Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. The United Kingdom Children's Cancer Study Group.

Abstract

Purpose: The aim of this study was to define the pharmacokinetics of carboplatin in children and use the data to develop a pediatric dose formula. It was anticipated that renal function would be a major determinant of carboplatin disposition and the relationship between carboplatin clearance and glomerular filtration rate (GFR) was examined in detail.Patients and Methods: Plasma carboplatin pharmacokinetics were measured as ultrafiltrable platinum in 22 patients (5 to 63 kg) following 200 to 1,000 mg/m2 of carboplatin. GFR was measured by the plasma clearance of chromium 51-edathamil ( treatment of neuroblastoma, pediatric brain tumors, and germ cell tumors, and the use of the drug in these diseases is increasing.'3 Studies in adults have shown that the pharmacokinetics of carboplatin have a major impact on the toxicity of the drug and also, probably, on its activity. Thus, a number of investigations have shown a relationship between carboplatin exposure, expressed as the area under the plasma carboplatin concentration versus time curve (AUC), and tolerance to the drug, in particular thrombocytopenia. 6The work reported by Horwich et al 7 with testicular teratoma patients suggests that inadequate carboplatin exposure (AUC < 4 mg/mL-min) may compromise activity in this chemotherapy-curable disease. Similarly, a retrospective analysis reported by Jodrell et al 8 implied that ovarian cancer patients who received carboplatin at doses calculated to have produced AUC values less than 4 mg/ mL* min were less likely to achieve a response than those calculated to have experienced exposures greater than 4 mg/mL, min. Finally, preliminary results from a randomized study in ovarian cancer of an AUC of 6 mg/ mL* min administered every 4 weeks for six courses vs an AUC of 12 mg/mL-min administered every 4 weeks for four courses, suggests that the complete response rate is higher in the high AUC arm. 9In adults, for a given surface area-based dose of carboplatin, the AUC achieved varies over a twofold to

Estimation of glomerular filtration rate in cancer patients

“…Evaluation of the models developed in the independent validation dataset suggests that the formulae described here represent an improvement on those currently available. These formulae are not recommended for use in paediatric patients, where the dosing of carboplatin should be estimated from weight and 51 Cr-EDTA halflife (Newell et al, 1993) or from direct determination of carboplatin pharmacokinetics (Peng et al, 1995). Nor should these formulae be used in patients with acute renal failure, as they constitute an entirely different population to that studied.…”

Body surface area estimation in children using weight alone: application in paediatric oncology

“…In some cases, closer correlations exist between some other measurable parameter e.g. carboplatin clearance and glomerular filtration rate (GFR) and this has formed the basis for GFR-based dosing regimes in many paediatric and adult treatment protocols (Calvert et al, 1989;Newell et al, 1993). These variations in inter-individual drug handling have stimulated recent research into the individualization of treatment of paediatric cancers in order to optimize outcome Body surface area estimation using weight alone 25…”

Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy

“…Therefore optimum treatment with Pt drugs may necessitate adjustment for interindividual pharmacokinetic differences. Renal function-based dosing formulae have been developed for carboplatin administration to children (Marina et al, 1993;Newell et al, 1993;Chatelut et al, 1996) because carboplatin is cleared primarily by glomerular filtration.Although pharmacokinetics is one determinant of the clinical efficacy of Pt complexes, intracellular factors are certain to play an additional role. Pt complexes exert their anti-tumour effect by reacting with DNA (Roberts and Thomson, 1979;Sherman and Lippard, 1987;Fichtinger-Schepman et al, 1995 (Poirier et al, 1982;Fichtinger-Schepman et al, 1985;Terheggen et al, 1988; Tilby et al, 1991).…”

“…Therefore optimum treatment with Pt drugs may necessitate adjustment for interindividual pharmacokinetic differences. Renal function-based dosing formulae have been developed for carboplatin administration to children (Marina et al, 1993;Newell et al, 1993;Chatelut et al, 1996) because carboplatin is cleared primarily by glomerular filtration.…”

“…The activity and toxicity of cisplatin and carboplatin depend upon both pharmacokinetic and pharmacodynamic factors. A number of clinical pharmacokineticpharmacodynamic relationships have been described for cisplatin (Campbell et al, 1983; Reece et al, 1987;Thomas et al, 1994) and carboplatin (Egorin et al, 1984;Newell et al, 1987Newell et al, , 1993Harland et al, 1991;Horwich et al, 1991;Sorensen et al, 1991;Jodrell et al, 1992), and interpatient variability in tumour response to and/or tolerance of platinum (Pt)-complex therapy may relate to plasma levels more closely than to dose. Therefore optimum treatment with Pt drugs may necessitate adjustment for interindividual pharmacokinetic differences.…”