Population Pharmacokinetic And Pharmacodynamics Modelling Of Ibutilide

Ibutilide,a Class III antiarrhythmic drug which was marketed in the United States and China in 1999 and 2007,respectively,is used for rapid cardioversion in patients with persistent atrial fibrillation(AF)and atrial flutter(AF)within 90 days.However,similar to other antiarrhythmic regimens used for cardioversion,ibutilide is prone to induce Torsade de pointes(TdP)during the course of treatment.Mechanisms for the increased risk of torsade de pointes remain unclear,but TdP is more likely to occur at a slower ventricular rate and a longer QT interval in the ECG.Whereas,it is not clear which population are prone to TdP before the treatment of ibutilide,so continuous ECG monitoring is required during the administration.For Ibutilide intended population,if the inter-individual variability of patients can be determined prior to treatment,the aim of individualized administration may be better achieved.Therefore,it is necessary to study the dose,pharmacokinetics(PK)and pharmacodynamics(PD)of ibutilide to identify which populations are more sensitive to ibutilide.To the best of our knowledge,there is no reports regarding to the PK and PD of ibutilide.The purpose of this study is to establish the population PK model based on the data of healthy subjects,on the basis of the final PK model,the PK/PD model was constructed with the QT interval as the pharmacodynamic index to study the PK/PD relationship of ibutilide in human body,so as to obtain a quantitative relationship between ibutilide dose,plasma concentration and prolongation of QT interval.At the same time,we analyzed the inter-and intra-variability of ibutilide to understand the population sensitivity characteristics of ibutilide and to provide reference for clinical treatment,and use the final PK/PD model to predict the QT response in patients with AF and/or AFL.