title: Pharmacokinetic and pharmacodynamic analysis of hyperthermic intraperitoneal oxaliplatin-induced neutropenia in subjects with peritoneal carcinomatosis.
abstract: The objective of this study was to characterize the pharmacokinetics and the time course of the neutropenia-induced by hyperthermic intraperitoneal oxaliplatin (HIO) after cytoreductive surgery in cancer patients with peritoneal carcinomatosis. Data from 30 patients who received 360 mg/m(2) of HIO following cytoreductive surgery were used for pharmacokinetic-pharmacodynamic (PK/PD) analysis. The oxaliplatin plasma concentrations were characterized by an open two-compartment pharmacokinetic model after first-order absorption from peritoneum to plasma. An oxaliplatin-sensitive progenitor cell compartment was used to describe the absolute neutrophil counts in blood. The reduction of the proliferation rate of the progenitor cells was modeled by a linear function of the oxaliplatin plasma concentrations. The typical values of oxaliplatin absorption and terminal half-lives were estimated to be 2.2 and 40 h, with moderate interindividual variability. Oxaliplatin reduced the proliferation rate of the progenitor cells by 18.2% per mg/L. No patient's covariates were related to oxaliplatin PK/PD parameters. Bootstrap and visual predictive check evidenced the model was deemed appropriate to describe oxaliplatin pharmacokinetics and the incidence and severity of neutropenia. A peritoneum oxaliplatin exposure of 65 and 120 mg·L/h was associated with a 20% and 33% incidence of neutropenia grade 4. The time course of neutropenia following HIO administration was well described by the semiphysiological PK/PD model. The maximum tolerated peritoneum oxaliplatin exposure is 120 mg L/h and higher exposures should be avoided in future studies. We suggest the prophylactic use of granulocyte colony stimulating factor for patients treated with HIO exposure higher than 65 mg L/h.
authors.affiliation: Platform of Oncology, USP Hospital San Jaime, Partida de Loma s/n, 03184 Torrevieja, Alicante, Spain. belen.valenzuela@usphospitales.com
authors.forename: Belén
authors.initials: B
authors.lastname: Valenzuela
authors.forename: Ricardo
authors.initials: R
authors.lastname: Nalda-Molina
authors.forename: Pere
authors.initials: P
authors.lastname: Bretcha-Boix
authors.forename: Vanesa
authors.initials: V
authors.lastname: Escudero-Ortíz
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Duart
authors.forename: Vicente
authors.initials: V
authors.lastname: Carbonell
authors.forename: Manuel
authors.initials: M
authors.lastname: Sureda
authors.forename: José Pascual
authors.initials: JP
authors.lastname: Rebollo
authors.forename: Josep
authors.initials: J
authors.lastname: Farré
authors.forename: Antonio
authors.initials: A
authors.lastname: Brugarolas
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Pérez-Ruixo
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002277:Carcinoma / Q000188:drug therapy / Q000503:physiopathology* / Q000601:surgery; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005260:Female; D006207:Half-Life; D006801:Humans; D006979:Hyperthermia, Induced; D007263:Infusions, Parenteral; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009503:Neutropenia / Q000139:chemically induced* / Q000503:physiopathology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000077150:Oxaliplatin; D010529:Peritoneal Cavity; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000503:physiopathology* / Q000601:surgery; D012984:Software
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin