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Pharmacokinetic and Pharmacodynamic Analysis of Hyperthermic Intraperitoneal Oxaliplatin-Induced Neutropenia in Subjects with Peritoneal Carcinomatosis

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An Erratum to this article was published on 26 February 2011

Abstract

The objective of this study was to characterize the pharmacokinetics and the time course of the neutropenia-induced by hyperthermic intraperitoneal oxaliplatin (HIO) after cytoreductive surgery in cancer patients with peritoneal carcinomatosis. Data from 30 patients who received 360 mg/m2 of HIO following cytoreductive surgery were used for pharmacokinetic–pharmacodynamic (PK/PD) analysis. The oxaliplatin plasma concentrations were characterized by an open two-compartment pharmacokinetic model after first-order absorption from peritoneum to plasma. An oxaliplatin-sensitive progenitor cell compartment was used to describe the absolute neutrophil counts in blood. The reduction of the proliferation rate of the progenitor cells was modeled by a linear function of the oxaliplatin plasma concentrations. The typical values of oxaliplatin absorption and terminal half-lives were estimated to be 2.2 and 40 h, with moderate interindividual variability. Oxaliplatin reduced the proliferation rate of the progenitor cells by 18.2% per mg/L. No patient’s covariates were related to oxaliplatin PK/PD parameters. Bootstrap and visual predictive check evidenced the model was deemed appropriate to describe oxaliplatin pharmacokinetics and the incidence and severity of neutropenia. A peritoneum oxaliplatin exposure of 65 and 120 mg·L/h was associated with a 20% and 33% incidence of neutropenia grade 4. The time course of neutropenia following HIO administration was well described by the semiphysiological PK/PD model. The maximum tolerated peritoneum oxaliplatin exposure is 120 mg L/h and higher exposures should be avoided in future studies. We suggest the prophylactic use of granulocyte colony stimulating factor for patients treated with HIO exposure higher than 65 mg L/h.

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ACKNOWLEDGMENTS

The authors would like to thank the patients, medical, nursing, and laboratory staff of the USP Hospital San Jaime who participated in the present study. The authors indicated no potential conflicts of interest.

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Authors and Affiliations

  1. Platform of Oncology, USP Hospital San Jaime, Partida de la Loma s/n, 03184, Torrevieja, Alicante, Spain

    Belén Valenzuela, Pere Bretcha-Boix, Vanesa Escudero-Ortíz, Manuel Sureda, José Pascual Rebollo, Josep Farré & Antonio Brugarolas

  2. Pharmaceutical Sciences Department, University Miguel Hernandez, Alicante, Spain

    Ricardo Nalda-Molina, Maria José Duart & Juan José Pérez-Ruixo

  3. AINIA Technology Centre, Paterna, Valencia, Spain

    Vicente Carbonell

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  1. Belén Valenzuela
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Correspondence to Belén Valenzuela.

Additional information

Valenzuela B and Nalda-Molina R both deserve to be considered as first authors.

An erratum to this article can be found at http://dx.doi.org/10.1208/s12248-011-9262-0

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Valenzuela, B., Nalda-Molina, R., Bretcha-Boix, P. et al. Pharmacokinetic and Pharmacodynamic Analysis of Hyperthermic Intraperitoneal Oxaliplatin-Induced Neutropenia in Subjects with Peritoneal Carcinomatosis. AAPS J 13, 72–82 (2011). https://doi.org/10.1208/s12248-010-9249-2

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