Wilde Stefan, Jetter Alexander, Rietbrock Stephan, Kasel Dirk, Engert Andreas, Josting Andreas, Klimm Beate, Hempel Georg, Reif Stefanie, Jaehde Ulrich, Merkel Ute, Busse Dagmar, Schwab Matthias, Diehl Volker, Fuhr Uwe
Department of Pharmacology, University Hospital, University of Cologne, Cologne, Germany.
Clin Pharmacokinet. 2007;46(4):319-33. doi: 10.2165/00003088-200746040-00005.
The BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) chemotherapy regimen for the treatment of advanced Hodgkin's lymphoma has a superior outcome, but its toxicity (mainly haematotoxicity) is pronounced and highly variable. The present study was conducted to address the role of pharmacokinetics in individual toxicity.
Three plasma samples and a 24-hour urine collection for day 1 of the first three cycles of chemotherapy were analysed in 30 patients, and the pharmacokinetic parameters of the respective drugs were estimated by population pharmacokinetic methods (nonlinear mixed-effects model [NONMEM] software). Demographic data, doses and durations of infusion were also recorded. The effect of these parameters on platelet counts was estimated by analysis of covariance using a general linear model.
The pharmacokinetic parameters and respective covariates were similar to the published data. The body surface area, peak concentrations of etoposide, urinary recovery of dechloroethylcyclophosphamide (formed by cytochrome P450 [CYP] 3A4) relative to the cyclophosphamide dose and number of cycles had a significant effect on toxicity. These factors explained 37% of the interindividual variability in the change in platelet counts from day 1 to day 8 of each cycle.
The results show that the individual pharmacokinetics of BEACOPP drugs are an important link between dosage and toxicity. Accordingly, individualisation of treatment based on pharmacokinetics may result in more uniform toxicity. Individualisation may also allow escalation of the mean dose, which is probably related to better efficacy. As a consequence of the present study, infusion rates should be standardised, and the potential of a dose reduction in the first cycle and of CYP3A4 phenotyping should be addressed in clinical studies.
用于治疗晚期霍奇金淋巴瘤的BEACOPP（博来霉素、依托泊苷、多柔比星、环磷酰胺、长春新碱、丙卡巴肼和泼尼松）化疗方案疗效更佳，但毒性（主要是血液毒性）显著且个体差异很大。本研究旨在探讨药代动力学在个体毒性中的作用。
对30例患者化疗前三个周期第1天的三份血浆样本和24小时尿液进行分析，采用群体药代动力学方法（非线性混合效应模型[NONMEM]软件）估算各药物的药代动力学参数。同时记录人口统计学数据、剂量和输注持续时间。使用通用线性模型通过协方差分析评估这些参数对血小板计数的影响。
药代动力学参数及相关协变量与已发表数据相似。体表面积、依托泊苷的峰浓度、相对于环磷酰胺剂量的去氯乙基环磷酰胺（由细胞色素P450 [CYP] 3A4形成）的尿回收率以及周期数对毒性有显著影响。这些因素解释了每个周期第1天至第8天血小板计数变化中37%的个体间差异。
结果表明，BEACOPP药物的个体药代动力学是剂量与毒性之间的重要联系。因此，基于药代动力学的个体化治疗可能会使毒性更趋一致。个体化还可能允许提高平均剂量，这可能与更好的疗效相关。基于本研究结果，输注速率应标准化，并且在临床研究中应探讨在第一个周期降低剂量的可能性以及CYP3A4表型分析。
