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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

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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

Keywords

Oxaliplatin HIPEC Population pharmacokinetic Thrombocytopenia NONMEM 

Notes

Acknowledgments

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

Conflict of interest

None.

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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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