Body-Surface A rea-Based D osing D oes N ot I ncrease Accuracy o f P redicting C isplatin E xposure

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 5 93) or once every 3 weeks (n 5 175) at dose levels of 50 to 100 mg/m 2 (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 5 0.63). The mean plasma clearance of unbound cisplatin (CLfree) was 57.1 6 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 m 2 (mean, 1.86 6 0.19 m 2 ), with an interpatient variability of 10.4%. When CLfree was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CLfree and BSA (r 5 0.42). Intrapatient variability in CLfree, calculated from 90 patients was 12.1% 6 7.8% (range, 0.30% to 32.7%). Conclusion: In view of the high interpatient variability in CLfree relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin. J Clin Oncol 19:3733-3739. © 2001 by American Society of Clinical Oncology.