1. Population Pharmacokinetics and Dosing Recommendations for Cisplatin during Intraperitoneal Peroperative Administration
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Xavier Pivot, Bruno Chauffert, Jean-Pierre Kantelip, Emmanuel Guardiola, Vincent Jullien, Bruno Heyd, Bernard Royer, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Pharmacologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epilepsies de l'Enfant et Plasticité Cérébrale (U1129), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Service de chirurgie viscérale et digestive - Unité de transplantation hépatique, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( UR 3920) (PCVP / CARDIO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Cochin-Saint Vincent de Paul, Epilepsies de l'Enfant et Plasticité Cérébrale ( U1129 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) ( HOTE GREFFON ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) ( PCVP / CARDIO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ) -Université Bourgogne Franche-Comté [COMUE] ( UBFC ), and Saas, Philippe
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MESH: Combined Modality Therapy ,MESH : Aged ,MESH : Dose-Response Relationship, Drug ,MESH : Models, Biological ,MESH: Risk Assessment ,030226 pharmacology & pharmacy ,MESH: Dose-Response Relationship, Drug ,Intraoperative Period ,MESH : Metabolic Clearance Rate ,0302 clinical medicine ,[ SDV.IMM ] Life Sciences [q-bio]/Immunology ,Medicine ,MESH : Female ,Pharmacology (medical) ,MESH : Risk Assessment ,Ovarian Neoplasms ,MESH: Aged ,Volume of distribution ,education.field_of_study ,MESH: Middle Aged ,Middle Aged ,MESH : Adult ,MESH : Nonlinear Dynamics ,Combined Modality Therapy ,3. Good health ,MESH : Antineoplastic Agents ,MESH: Nonlinear Dynamics ,MESH: Ovarian Neoplasms ,Area Under Curve ,030220 oncology & carcinogenesis ,Toxicity ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,MESH : Intraoperative Period ,Risk assessment ,Monte Carlo Method ,Injections, Intraperitoneal ,MESH: Injections, Intraperitoneal ,Adult ,medicine.medical_specialty ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Metabolic Clearance Rate ,MESH : Drug Administration Schedule ,Population ,Urology ,Antineoplastic Agents ,MESH: Monte Carlo Method ,MESH: Drug Administration Schedule ,Models, Biological ,Risk Assessment ,Drug Administration Schedule ,MESH : Cisplatin ,03 medical and health sciences ,Pharmacokinetics ,Humans ,MESH : Middle Aged ,Dosing ,education ,Aged ,MESH: Intraoperative Period ,MESH: Metabolic Clearance Rate ,Pharmacology ,MESH : Injections, Intraperitoneal ,MESH: Humans ,Dose-Response Relationship, Drug ,MESH : Ovarian Neoplasms ,business.industry ,MESH : Humans ,MESH: Models, Biological ,MESH: Adult ,Nomogram ,NONMEM ,MESH : Monte Carlo Method ,Nonlinear Dynamics ,MESH: Cisplatin ,MESH: Antineoplastic Agents ,MESH: Area Under Curve ,MESH : Area Under Curve ,Cisplatin ,MESH : Combined Modality Therapy ,business ,MESH: Female - Abstract
International audience; 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 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. 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.
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- 2009
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