Gurney H
Department of Medical Oncology and Palliative Care, Westmead Hospital, Westmead, NSW, Australia.
J Clin Oncol. 1996 Sep;14(9):2590-611. doi: 10.1200/JCO.1996.14.9.2590.
To review the current dose-calculation practice and propose a non-body-surface area (BSA)-based dose-calculation method.
Data that supported the introduction of BSA-based dose calculation in the late 1950s were reviewed. Data on 18 drugs that correlated pharmacokinetic (PK) variables for cytotoxic drugs with BSA were examined. Other methods of dose calculation, such as therapeutic drug monitoring (TDM) and adaptive control, were also examined.
The BSA-based method of dose calculation was adopted without adequate investigation of its accuracy. BSA fails to standardize the marked interpatient variation in PK for most cytotoxic drugs. A definite correlation was found between PK variables and BSA for only one drug (docetaxel). PK parameters correlate with toxicity, as well as response in some tumors, but do not completely explain the variation in drug effect between individuals. The complexities of TDM may make its universal use impractical. A non-BSA-based dose calculation method is proposed that defines three mandatory steps: prime dose, modified dose, and toxicity-adjusted dose (PMT dosing). Prime dose is the fixed dose of a drug used alone or in combination and is derived from the reanalysis of phase I/II studies and from clinical practice. Modified dose is an adjustment of the prime dose before administration, based on dose-adjustment guidelines that predict the drug-handling ability of an individual. Population pharmacodynamic studies may be used for the development of these guidelines. Subsequent doses are adjusted in each patient according to a target toxicity, such as nadir neutrophil count or other objective toxicity, that serves as a surrogate marker for potential antitumor effect (toxicity-adjusted dose). Patients who are predicted to have very abnormal drug handling should be excluded from such a dosing scheme and TDM may be more suitable.
The routine use of BSA for dose calculation should be reevaluated. Other methods of dose calculation should be investigated. TDM may be impractical in all patients and remains unvalidated. PMT dosing ensures that the condition of each individual is considered, to predict drug effects better. Clinical dose-calculation systems such as PMT dosing should be evaluated prospectively.
回顾当前的剂量计算方法，并提出一种基于非体表面积（BSA）的剂量计算方法。
回顾了支持20世纪50年代末引入基于BSA的剂量计算的数据。研究了18种将细胞毒性药物的药代动力学（PK）变量与BSA相关联的药物数据。还研究了其他剂量计算方法，如治疗药物监测（TDM）和自适应控制。
基于BSA的剂量计算方法在未充分研究其准确性的情况下被采用。对于大多数细胞毒性药物，BSA未能使患者间显著的PK差异标准化。仅发现一种药物（多西他赛）的PK变量与BSA之间存在明确的相关性。PK参数与毒性以及某些肿瘤的反应相关，但不能完全解释个体间药物效应的差异。TDM的复杂性可能使其普遍应用不切实际。提出了一种基于非BSA的剂量计算方法，该方法定义了三个必要步骤：初始剂量、调整剂量和毒性调整剂量（PMT给药法）。初始剂量是单独使用或联合使用的固定药物剂量，来自对I/II期研究的重新分析和临床实践。调整剂量是在给药前根据预测个体药物处理能力的剂量调整指南对初始剂量进行的调整。群体药效学研究可用于制定这些指南。随后根据目标毒性（如最低点中性粒细胞计数或其他客观毒性）对每位患者的后续剂量进行调整，该目标毒性作为潜在抗肿瘤效应的替代标志物（毒性调整剂量）。预计药物处理能力非常异常的患者应排除在这种给药方案之外，TDM可能更合适。
应重新评估常规使用BSA进行剂量计算的情况。应研究其他剂量计算方法。TDM可能并非对所有患者都切实可行且尚未得到验证。PMT给药法确保考虑到每个个体的情况，以便更好地预测药物效果。应前瞻性地评估诸如PMT给药法等临床剂量计算系统。
