阿戈美拉汀及其代谢物在中国健康志愿者中的半生理群体药代动力学模型。
A semiphysiological population pharmacokinetic model of agomelatine and its metabolites in Chinese healthy volunteers.
机构信息
Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
出版信息
Br J Clin Pharmacol. 2019 May;85(5):1003-1014. doi: 10.1111/bcp.13902. Epub 2019 Mar 21.
AIMS
Agomelatine is an antidepressant for major depressive disorders. It undergoes extensive first-pass hepatic metabolism and displays irregular absorption profiles and large interindividual variability (IIV) and interoccasion variability of pharmacokinetics. The objective of this study was to characterize the complex pharmacokinetics of agomelatine and its metabolites in healthy subjects.
METHODS
Plasma concentration-time data of agomelatine and its metabolites were collected from a 4-period, cross-over bioequivalence study, in which 44 healthy subjects received 25 mg agomelatine tablets orally. Nonlinear mixed effects modelling was used to characterize the pharmacokinetics and variability of agomelatine and its metabolites. Deterministic simulations were carried out to investigate the influence of pathological changes due to liver disease on agomelatine pharmacokinetics.
RESULTS
A semiphysiological pharmacokinetic model with parallel first-order absorption and a well-stirred liver compartment adequately described the data. The estimated IIV and interoccasion variability of the intrinsic clearance of agomelatine were 130.8% and 28.5%, respectively. The IIV of the intrinsic clearance turned out to be the main cause of the variability of area under the curve-based agomelatine exposure. Simulations demonstrated that a reduction in intrinsic clearance or liver blood flow, and an increase in free drug fraction had a rather modest influence on agomelatine exposures (range: -50 to 200%). Portosystemic shunting, however, substantially elevated agomelatine exposure by 12.6-109.1-fold.
CONCLUSIONS
A semiphysiological pharmacokinetic model incorporating first-pass hepatic extraction was developed for agomelatine and its main metabolites. The portosystemic shunting associated with liver disease might lead to significant alterations of agomelatine pharmacokinetics, and lead to substantially increased exposure.
目的
阿戈美拉汀是一种用于治疗重度抑郁症的抗抑郁药。它在肝脏中经历广泛的首过代谢，表现出不规则的吸收特征和较大的个体间变异（IIV）和药代动力学的间变异性。本研究的目的是描述健康受试者中阿戈美拉汀及其代谢物的复杂药代动力学特征。
方法
从一项 4 期交叉生物等效性研究中收集了阿戈美拉汀及其代谢物的血浆浓度-时间数据，该研究中 44 名健康受试者口服 25mg 阿戈美拉汀片。使用非线性混合效应模型来描述阿戈美拉汀及其代谢物的药代动力学和变异性。进行确定性模拟以研究因肝脏疾病引起的病理变化对阿戈美拉汀药代动力学的影响。
结果
具有平行一级吸收的半生理药代动力学模型和充分搅拌的肝脏隔室充分描述了数据。阿戈美拉汀内在清除率的估计个体内变异和间变异性分别为 130.8%和 28.5%。内在清除率的个体内变异是导致基于曲线下面积的阿戈美拉汀暴露变异性的主要原因。模拟表明，内在清除率或肝血流量的降低以及游离药物分数的增加对阿戈美拉汀暴露的影响相当小（范围：-50 至 200%）。然而，门体分流会使阿戈美拉汀暴露量增加 12.6-109.1 倍。
结论
开发了一种包含首过肝脏提取的半生理药代动力学模型，用于阿戈美拉汀及其主要代谢物。与肝脏疾病相关的门体分流可能导致阿戈美拉汀药代动力学的显著改变，并导致暴露量显著增加。
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