Individual dosing of carboplatin based on drug monitoring in children receiving high-dose chemotherapy

Individual dosing of carboplatin based on drug monitoring was performed within a multi-centric phase I study based on high AUC-levels in children. Twelve patients (aged 3-17 years old) have been included: 3, 5, and 4 patients at the overall target ultrafilterable carboplatin AUC of 20, 25, or 30 mg/ml×min, respectively. Carboplatin was administered as a daily 60-min infusion, repeated on five consecutive days. The initial daily dose corresponding to the three first days was calculated according to the carboplatin clearance (CL) predicted from patients' characteristics (body weight, serum creatinine and nephrectomy status). Three blood samples were taken per patient. The individual CL were estimated by MAP (maximum a posteriori approach) Bayesian method implemented in the MP-K program. The doses for day 4 and 5 was adjusted in order to obtain the overall target AUC. Drug monitoring led to a change in the carboplatin dose (overall administered dose versus overall dose planned) ranging from -41% to +45%. Pharmacokinetics were performed at day 5 for 7/12 children: mean relative change between day 1 and day 5 was -11% showing a statistically significant, but limited, decrease of CL from day 1 to day 5. The percentage of difference between the observed and target overall AUC ranged between -7% and +14%. Three patients (one at each AUC level) who were previously treated with cisplatin experienced dose-limiting hearing loss. In conclusion, drug monitoring and dose adjustment is needed for the control of carboplatin plasma exposure when administering high doses of carboplatin in children.