COMPARISON OF METHODS FOR THE ESTIMATION OF CARBOPLATIN PHARMACOKINETICS IN PEDIATRIC CANCER-PATIENTS

The antitumour and toxic effects of platinum drugs, in particular carb oplatin, have been related to their plasma concentration and this has led to the concept of a target area under the plasma concentration-tim e curve (AUG) for carboplatin dosing, A formula based on renal functio n has been successfully applied to carboplatin dosing in adults and mo dified versions have also been proposed for paediatric patients. In or der to monitor carboplatin AUC with maximum efficiency and minimum pat ient inconvenience, limited sampling strategies are desirable. A popul ation method with Bayesian estimation is described, based on one or tw o samples taken following a dose of carboplatin. Population data were obtained from 22 paediatric patients treated with 200-1000 mg/m(2) car boplatin as a 60-90 min infusion. Ultrafilterable carboplatin was dete rmined 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 mea ns and covariance matrix for the Bayesian estimator using a lognormal distribution. The test data sets consisted of ultrafilterable carbopla tin 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 m odel parameters. Results from the Bayesian analysis and other methods for the estimation of AUG, including relating clearance to surface are a or to renal function, were evaluated by comparing the AUC estimate w ith the AUC determined by model-independent analysis. Overall, the opt imal 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 dur ing the infusion improved the estimate slightly (median bias -2%, prec ision 3%). Bayesian estimation produced more reliable estimates of AUC compared to values based on renal function, which in turn was slightl y better than using surface area. A technique, developed in adult pati ents, for estimating AUC from a measurement of 24 h total plasma plati num was comparable to estimates based on renal function, but was less reliable. The estimation of carboplatin AUC can be performed using onl y one or two plasma samples and Bayesian analysis. This approach is le ss biased and more precise than methods based on surface area, renal f unction or total platinum at 24 h postdose, but is probably best used in combination with dosing based on renal function.