Journal Article

Population Pharmacokinetics and Dosing Recommendations for Cisplatin during Intraperitoneal Peroperative Administration

Royer, Bernard, Jullien, Vincent, Heyd, Bruno, Chauffert, Bruno, Guardiola, Emmanuel, Pivot, Xavier, Kantelip, Jean-Pierre

2009

Overview

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.

• Publisher: Springer International Publishing,Adis International,Wolters Kluwer Health, Inc,Springer Nature B.V,Springer Verlag
• Subject: Adult / Aged / Antineoplastic Agents / Antineoplastic Agents - pharmacokinetics / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Area Under Curve / Biological and medical sciences / Chemical properties / Chemotherapy / Cisplatin / Cisplatin - pharmacokinetics / Cisplatin - pharmacology / Cisplatin - therapeutic use / Combined Modality Therapy / Complications and side effects / Dosage and administration / Dose-Response Relationship, Drug / Drug Administration Schedule / Drug therapy / Female / General pharmacology / Health aspects / Humans / Immunology / Injections, Intraperitoneal / Internal Medicine / Intraoperative Period / Life Sciences / Medical sciences / Medicine / Medicine & Public Health / Metabolic Clearance Rate / Middle Aged / Models, Biological / Monte Carlo Method / Neoadjuvant therapy / Nonlinear Dynamics / Original Research Article / Ovarian cancer / Ovarian Neoplasms / Ovarian Neoplasms - drug therapy / Ovarian Neoplasms - metabolism / Ovarian Neoplasms - surgery / Pharmacokinetics / Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions / Pharmacology. Drug treatments / Pharmacology/Toxicology / Pharmacotherapy / Risk Assessment