Randomized C ross-Over E valuation o f B ody-Surface Area-Based D osing V ersus F lat-Fixed D osing o f P aclitaxel

Purpose: Despite dose calculation using body-surface area (BSA), pharmacokinetics of most anticancer drugs show wide interindividual variability. In this study, we evaluated the role of BSA in paclitaxel disposition. Patients and Methods: Paclitaxel pharmacokinetics were prospectively studied in 12 patients that were treated in a randomized cross-over design with paclitaxel (3-hour infusion at a 3-week interval) at 175 mg/m 2 in cycle 1 (A) and a flat-fixed dose of 300 mg in cycle 2 (B), or vice versa. Blood samples were collected up to 24 hours after dosing and analyzed for total and unbound paclitaxel. Results: The area under the curves (AUC) of unbound paclitaxel were similar in both dosing groups, with mean values SD (A v B) of 1.34 0.158 versus 1.30 0.329 Mh, indicating that BSA-based dosing reduced the coefficient of variation by 53.3%. Unbound and total paclitaxel clearance was also significantly related to various bodysize measures, including BSA (R > 0.617; P 0.621; P 0.630; P < .028). We hypothesize that this is caused by the association of paclitaxel in the circulation with Cremophor EL, the distribution of which is linked to total blood volume, and thus to BSA. Conclusion: This study indicates that paclitaxel disposition is significantly related to BSA. This provides a pharmacokinetic rationale for BSA-based dosing of this drug. J Clin Oncol 21:197-202. © 2003 by American Society of Clinical Oncology. I N MEDICINE, most drugs for adult patients are administered at a flat-fixed dose. Only the dosage of some drugs with a small therapeutic index, such as aminoglycosides, cyclosporine, phenytoin, and sympaticomimetics, are based on the body weight of the patient and are adjusted by monitoring either serum drug levels or clinical outcome. In contrast, in oncology, the dosage of nearly all cytotoxic drugs is based on body-surface area (BSA) of the patient. 1 The optimal dose of a cytotoxic drug is expected to result in two important clinical end points—a maximum antitumor effect and a minimum of toxicity. Studies on the appropriate rate of input (ie, dose and schedule) of antitumor agents are difficult because the desired tumor responses cannot be observed immediately and may vary as a result of differences in drug sensitivity; furthermore, possible toxic effects may be severe and life threatening. Therefore, pharmacokinetic variables such as drug clearance, area under the curve (AUC), and volume of distribution may serve as surrogate end points. Gurney 1 has described a positive correlation of several pharmacokinetic parameters, especially AUC, with the toxicity of anticancer drugs, although a correlation with the tumor response is found less often. However, for most cytotoxic agents, no significant correlation has been noticed between BSA and drug clearance or AUC. 1,2 Because normalization of drug dose to BSA seems unlikely to have a relevant effect on tumor response or toxicity of most anticancer drugs, this common method of dose calculation has been questioned. 1-4 The antineoplastic agent paclitaxel is widely used to treat a variety of solid tumors, particularly ovarian and breast cancer. 5 Dose calculation of paclitaxel is based on BSA, using a dosing schedule of 135 to 225 mg/m 2 that is usually administered as a 3-hour infusion every 3 weeks. Despite this dose adjustment based on BSA, a wide interpatient variability persists for total paclitaxel clearance. 6 In the present report, we prospectively studied paclitaxel disposition in 12 patients treated in a randomized cross-over design with BSA-based versus flat-fixed dosing to provide a pharmacokinetic rationale for appropriate dosing strategies for this agent.