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Population pharmacokinetics of hyperthermic intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis after cytoreductive surgery

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Abstract

Purpose

To characterize the hyperthermic intraperitoneal oxaliplatin (HIO) pharmacokinetics in peritoneum and plasma in patients with peritoneal carcinomatosis (PC) after cytoreductive surgery (CRS).

Methods

Data from 36 patients receiving HIO diluted in isotonic 4 % icodextrin were combined with data from 13 patients receiving HIO diluted in isotonic 5 % dextrose. Total oxaliplatin in peritoneal and plasma fluids were used to characterize an open two-compartment disposition model with linear distribution and elimination and first-order absorption from peritoneum to plasma using NONMEM software. The effect of patient- and treatment-related covariates on oxaliplatin pharmacokinetic parameters was explored.

Results

The typical value (interindividual variability, %) in k a , CL, and V ss were 0.57 h−1 (43 %), 1.71 L h−1 (39 %), and 77 L (65 %), respectively. No significant effect of age, body surface area, sex, creatinine clearance, liver metastases, PC index, and complete cytoreduction on pharmacokinetic parameters was found. A 12–15 % reduction in peritoneal volume of distribution was observed in patients receiving HIO diluted in 5 % dextrose relative to those patients receiving HIO diluted in 4 % icodextrin.

Conclusions

The integration of peritoneal and plasma data demonstrated oxaliplatin linear absorption from peritoneum to plasma, non-specific distribution to a peripheral compartment, and linear elimination from the central compartment when HIO was administered with isotonic carrier solutions to PC patients who underwent CRS. Only the effect of the carrier solution had an impact in the peritoneal volume of distribution, but its clinical relevance seems to be limited, especially for short HIO infusions (<60 min).

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Acknowledgments

The authors would like to thank the patients, medical, nursing, and laboratory staff of the Hospital San Jaime who participated in the present study. This work was supported by Consellería de Sanidad of Comunidad Valenciana, Spain. Grant GE-079/11.

Conflict of interest

The author(s) indicated no potential conflicts of interest.

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Authors and Affiliations

  1. Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain

    Carlos Pérez-Ruixo & José Esteban Peris

  2. Platform of Oncology, Hospital San Jaime, Partida de La Loma s/n, 03184, Torrevieja, Alicante, Spain

    Belén Valenzuela, Pedro Bretcha-Boix, Vanesa Escudero-Ortiz & José Farré-Alegre

  3. Pharmacokinetics and Drug Metabolism, AMGEN, Valencia, Spain

    Juan José Pérez-Ruixo

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  1. Carlos Pérez-Ruixo
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Correspondence to Belén Valenzuela.

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Disclaimer: The views expressed in this article are the personal views of the authors reflecting their scientific knowledge of this topic and should not be understood or quoted as being made on behalf of the companies where the authors currently work.

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Pérez-Ruixo, C., Valenzuela, B., Peris, J.E. et al. Population pharmacokinetics of hyperthermic intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis after cytoreductive surgery. Cancer Chemother Pharmacol 71, 693–704 (2013). https://doi.org/10.1007/s00280-012-2060-2

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  • DOI: https://doi.org/10.1007/s00280-012-2060-2

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