Comparison of methods for the estimation of carboplatin pharmacokinetics in paediatric cancer patients

The antitumour and toxic effects of platinum drugs, in particular carboplatin, have been related to their plasma concentration and this has led to the concept of a target area under the plasma concentration-time curve (AUC) for carboplatin dosing. A formula based on renal function has been successfully applied to carboplatin dosing in adults and modified versions have also been proposed for paediatric patients. In order to monitor carboplatin AUC with maximum efficiency and minimum patient inconvenience, limited sampling strategies are desirable. A population method with Bayesian estimation is described, based on one or two samples taken following a dose of carboplatin. Population data were obtained from 22 paediatric patients treated with 200-1000 mg/m2 carboplatin as a 60-90 min infusion. Ultrafilterable carboplatin was determined by atomic absorption spectrophotometry. A two compartment model was fitted to each data set using the Maximum Likelihood estimator of the ADAPT programme. These parameter estimates provided the prior means and covariance matrix for the Bayesian estimator using a lognormal distribution. The test data sets consisted of ultrafilterable carboplatin concentrations in 23 patients (aged 1 month-18 years) who received similar treatment. The two compartment model was fitted to data sets containing one or two points, using the Bayesian maximum a posteriori (MAP) estimator and an error model derived from the population error model parameters. Results from the Bayesian analysis and other methods for the estimation of AUC, including relating clearance to surface area or to renal function, were evaluated by comparing the AUC estimate with the AUC determined by model-independent analysis. Overall, the optimal sampling strategy performed better than estimates based on renal function, which had a median bias of 5% and precision of 22%. With one data point at 60 min postinfusion, the median bias and precision were 3 and 6%, respectively. Addition of a second data point at 30 min during the infusion improved the estimate slightly (median bias -2%, precision 3%). Bayesian estimation produced more reliable estimates of AUC compared to values based on renal function, which in turn was slightly better than using surface area. A technique, developed in adult patients, for estimating AUC from a measurement of 24 h total plasma platinum was comparable to estimates based on renal function, but was less reliable. The estimation of carboplatin AUC can be performed using only one or two plasma samples and Bayesian analysis. This approach is less biased and more precise than methods based on surface area, renal function or total platinum at 24 h postdose, but is probably best used in combination with dosing based on renal function.