Friberg Lena E, Isbister Geoffrey K, Hackett L Peter, Duffull Stephen B
School of Pharmacy, University of Queensland, Brishane, Australia.
J Pharmacokinet Pharmacodyn. 2005 Aug;32(3-4):571-605. doi: 10.1007/s10928-005-0022-6.
Defining the pharmacokinetics of drugs in overdose is complicated. Deliberate self-poisoning is generally impulsive and associated with poor accuracy in dose history. In addition, early blood samples are rarely collected to characterize the whole plasma-concentration time profile and the effect of decontamination on the pharmacokinetics is uncertain. The aim of this study was to explore a fully Bayesian methodology for population pharmacokinetic analysis of data that arose from deliberate self-poisoning with citalopram. Prior information on the pharmacokinetic parameters was elicited from 14 published studies on citalopram when taken in therapeutic doses. The data set included concentration-time data from 53 patients studied after 63 citalopram overdose events (dose range: 20-1700 mg). Activated charcoal was administered between 0.5 and 4 h after 17 overdose events. The clinical investigator graded the veracity of the patients' dosing history on a 5-point ordinal scale. Inclusion of informative priors stabilised the pharmacokinetic model and the population mean values could be estimated well. There were no indications of non-linear clearance after excessive doses. The final model included an estimated uncertainty of the dose amount which in a simulation study was shown to not affect the model's ability to characterise the effects of activated charcoal. The effect of activated charcoal on clearance and bioavailability was pronounced and resulted in a 72% increase and 22% decrease, respectively. These findings suggest charcoal administration is potentially beneficial after citalopram overdose. The methodology explored seems promising for exploring the dose-exposure relationship in the toxicological settings.
确定药物过量时的药代动力学很复杂。蓄意自我中毒通常是冲动行为，且服药史的准确性较差。此外，很少采集早期血样来描绘整个血浆浓度-时间曲线，而且净化对药代动力学的影响也不确定。本研究的目的是探索一种完全贝叶斯方法，用于对西酞普兰蓄意自我中毒产生的数据进行群体药代动力学分析。关于药代动力学参数的先验信息来自14项已发表的关于西酞普兰治疗剂量的研究。数据集包括63次西酞普兰过量事件（剂量范围：20 - 1700毫克）后对53名患者进行研究的浓度-时间数据。在17次过量事件后的0.5至4小时之间给予了活性炭。临床研究人员用5分有序量表对患者服药史的准确性进行了分级。纳入信息先验稳定了药代动力学模型，并且可以很好地估计群体平均值。没有迹象表明过量剂量后存在非线性清除。最终模型包括剂量量的估计不确定性，但在模拟研究中表明这不会影响模型表征活性炭作用的能力。活性炭对清除率和生物利用度有显著影响，分别导致清除率增加72%和生物利用度降低22%。这些发现表明，西酞普兰过量后给予活性炭可能有益。所探索的方法对于在毒理学环境中探索剂量-暴露关系似乎很有前景。
