title: Rate and extent of oxaliplatin absorption after hyperthermic intraperitoneal administration in peritoneal carcinomatosis patients.
abstract: OBJECTIVE
  To determine the rate and extent of hyperthermic intraperitoneal oxaliplatin (HIO) absorption in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and the effect of the isotonic carrier solution on HIO absorption parameters.
  
  
  METHODS
  Full pharmacokinetic profiles collected in peritoneum and plasma from 57 subjects treated with CRS followed by 30 min of HIO were pooled with sparse plasma concentrations collected from 50 patients with solid tumors treated with intravenous oxaliplatin. Pharmacokinetic data were jointly analyzed with nonlinear mixed-effect model (NONMEM VII software). The effect of carrier solution (icodextrin 4 % vs. dextrose 5 %) and selected patient covariates on oxaliplatin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and nonparametric bootstrap.
  
  
  RESULTS
  An open linear two-compartment disposition model with linear absorption from peritoneum to plasma was used to characterize the oxaliplatin pharmacokinetics in peritoneum and plasma. No patient-related covariates were associated with oxaliplatin pharmacokinetics. The volume of distribution in the peritoneum (V a) exponentially decreased due to the carrier solute absorption. The reduction in V a was 1.76-fold faster when HIO was administered in dextrose 5 %, relative to icodextrin 4 %. For HIO durations of 30 min, the rate of oxaliplatin absorption ranges from 0.84 to 0.96 h(-1) for icodextrin 4 % and from 0.86 to 1.09 h(-1) for dextrose 5 %. The extent of HIO absorption was 38 %, regardless of the carrier solution.
  
  
  CONCLUSIONS
  Hyperthermic intraperitoneal oxaliplatin absorption is fast and incomplete. The small difference in oxaliplatin exposure between both carrier solutions evaluated is not clinically relevant for HIO durations of 30 min.
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pérez-Ruixo
authors.forename: José E
authors.initials: JE
authors.lastname: Peris
authors.forename: Vanesa
authors.initials: V
authors.lastname: Escudero-Ortiz
authors.forename: Pedro
authors.initials: P
authors.lastname: Bretcha-Boix
authors.forename: José
authors.initials: J
authors.lastname: Farré-Alegre
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Pérez-Ruixo
authors.forename: Belén
authors.initials: B
authors.lastname: Valenzuela
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007274:Injections, Intraperitoneal; D008297:Male; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin