Pharmacokinetics of cisplatin and relation to nephrotoxicity in paediatricpatients

Background: Cisplatin is a highly effective and frequently used drug in the chemotherapy of solid tumours in children, but only limited data are avail able on the pharmacokinetics of cisplatin and its associated nephrotoxicity in paediatric patients. Methods: We investigated the pharmacokinetics of free platinum (Pt) in 12 c hildren (25 courses) receiving cisplatin (75-120 mg/m(2)) either as a conti nuous 72-h infusion, prolonged single 6-h infusion or repetitive 1-h infusi ons. Plasma and urinary Pt concentrations were analysed using atomic absorp tion spectroscopy. Cisplatin-induced nephrotoxicity was determined using cr eatinine clearance and several glomerular and tubular marker proteins. Results: Using a two-compartment model the pharmacokinetic parameters for f ree Pt were: initial half-life 21.6 +/-9.6 min, terminal half-life 25.9 +/- 16.2 h, area under the plasma concentration-time curve (AUC) 13.5 +/-4.97 (mug/ml).h/(100 mg/m(2)) and cumulative renal elimination(infinity) 41.7 +/ -6.6% of dose. Higher cisplatin delivery rates led to higher peak concentra tions of free Pt in plasma and urine and to lower cumulative renal Pt elimi nation (P <0.01). During all courses, increases of urinary albumin and alph a1-microglobulin excretion were documented. The creatinine clearance decrea sed significantly to 70% of baseline values. Correlations were found betwee n both peak free Pt concentrations in plasma and in urine and the maximum o f urinary excretions of albumin and of N-acetyl-beta -D-glucosaminidase and the nadir of the glomerular filtration rate (P <0.05). Conclusions: With respect to nephrotoxicity, long-term infusions of cisplat in seem to be preferable over intermittent bolus administration in paediatr ic patients. The best predictive pharmacokinetic parameters for cisplatin-a ssociated nephrotoxicity in children are peak free Pt concentrations in pla sma and urine.