Population Pharmacokinetics of Hyperthermic Intraoperative Peritoneal Oxaliplatin in Wistar Rats
Amelia Ramon-Lopez1,2, María Isabel Mas-Fuster1, Francisco Javier Lacueva3, Patricio Más-Serrano1,2,4, Ricardo Nalda-Molina1,2.
1Miguel Hernández University, Department of Engineering, Division of Pharmacy and Pharmaceutics, School of Pharmacy, San Juan de Alicante, Alicante, Spain. 2Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain 3Miguel Hernández University, Department of Pathology and Surgery, School of Medicine, San Juan de Alicante, Alicante, Spain. 4Hospital General Universitario de Alicante, Pharmacy Department, Clinical Pharmacokinetics Unit, Alicante, Spain.
Introduction and Objective: Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is part of a multidisciplinary treatment proposed for patients suffering from peritoneal carcinomatosis. The evaluation of the efficacy and toxicity of HIPEC technique presents some difficulties, due in part to the lack of information about the pharmacokinetic (PK) behavior of the drugs administered in this procedure. Development of suitable animal models contributes to evaluate the impact of the multiple components in HIPEC separately and gives useful information for future clinical research. A significant impact of the dose, temperature and instillation time on PK parameters may significantly affect the plasma concentration profile and, therefore, the Area Under the plasma concentration-time Curve (AUCpla).
Therefore, the aim of this study was to characterize the population pharmacokinetics of hyperthermic intraoperative peritoneal oxaliplatin (HIPEO) in Wistar rats and to evaluate the effect of treatment-related covariates dose, instillation time and temperature on the pharmacokinetic parameters.
Methods: Rats were randomly allocated in six groups (G1-G6) and submitted to different experimental conditions of temperature, instillation time or dose. As a common procedure, all of rats underwent an intraperitoneal hyperthermic instillation (LIHI) with 100 mL of 5% dextrose solution under anesthetic conditions. Out of them, 36 were assigned to receive HIPEO administration, carried by the heated 5% dextrose solution, as used in HIPEC procedure. In addition, to allow determination of the fraction of dose absorbed (F), six rats of one additional group (G7) were administered with one dose of intravenous (IV) oxaliplatin undergoing LIHI procedures, without adding oxaliplatin in the instillation solution. This procedure ensured that IV administrations were done at similar surgical conditions to the HIPEC groups. Plasma samples were taken immediately after the IV or peritoneal oxaliplatin administration and at times 1, 10, 20, 30, 45, 60, 90, 150, 270 and 510 minutes. Samples were frozen after centrifugation until their analysis by graphite furnace atomic absorption spectrophotometry. The plasma concentrations profiles for all the groups were analyzed together with a nonlinear mixed effects model (NONMEM software v7.3). The impact of dose, temperature and instillation time on the PK parameters was explored. The graphs and statistical calculations were performed using the R software v3.3.2. Bootstrap analysis was conducted to calculate 95% confidence interval for final model parameter estimates and relative standard errors of estimate (%RSE) after generating 1000 datasets by resampling with replacement method (Wings for NONMEM program). Model validation was performed by visual analysis of goodness of fit plots and prediction-corrected Visual Predictive Check (pcVPC).
Results and Discussion: Intraperitoneal (n=115) and plasma (n=263) concentrations were successfully described according to a two-compartment model with first order absorption. No significant effect of dose, temperature and instillation time on pharmacokinetic parameters was found. However, an abrupt decrease in the elimination process was observed, reflected in the structural pharmacokinetic model through a modification in clearance. The typical parameters values and the interindividual variability (CV %) in clearance, central and peripheral volume of distributionwere 3.25 mL/min (39.1%), 53.6 mL (37.8%) and 54.1 mL (77.3%), respectively. Clearance decreased to 0.151 mL/min (39.1%) when the instillation was still ongoing, at 31.4 minutes, probably caused by the alteration of renal function attributed to surgery procedure and/or hyperthermia.
Conclusion: This study described the deterioration of the drug elimination process due to the procedure, and estimated the time at which this deterioration is most likely to occur. In addition, dose, instillation time and temperature had no influence in the PK parameters.
