Pharmacokinetic study of intralesional cisplatin for the treatment of hepatocellular carcinoma

BACKGROUND. In the current study the authors examined the pharmacokinetics of direct intralesional injection of cisplatin/epinephrine/bovine collagen gel in patients with hepatocellular carcinoma and cirrhosis. METHODS, Six patients with cirrhosis and unresectable hepatocellular carcin oma received a direct intralesional injection (range, 6.7-26.7 mg) into the ir tumors under ultrasonographic guidance. The authors determined the total cisplatin (Pt) concentration in the plasma and urine and nonprotein-bound free Pt in plasma ultrafiltrate using flameless atomic absorption spectrome try. Data from individual patients were analyzed to calculate the pharmacok inetic parameters via a noncompartmental method for constant infusion. To d emonstrate that the changes in pharmacokinetics are not related to the unde rlying cirrhosis, a similar methodology was applied to measure the pharmaco kinetic parameters of four similar patients who were treated with cisplatin , 75 mg/m(2), as a 1-hour intravenous infusion. RESULTS, The time to attain maximum concentration of total Pt after intrale sional injection was dose-dependent and ranged from 2-13 hours. The concent ration-time curve was biphasic in nature. The initial half-life of total Pt in patients who received an intralesional injection varied with the cispla tin dose. The initial half-life for cisplatin doses < 15 mg was approximate ly 9 hours and the initial half-life at higher cisplatin doses (> 15 mg) wa s approximately 25 hours. The area under the curve (AUC) was dose-dependent with values ranging from 38-150 mum/mL.hour. Pharmacokinetic parameters fo r free Pt (ultrafiltrate) were significantly different. The time to attain maximum concentration (t-max) and terminal half-life were shorter and the a verage AUC was approximately 100-fold lower than total Pt. After the intrav enous infusion of cisplatin, the t-max for total and free Pt was 1.3 hours and 1.1 hours, respectively. The terminal half-life and average AUC for tot al Pt was 194 hours and 247 mug/mL per hour, respectively, and its correspo nding parameters for free Pt after intravenous infusion were much lower, si milar to the findings for the intralesional injection. CONCLUSIONS, The prolonged t-max and initial half-life noted with the intra lesional injection of cisplatin/epinephrine/collagen gel are consistent wit h its proclaimed ability to retain cisplatin at the tumor and delay its rel ease in systemic circulation. The kinetics of intralesional cisplatin injec tion also suggest local sequestration of the drug in the injected site. Par ameters of intravenous cisplatin infusion in cirrhotic patients are similar to those of patients from the historic control group. (C) 2001 American Ca ncer Society.