苯达莫司汀药代动力学特征及在惰性非霍奇金淋巴瘤患者中的暴露-反应关系。
Bendamustine pharmacokinetic profile and exposure-response relationships in patients with indolent non-Hodgkin's lymphoma.
机构信息
Cognigen Corporation, 395 South Youngs Road, Buffalo, NY 14221, USA.
出版信息
Cancer Chemother Pharmacol. 2010 Nov;66(6):1039-49. doi: 10.1007/s00280-010-1254-8. Epub 2010 Feb 6.
PURPOSE
The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin's lymphoma, and supported understanding of exposure-response relationships for efficacy and safety.
METHODS
Bendamustine was administered as a 60-min 120 mg/m(2) intravenous infusion on days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined.
RESULTS
Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t (1/2) (40 min) was considered the pharmacologically relevant (beta elimination) t (1/2) since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m(2) administration, except bendamustine C (max) was a significant (P value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics.
CONCLUSIONS
The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t (1/2) and low concentrations of bendamustine observed by 12 h after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine C (max) increases.
目的
在利妥昔单抗难治性、复发性惰性 B 细胞非霍奇金淋巴瘤患者中确定苯达莫司汀及其活性代谢物的药代动力学特征，并支持对疗效和安全性的暴露-反应关系的理解。
方法
苯达莫司汀以 60 分钟 120mg/m(2)静脉输注的方式在六个 21 天周期的第 1 天和第 2 天给药。进行了药代动力学模型的开发，并进行了协变量评估。检查了苯达莫司汀暴露与应答状态或中性粒细胞减少症、血小板减少症、疲劳、恶心和呕吐发生之间的相关性。
结果
在单次给予苯达莫司汀 HCl 后，浓度呈三相下降，快速分布、中间和缓慢终末相。中间 t (1/2)（40 分钟）被认为是具有药理学相关性（β消除）的 t (1/2)，因为初始阶段占 AUC 的 99%。年龄、性别、轻度/中度肾功能或轻度肝功能损害不会改变药代动力学。代谢物浓度相对母体较低。由于在给予 120mg/m(2)后暴露范围有限，除苯达莫司汀 C(max)是患者恶心概率的显著（P 值=0.013）预测因子外，未观察到暴露与安全性或疗效指标之间的相关性，大多数患者均使用了止吐药预处理。
结论
基于 BSA 的苯达莫司汀给药方案实现了目标暴露，并与高治疗反应率相关。鉴于在给药后 12 小时观察到的苯达莫司汀半衰期短且浓度低，这些分析描述的苯达莫司汀单次剂量特征预计将代表多剂量特征。恶心的发生与苯达莫司汀暴露显著相关，随着苯达莫司汀 C(max)的增加，恶心的概率增加。
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