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Impact of Laparotomy and Intraperitoneal Hyperthermic Instillation (LIHI) on the oxaliplatin pharmacokinetics after intravenous administration in Wistar rats

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Abstract

Purpose

In peritoneal metastasis condition, the fact that most of the disease is limited to the peritoneal cavity laid the foundations for a surgical treatment, including intraperitoneal hyperthermic chemotherapy (HIPEC). The aim of this study was to evaluate the impact of the surgical procedures implied in open HIPEC technique, referred to laparotomy procedures followed by an intraperitoneal hyperthermic instillation (LIHI) on oxaliplatin tissue distribution and elimination. To delimit the influence of this procedure alone, oxaliplatin was administered as an intravenous (iv) bolus in both groups.

Methods

An experimental model in Wistar rats was employed, and LIHI was evaluated as a dichotomous covariate by using a population pharmacokinetic (PK) approach. Rats were randomized in two groups receiving 1.5 mg iv oxaliplatin alone or 1.5 mg iv oxaliplatin under LIHI conditions, carrying out a hyperthermic 5% dextrose instillation. The oxaliplatin plasma concentrations were characterized by an open two-compartment PK model.

Results

Results concluded that surgical conditions affect the oxaliplatin elimination and distribution from blood to peripheral tissues, increasing the systemic drug exposure. Concretely, oxaliplatin peripheral volume of distribution, and clearance decreased by 48.6% and 55.3%, respectively, compared to the control group that resulted in a two-fold increase of the area under the concentration time curve.

Conclusions

Comparison in clinical practice of oxaliplatin PK parameters obtained after iv administrations with those obtained after HIPEC interventions must be done carefully. This would limit the use of iv PK parameters to simulate new scenarios for oxaliplatin in HIPEC.

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Abbreviations

HIPEC:

Hyperthermic intraperitoneal chemotherapy

PM:

Peritoneal metastasis

PK:

Pharmacokinetic

LIHI:

Laparotomy + intraperitoneal hyperthermic instillation

iv:

Intravenous

\(AU{{C}_{pla~0-\infty }}\) :

Area under the plasma concentration time curve from time zero to infinite

CL:

Clearance

V 1 :

Central volume of distribution

Q :

Intercompartmental clearance

V 2 :

Peripheral volume of distribution

IIV:

Interindividual variability

CV:

Coefficient of variation

GOF:

Goodness of fit plots

NPDE:

Normalized prediction distribution errors

OFV:

Objective function value

NPBS:

Nonparametric bootstrap

pcVPC:

Prediction-corrected visual predictive check

CI:

Confidence intervals

SD:

Standard deviation

RSE:

Relative standard errors

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Acknowledgements

The authors would like to acknowledge the Animal Experimentation Service of San Juan de Alicante, UMH, for all the assistance received.

Funding

This study was funded by the Fundación Navarro Tripodi and from Proyecto Bancaja-UMH. The funding sources had no involvement in study design, collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the article for publication.

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Authors and Affiliations

  1. Division of Pharmacy and Pharmaceutics, Department of Engineering, School of Pharmacy, Miguel Hernández University, San Juan de Alicante, Alicante, Spain

    María Isabel Mas-Fuster, Amelia Ramon-Lopez, Patricio Más-Serrano & Ricardo Nalda-Molina

  2. Department of Pathology and Surgery, School of Medicine, Miguel Hernández University, San Juan de Alicante, Alicante, Spain

    Javier Lacueva & Antonio Compañ

  3. Clinical Pharmacokinetics Unit, Pharmacy Department, Hospital General Universitario de Alicante, Alicante, Spain

    Patricio Más-Serrano

Authors
  1. María Isabel Mas-Fuster
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  2. Amelia Ramon-Lopez
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  3. Javier Lacueva
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  4. Antonio Compañ
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  5. Patricio Más-Serrano
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  6. Ricardo Nalda-Molina
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Corresponding author

Correspondence to Amelia Ramon-Lopez.

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Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Research involving animals

Development of experimental model was held at the Animal Experimentation Service of San Juan de Alicante, attached to Miguel Hernández University of Elche (UMH). At the end of the procedure, rats were sacrificed. Care of the animals and drug administration were performed under veterinary control according to European Union Directive 2010/63/EU for animal experiments and with approval from the Ethics Committee of the UMH.

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Mas-Fuster, M.I., Ramon-Lopez, A., Lacueva, J. et al. Impact of Laparotomy and Intraperitoneal Hyperthermic Instillation (LIHI) on the oxaliplatin pharmacokinetics after intravenous administration in Wistar rats. Cancer Chemother Pharmacol 79, 621–627 (2017). https://doi.org/10.1007/s00280-017-3244-6

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  • DOI: https://doi.org/10.1007/s00280-017-3244-6

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