Population pharmacokinetics of hyperthermic intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis after cytoreductive surgery

• Published in: Cancer chemotherapy and pharmacology Vol. 71; no. 3; pp. 693 - 704
• Main Authors: Pérez-Ruixo, Carlos, Valenzuela, Belén, Peris, José Esteban, Bretcha-Boix, Pedro, Escudero-Ortiz, Vanesa, Farré-Alegre, José, Pérez-Ruixo, Juan José
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.03.2013; Springer; Springer Nature B.V
• Subjects: Abdomen; Aged; Algorithms; Analysis of Variance; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Area Under Curve; Biological and medical sciences; Cancer Research; Carcinoma - drug therapy; Carcinoma - metabolism; Carcinoma - surgery; Combined Modality Therapy; Female; Gastroenterology. Liver. Pancreas. Abdomen; Half-Life; Humans; Hyperthermia, Induced; Injections, Intraperitoneal; Laparotomy; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Models, Statistical; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Organoplatinum Compounds - pharmacokinetics; Organoplatinum Compounds - therapeutic use; Original Article; Peritoneal Neoplasms - drug therapy; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - surgery; Peritoneum - metabolism; Pharmaceutical Solutions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Population; Software; Tumors; Population pharmacokinetics; Oxaliplatin; Hyperthermic intraperitoneal chemotherapy (HIPEC); Peritoneal carcinomatosis; Antineoplastic agent; Human; Intraperitoneal hyperthermic chemotherapy; Malignant tumor; Intraperitoneal; Alkylating agent; Treatment; Abdominal disease; Surgery; Cancer; Platinum II Complexes
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-012-2060-2

Purpose To characterize the hyperthermic intraperitoneal oxaliplatin (HIO) pharmacokinetics in peritoneum and plasma in patients with peritoneal carcinomatosis (PC) after cytoreductive surgery (CRS). Methods Data from 36 patients receiving HIO diluted in isotonic 4 % icodextrin were combined with data from 13 patients receiving HIO diluted in isotonic 5 % dextrose. Total oxaliplatin in peritoneal and plasma fluids were used to characterize an open two-compartment disposition model with linear distribution and elimination and first-order absorption from peritoneum to plasma using NONMEM software. The effect of patient- and treatment-related covariates on oxaliplatin pharmacokinetic parameters was explored. Results The typical value (interindividual variability, %) in k a , CL, and V ss were 0.57 h −1 (43 %), 1.71 L h −1 (39 %), and 77 L (65 %), respectively. No significant effect of age, body surface area, sex, creatinine clearance, liver metastases, PC index, and complete cytoreduction on pharmacokinetic parameters was found. A 12–15 % reduction in peritoneal volume of distribution was observed in patients receiving HIO diluted in 5 % dextrose relative to those patients receiving HIO diluted in 4 % icodextrin. Conclusions The integration of peritoneal and plasma data demonstrated oxaliplatin linear absorption from peritoneum to plasma, non-specific distribution to a peripheral compartment, and linear elimination from the central compartment when HIO was administered with isotonic carrier solutions to PC patients who underwent CRS. Only the effect of the carrier solution had an impact in the peritoneal volume of distribution, but its clinical relevance seems to be limited, especially for short HIO infusions (<60 min).