Chugh Rashmi, Wagner Thomas, Griffith Kent A, Taylor Jeremy M G, Thomas Dafydd G, Worden Francis P, Leu Kirsten M, Zalupski Mark M, Baker Laurence H
Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Cancer. 2007 Jun 1;109(11):2315-22. doi: 10.1002/cncr.22669.
Ifosfamide is a chemotherapeutic agent that requires cytochrome P450 3A (CYP3A) for bioactivation and metabolism. To the authors' knowledge, the correlation between dose, pharmacokinetics, CYP3A, and toxicity has not been fully evaluated. A randomized Phase II trial was performed on 22 soft tissue sarcoma patients treated with doxorubicin (60 mg/m(2)/cycle) and either high-dose ifosfamide (12 g/m(2)/cycle) or standard-dose ifosfamide (6 g/m(2)/cycle). The pharmacokinetics of ifosfamide and CYP3A measurements observed are reported.
Pharmacokinetic parameters for ifosfamide, 2-dichloroethylifosfamide (2-DCE), and 3-dichloroethylifosfamide (3-DCE) were collected after the first ifosfamide infusion in 13 patients. Bayesian designed limited pharmacokinetic data were collected from an additional 41 patients. The erythromycin breath test (ERMBT) was performed on 81 patients as an in vivo phenotypic assessment of CYP3A activity.
Fourteen-hour (peak) plasma levels of ifosfamide, 2-DCE, and 3-DCE were found to correlate strongly with the respective area under the curve (AUC) 0-24 values (r=0.97, 0.94, and 0.95; P<.0001). Patients who experienced a grade 3-4 absolute neutrophil count (ANC), platelet, or creatinine toxicity (using the National Cancer Institute Common Toxicity Criteria [version 2]) were found to have statistically significantly higher median 14-hour plasma levels of ifosfamide, 2-DCE, and 3-DCE compared with patients with grade 0-2 toxicity. ERMBT was not found to correlate with pharmacokinetic parameters of ifosfamide and metabolites or toxicity.
The 14-hour plasma level of ifosfamide, 2-DCE, and 3-DCE is a simple and appropriate substitute for describing the AUC of ifosfamide after 1 day of a 1-hour to 2-hour infusion of drug. Fourteen-hour plasma levels of ifosfamide and metabolites are useful predictors of neutropenia, thrombocytopenia, and creatinine toxicity. ERMBT was not found to accurately correlate with ifosfamide pharmacokinetics or clinical toxicity.
异环磷酰胺是一种化疗药物，需要细胞色素P450 3A（CYP3A）进行生物活化和代谢。据作者所知，剂量、药代动力学、CYP3A与毒性之间的相关性尚未得到充分评估。对22例接受多柔比星（60mg/m²/周期）治疗的软组织肉瘤患者进行了一项随机II期试验，这些患者同时接受高剂量异环磷酰胺（12g/m²/周期）或标准剂量异环磷酰胺（6g/m²/周期）治疗。报告了观察到的异环磷酰胺的药代动力学及CYP3A测量结果。
在13例患者首次输注异环磷酰胺后收集其异环磷酰胺、2-二氯乙基异环磷酰胺（2-DCE）和3-二氯乙基异环磷酰胺（3-DCE）的药代动力学参数。从另外41例患者中收集了贝叶斯设计的有限药代动力学数据。对81例患者进行了红霉素呼气试验（ERMBT），作为CYP3A活性的体内表型评估。
发现异环磷酰胺、2-DCE和3-DCE的14小时（峰值）血浆水平与各自的曲线下面积（AUC）0-24值密切相关（r = 0.97、0.94和0.95；P <.0001）。与0-2级毒性的患者相比，经历3-4级绝对中性粒细胞计数（ANC）、血小板或肌酐毒性（使用美国国立癌症研究所通用毒性标准[第2版]）的患者，其异环磷酰胺、2-DCE和3-DCE的14小时血浆中位数水平在统计学上显著更高。未发现ERMBT与异环磷酰胺及其代谢产物的药代动力学参数或毒性相关。
异环磷酰胺、2-DCE和3-DCE的14小时血浆水平是在1小时至2小时输注药物1天后描述异环磷酰胺AUC的简单且合适的替代指标。异环磷酰胺及其代谢产物的14小时血浆水平是中性粒细胞减少、血小板减少和肌酐毒性的有用预测指标。未发现ERMBT与异环磷酰胺药代动力学或临床毒性准确相关。
