Comets E, Mentré F, Pousset F, Diquet B, Montalescot G, Ankri A, Mallet A, Lechat P
INSERM U436, Modélisation Mathématique et Statistique en Biologie et Médecine, Institut de Physiopathologie et de Génétique Cardiovasculaire, Centre Hôpital Universitaire Pitié-Salpêtrière, Paris, France.
Ther Drug Monit. 1998 Dec;20(6):631-9. doi: 10.1097/00007691-199812000-00009.
This study was designed to construct a pharmacokinetic/pharmacodynamic model describing the evolution of International Normalized Ratio (INR) under oral anticoagulation treatment by fluindione in patients and to develop a method for individualization of fluindione dosage. Three indirect response models describing the concentration-INR relationship were tested using a nonparametric estimation method. INR was modelled as a quantity being produced and eliminated. According to a log-likelihood ratio test, the evolution of INR was best modelled as an inhibition of its elimination by fluindione. The selected model was evaluated in 24 additional patients with INR measurements (after 2, 3, 4, 6, and 10 doses). Using a Bayesian method with data until day 4, INR was correctly predicted for days 6 and 10. The population characteristics of fluindione were estimated, pooling the two groups of patients. A Bayesian method for individualization of dosage regimen was developed, based on a risk function for INR at steady state. Prescription rules for fluindione were derived using this method retrospectively on the 73 patients in this study.
本研究旨在构建一个药代动力学/药效学模型，描述患者接受氟茚二酮口服抗凝治疗时国际标准化比值（INR）的变化情况，并开发一种氟茚二酮剂量个体化方法。使用非参数估计方法测试了三种描述浓度-INR关系的间接反应模型。将INR建模为一个产生和消除的量。根据对数似然比检验，INR的变化最好建模为氟茚二酮对其消除的抑制作用。在另外24例有INR测量值的患者中（在给予2、3、4、6和10剂后）对所选模型进行了评估。使用贝叶斯方法并结合第4天之前的数据，正确预测了第6天和第10天的INR。合并两组患者后估计了氟茚二酮的群体特征。基于稳态时INR的风险函数，开发了一种剂量方案个体化的贝叶斯方法。使用该方法对本研究中的73例患者进行回顾性分析，得出了氟茚二酮的处方规则。
