Population pharmacokinetics and dosing recommendations for cisplatin during intraperitoneal peroperative administration: development of a limited sampling strategy for toxicity risk assessment.
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.


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 distribution in the Uf Pt model, and both IP and serum protein concentrations for the clearance from the central compartment in 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.


CONCLUSIONS
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.
Royer
Bernard
B
UMR645, INSERM, Besançon, France. broyer@chu-besancon.fr
Jullien
Vincent
V
Guardiola
Emmanuel
E
Heyd
Bruno
B
Chauffert
Bruno
B
Kantelip
Jean-Pierre
JP
Pivot
Xavier
X
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007432:Intraoperative Period; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D017711:Nonlinear Dynamics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery*; D018570:Risk Assessment
D000970:Antineoplastic Agents; D002945:Cisplatin