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Body-Surface Area–Based Dosing Does Not Increase Accuracy of Predicting Cisplatin Exposure

From the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, the Netherlands.

Address reprint requests to Alex Sparreboom, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email: sparreboom{at}onch.azr.nl

PURPOSE: Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population.

PATIENTS AND METHODS: Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel. Cisplatin was administered either weekly (n = 93) or once every 3 weeks (n = 175) at dose levels of 50 to 100 mg/m² (3-hour infusion). Analysis of 485 complete courses was based on measurement of total and non–protein-bound cisplatin in plasma by atomic absorption spectrometry.

RESULTS: No pharmacokinetic interaction was found between cisplatin and the anticancer drugs used in combination therapies. A linear correlation was observed between area under the curves of unbound and total cisplatin (r = 0.63). The mean plasma clearance of unbound cisplatin (CL_free) was 57.1 ± 14.7 L/h (range, 31.0 to 116 L/h), with an interpatient variability of 25.6%. BSA varied between 1.43 and 2.40 m² (mean, 1.86 ± 0.19 m²), with an interpatient variability of 10.4%. When CL_free was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CL_free and BSA (r = 0.42). Intrapatient variability in CL_free, calculated from 90 patients was 12.1% ± 7.8% (range, 0.30% to 32.7%).

CONCLUSION: In view of the high interpatient variability in CL_free relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin.

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