Studies on Age-Dependent Plasma Platinum Pharmacokinetics and Ototoxicity of Cisplatin

Abstract

The age-related difference of cisplatin (CDDP) pharmacokinetics and ototoxicity were studied in 6 children with solid tumors who received CDDP infusion. CDDP was administered intravenously for 6 hours at a dosage of 30-120 mg/m² and plasma-free platinum concentrations were determined by atomic absorption spectrophotometry. Plasma-free platinum concentrations ranged from 1.0 to 2.1 μg/ml at the end of infusions and declined rapidly with T_1/2 of 0.6∼1.5 hours. Pharmacokinetic parameters of plasma-free platinum were analyzed in 13 CDDP infusions by the one-compartment open model method. Parameters (K_e, cl, T_1/2 and Vd) of free platinum pharmacokinetics were 0.66hr⁻¹, 7.71l/hr, 1.35 hr and 15.71l in the younger group (age: 1.7-6.5 years old) and 1.44 hr⁻¹, 11.41l /hr, 0.61 hr and 8.99l in the older group (age: 12.2-15.7 years old), respectively. Up to 600mg/m² of the cumulative dosage of CDDP caused minimal ototoxicity in the older group; however, in the younger group, hearing loss at a high frequency zone (6000 and 8000 Hz) began to appear at a cumulative dosage of 200 mg/m² and progressed to middle zone (3000 Hz) when dosages surpassed 400mg/m². These data indicate that the pharmacokinetic difference in age possesses a large distribution volume (Vd) and that slower elimination of the drug in a younger age group is an important factor for age-dependent ototoxicity.