Clinical Pharmacokinetics

, Volume 48, Issue 3, pp 169–180

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

DOI: 10.2165/00003088-200948030-00003

Cite this article as:
Royer, B., Jullien, V., Guardiola, E. et al. Clin Pharmacokinet (2009) 48: 169. doi:10.2165/00003088-200948030-00003

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.

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
  7. 7.Laboratoire de Pharmacologie CliniqueCHU Jean Minjoz, bvd FlemingBesançon CedexFrance