Rate and extent of oxaliplatin absorption after hyperthermic intraperitoneal administration in peritoneal carcinomatosis patients

• Published in: Cancer chemotherapy and pharmacology Vol. 73; no. 5; pp. 1009 - 1020
• Main Authors: Pérez-Ruixo, Carlos, Peris, José E., Escudero-Ortiz, Vanesa, Bretcha-Boix, Pedro, Farré-Alegre, José, Pérez-Ruixo, Juan José, Valenzuela, Belén
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2014; Springer; Springer Nature B.V
• Subjects: Abdomen; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cancer Research; Cohort Studies; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Hyperthermia, Induced; Injections, Intraperitoneal; Male; Medical sciences; Medicine; Medicine & Public Health; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - pharmacology; Organoplatinum Compounds - therapeutic use; Original Article; Peritoneal Neoplasms - drug therapy; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - pathology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Tumors; Oxaliplatin bioavailability; Hyperthermic intraperitoneal chemotherapy; Pharmacokinetics; Cytoreductive surgery; Peritoneal carcinomatosis; NONMEM; Antineoplastic agent; Human; Intraperitoneal hyperthermic chemotherapy; Intraperitoneal administration; Malignant tumor; Bioavailability; Alkylating agent; Absorption; Oxaliplatin; Treatment; Abdominal disease; Surgery; Cancer; Platinum II Complexes
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-014-2436-6

Purpose 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.