Clinical pharmacokinetics of carboplatin in children

Abstract

The present study was undertaken to evaluate in children the plasma pharmacokinetics of free carboplatin given at different doses and schedules and to evaluate the inter- and intrapatient variability and the possible influence of schedule on drug exposure. A total of 35 children (age range, 1–17 years) with malignant tumors were studied. All patients had normal renal function (creatinine clearance corrected for surface body area, above 70 ml min⁻¹ m⁻²; range, 71–151 ml min⁻¹ m⁻²) and none had renal involvement by malignancy. Carboplatin was given at the following doses and schedules: 175, 400, 500, and 600 mg/m² given as a 1-h infusion; 1,200 mg/m² divided into equal doses and infused over 1 h on 2 consecutive days; and 875 and 1,200 mg/m² given as a 5-day continuous infusion. A total of 57 courses were studied. Carboplatin levels in plasma ultrafiltrate (UF) samples were measured both by high-performance liquid chromatography and by atomic absorption spectrophotometry. Following a 1-h infusion, carboplatin free plasma levels decayed biphasically; the disappearance half-lives, total body clearance, and apparent volume of distribution were similar for different doses. In children with normal renal function as defined by creatinemia and blood urea nitrogen (BUN) and creatinine clearance, we found at each dose studied a limited interpatient variability of the peak plasma concentration (C_max) and the area under the concentration-time curve (AUC) and a linear correlation between the dose and both C_max (r=0.95) and AUC (r=0.97). The mean value ± SD for the dose-normalized AUC was 13±2 min m² l⁻¹ (n=57). The administration schedule does not seem to influence drug exposure, since prolonged i.v. infusion or bolus administration of 1,200 mg/m² achieved a similar AUC (13.78±2.90 and 15.05±1.44 mg ml⁻¹ min, respectively). In the nine children studied during subsequent courses a limited interpatient variability was observed and no correlation (r=0.035) was found between AUC and subsequent courses by a multivariate analysis of dose, AUC, and course number. The pharmacokinetic parameters were similar to those previously reported in adults; however, a weak correlation (r=0.52,P=0.03) between carboplatin total body clearance and creatinine clearance varying within the normal range was observed. A dosing formula appears unnecessary in children with normal renal function since a generally well-predictable free carboplatin AUC is achieved following a given dose.