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Aims: Carboplatin dosage is calculated by using the estimated glomerular filtration rate (GFR) to achieve a target plasma area under the plasma concentration–time curve (AUC). The aims of the present study were to investigate factors that influence the pharmacokinetics of carboplatin in children with high‐risk neuroblastoma, and whether target exposures for carboplatin were achieved using current treatment protocols. Methods: Data on children receiving high‐dose carboplatin, etoposide and melphalan for neuroblastoma were obtained from two study sites [European International Society for Paediatric Oncology (SIOP) Neuroblastoma study, Children's Hospital at Westmead; n = 51]. A population pharmacokinetic model was built for carboplatin to evaluate various dosing formulas. The pharmacokinetics of etoposide and melphalan was also investigated. The final model was used to simulate whether target carboplatin AUC (16.4 mg ml–1·min) would be achieved using the paediatric Newell formula, modified Calvert formula and weight‐based dosing. Results: Allometric weight was the only significant, independent covariate for the pharmacokinetic parameters of carboplatin, etoposide and melphalan. The paediatric Newell formula and modified Calvert formula were suitable for achieving the target AUC of carboplatin for children with a GFR <100 ml min–1 1.73 m–2 but not for those with a GFR ≥100 ml min–1 1.73 m–2. A weight‐based dosing regimen of 50 mg kg–1 achieved the target AUC more consistently than the other formulas, regardless of renal function. Conclusions: GFR did not appear to influence the pharmacokinetics of carboplatin after adjusting pharmacokinetic parameters for weight. This model‐based approach validates the use of weight‐based dosing as an appropriate alternative for carboplatin in children with either mild renal impairment or normal renal function. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Busulfan is widely used in a neuroblastoma setting, with several studies reporting marked inter-patient variability in busulfan pharmacokinetics and pharmacodynamics. The current study reports on the pharmacokinetics of oral versus intravenous (IV) busulfan in high-risk neuroblastoma patients treated on the European HR-NBL-1/SIOPEN study. Methods: Busulfan was administered four times daily for 4days to children aged 0.7–13.1years, either orally (1.45–1.55mg/kg) or by the IV route (0.8–1.2mg/kg according to body weight strata). Blood samples were obtained prior to administration, 2, 4, and 6h after the start of administration on dose 1. Busulfan analysis was carried out by gas chromatography–mass spectrometry and data analysed using a NONMEM population pharmacokinetic approach. Results: Busulfan plasma concentrations obtained from 38 patients receiving IV busulfan and 25 patients receiving oral busulfan, were fitted simultaneously using a one-compartment pharmacokinetic model. Lower variability in drug exposure was observed following IV administration, with a mean busulfan area under the plasma concentration versus time curve (AUC) of 1146±187μM.min (range 838–1622), as compared to 953±290μM.min (range 434–1427) following oral busulfan. A total of 87% of children treated with IV busulfan achieved AUC values within the target of 900–1500μM.min versus 56% of patients following oral busulfan. Busulfan AUC values were significantly higher in HR-NBL-1/SIOPEN trial patients who experienced hepatic toxicity or veno-occlusive disease (VOD) (1177±189μM.min versus 913±256μM.min; p =0.0086). Further stratification based on route of administration suggested that the incidence of hepatic toxicity was related to both high busulfan AUC and oral drug administration. Conclusion: The reduced pharmacokinetic variability and improved control of busulfan AUC observed following IV administration support its utility within the ongoing HR-NBL-1/SIOPEN trial. [Copyright &y& Elsevier]

Estimation of glomerular filtration rate (GFR) using the clearance of chromium 51 EDTA (51Cr-EDTA) (or other radiolabelled isotopes) is reliable, but invasive and not always practicable. Mathematical models have been devised for estimating GFR using readily obtainable patient characteristics. Unfortunately, these models were developed using various patient populations and may not provide the optimal prediction of GFR in children with cancer. The current study uses population pharmacokinetics to determine the relationship between 51Cr-EDTA clearance, and patient covariates in 50 paediatric cancer patients. These models were validated using a separate group of 43 children and were compared with previously published models of renal function. Body size was the major determinant of 51Cr-EDTA clearance and inclusion of weight or surface area reduced the residual variability between individuals (coefficient of variation) from 61 to 32%. Serum creatinine was the only other parameter that significantly improved the model. Mean percentage error values of -5.0 and -1.1% were observed for models including weight alone or weight and creatinine, respectively, with precision estimates of 21.7 and 20.0%. These simple additive models provide a more rationale approach than the use of complex formulae, involving additional parameters, to predict renal function.British Journal of Cancer (2004) 90, 60-64. doi:10.1038/sj.bjc.6601484 www.bjcancer.com [ABSTRACT FROM AUTHOR]