Clinical Pharmacokinetics

, Volume 48, Issue 3, pp 169–180 | Cite as

Population Pharmacokinetics and Dosing Recommendations for Cisplatin during Intraperitoneal Peroperative Administration

Development of a Limited Sampling Strategy for Toxicity Risk Assessment
  • Bernard Royer
  • Vincent Jullien
  • Emmanuel Guardiola
  • Bruno Heyd
  • Bruno Chauffert
  • Jean-Pierre Kantelip
  • Xavier Pivot
Original Research Article

Abstract

Background: Ovarian cancer is the leading cause of gynaecological cancer-related death in Western countries. Intraperitoneal (IP) peroperative chemotherapy is an interesting therapeutic option. However, very few data are available regarding pharmacokinetics and especially population pharmacokinetics.

Patients and methods: Thirty-one patients with advanced epithelial cancer classified as International Federation of Gynecology and Obstetrics stage IIIC were included in the study. Blood and IP samples were taken over a 24-hour period during and after IP treatment. Both total and ultrafiltered (Uf) platinum (Pt) concentrations were analysed using a population approach with nonlinear mixed-effects modelling (NONMEM®) software. Improvement of the model with covariates was performed as well as assessment of the model using bootstrap and posterior visual predictive methods.

Results: Both IP fluid and serum pharmacokinetics were satisfactorily described with a three-compartment model for both Uf Pt and total Pt concentrations. The covariates were bodyweight for the IP volume of the total Pt model. A nomogram, based on the results of the Monte Carlo simulations, displays a dose recommendation regarding both the risk of renal toxicity and the potent efficacy of the treatment. A limited sampling strategy (LSS) allowing the estimation of potential risk of renal toxicity is also described.

Conclusion: The pharmacokinetics of cisplatin during peroperative IP chemotherapy could be successfully fitted with the present model, which allowed a dosing strategy accompanied by an LSS to facilitate the follow-up of patients.

Notes

Acknowledgements

The authors are very grateful to Dr Pauline Gerritsen-van Schieveen for her careful reading of the manuscript and her help with the English formulation. This work was supported by a grant from the Ligue contre le Cancer, Comité du Doubs. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Bernard Royer
    • 1
    • 2
  • Vincent Jullien
    • 3
  • Emmanuel Guardiola
    • 4
  • Bruno Heyd
    • 5
  • Bruno Chauffert
    • 6
  • Jean-Pierre Kantelip
    • 2
  • Xavier Pivot
    • 1
    • 4
  1. 1.UMR645, INSERMBesançonFrance
  2. 2.Laboratoire de Pharmacologie CliniqueHôpital Jean Minjoz, CHU BesançonBesançonFrance
  3. 3.Groupe Hospitalier Cochin Saint-Vincent de PaulU663, INSERM, Université Paris-Descartes, Service de Pharmacologie CliniqueParisFrance
  4. 4.Service d’OncologieHôpital Jean MinjozBesançonFrance
  5. 5.Service de Chirurgie OncologiqueHôpital Jean MinjozBesançonFrance
  6. 6.Centre Régional de Lutte contre le Cancer LeclercDijonFrance

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