Therapeutic drug monitoring of carboplatin in high-dose protocol (TI-CE) for advanced germ cell tumors: pharmacokinetic results of a phase 2 multicenter study

PURPOSE: We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling inter-patient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative. EXPERIMENTAL DESIGN: Eighty nine patients receiving carboplatin for 3 consecutive days during 3 cycles were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/ml over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction. RESULTS: The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentile, respectively). The new covariate equation [CL (mL/min) = 130.7 x (Scr/83)–0.826 x (BW/76)+0.907 x (Age/36)–0.223 with Scr in μM, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared to other equations. CONCLUSION: TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young males patients could be used if TDM cannot be implemented.

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