cytoreductive surgery. Cancer Chemother Pharmacol 71:693–704PubMedCrossRefGoogle Scholar
  20. 20.
    Valenzuela B, Nalda-Molina R, Bretcha-Boix P, Escudero-Ortiz V, Duart MJ, Carbonell V, Sureda M, Rebollo JP, Farre J, Brugarolas A, Perez-Ruixo JJ (2011) Pharmacokinetic and pharmacodynamic analysis of hyperthermic intraperitoneal oxaliplatin-induced neutropenia in subjects with peritoneal carcinomatosis. AAPS J 13:72–82PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Perez-Ruixo C, Peris JE, Escudero-Ortiz V, Bretcha-Boix P, Farre-Alegre J, Perez-Ruixo JJ, Valenzuela B (2014) Rate and extent of oxaliplatin absorption after hyperthermic intraperitoneal administration in peritoneal carcinomatosis patients. Cancer Chemother Pharmacol 73(5):1009–1020Google Scholar
  22. 22.
    Perez-Ruixo C, Valenzuela B, Peris JE, Bretcha-Boix P, Escudero-Ortiz V, Farre-Alegre J, Perez-Ruixo JJ (2013) Neutrophil dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery and hyperthermic intraperitoneal oxaliplatin. Clin Pharmacokinet 52:1111–1125PubMedCrossRefGoogle Scholar
  23. 23.
    Elias D, Raynard B, Bonnay M, Pocard M (2006) Heated intra-operative intraperitoneal oxaliplatin alone and in combination with intraperitoneal irinotecan: pharmacologic studies. Eur J Surg Oncol 32:607–613PubMedCrossRefGoogle Scholar
  24. 24.
    LeRoy AF, Wehling ML, Sponseller HL, Friauf WS, Solomon RE, Dedrick RL, Litterst CL, Gram TE, Guarino AM, Becker DA (1977) Analysis of platinum in biological materials by flameless atomic absorption spectrophotometry. Biochem Med 18:184–191PubMedCrossRefGoogle Scholar
  25. 25.
    Royer B, Kalbacher E, Onteniente S, Jullien V, Montange D, Piedoux S, Thiery-Vuillemin A, Delroeux D, Pili-Floury S, Guardiola E, Combe M, Muret P, Nerich V, Heyd B, Chauffert B, Kantelip JP, Pivot X (2012) Intraperitoneal clearance as a potential biomarker of cisplatin after intraperitoneal perioperative chemotherapy: a population pharmacokinetic study. Br J Cancer 106:460–467PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Urien S, Lokiec F (2004) Population pharmacokinetics of total and unbound plasma cisplatin in adult patients. Br J Clin Pharmacol 57:756–763PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Brendel K, Comets E, Laffont C, Laveille C, Mentre F (2006) Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharm Res 23:2036–2049PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Brendel K, Comets E, Laffont C, Mentre F (2010) Evaluation of different tests based on observations for external model evaluation of population analyses. J Pharmacokinet Pharmacodyn 37:49–65PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Savic RM, Karlsson MO (2009) Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J 11:558–569PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Jacquet P, Sugarbaker PH (1996) Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res 82:359–374PubMedCrossRefGoogle Scholar
  31. 31.
    Graham MA, Lockwood GF, Greenslade D, Brienza S, Bayssas M, Gamelin E (2000) Clinical pharmacokinetics of oxaliplatin: a critical review. Clin Cancer Res 6:1205–1218PubMedGoogle Scholar
  32. 32.
    Royer B, Guardiola E, Polycarpe E, Hoizey G, Delroeux D, Combe M, Chaigneau L, Samain E, Chauffert B, Heyd B, Kantelip JP, Pivot X (2005) Serum and intraperitoneal pharmacokinetics of cisplatin within intraoperative intraperitoneal chemotherapy: influence of protein binding. Anticancer Drugs 16:1009–1016PubMedCrossRefGoogle Scholar
  33. 33.
    Royer B, Delroeux D, Guardiola E, Combe M, Hoizey G, Montange D, Kantelip JP, Chauffert B, Heyd B, Pivot X (2008) Improvement in intraperitoneal intraoperative cisplatin exposure based on pharmacokinetic analysis in patients with ovarian cancer. Cancer Chemother Pharmacol 61:415–421PubMedCrossRefGoogle Scholar
  34. 34.
    Comets E, Brendel K, Mentre F (2008) Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Programs Biomed 90:154–166PubMedCrossRefGoogle Scholar
  35. 35.
    Mahteme H, Wallin I, Glimelius B, Pahlman L, Ehrsson H (2008) Systemic exposure of the parent drug oxaliplatin during hyperthermic intraperitoneal perfusion. Eur J Clin Pharmacol 64:907–911PubMedCrossRefGoogle Scholar
  36. 36.
    Cotte E, Colomban O, Guitton J, Tranchand B, Bakrin N, Gilly FN, Glehen O, Tod M (2011) Population pharmacokinetics and pharmacodynamics of cisplatinum during hyperthermic intraperitoneal chemotherapy using a closed abdominal procedure. J Clin Pharmacol 51:9–18PubMedCrossRefGoogle Scholar
  37. 37.
    Jardim DL, Rodrigues CA, Novis YA, Rocha VG, Hoff PM (2012) Oxaliplatin-related thrombocytopenia. Ann Oncol 23:1937–1942PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Quentin Chalret du Rieu
    • 1
    • 2
  • Mélanie White-Koning
    • 1
    • 2
  • Laetitia Picaud
    • 3
  • Isabelle Lochon
    • 1
    • 2
  • Sabrina Marsili
    • 1
    • 2
  • Laurence Gladieff
    • 4
  • Etienne Chatelut
    • 1
    • 2
    Email author
  • Gwenaël Ferron
    • 1
    • 2
    • 3
  1. 1.EA4553Univ. Toulouse III Paul SabatierToulouseFrance
  2. 2.Institut Claudius RegaudIUCT-O, Laboratoire de PharmacologieToulouseFrance
  3. 3.Institut Claudius RegaudIUCT-O, Département de Chirurgie OncologiqueToulouseFrance
  4. 4.Institut Claudius RegaudIUCT-O, Département d’Oncologie MédicaleToulouseFrance

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