Efficacy,safety And Population Pharmacokinetics Of Propafenone In Chinese Children With Premature Contractions

BackgroundsPremature contractions has high morbidity in children,which can be detected in 18-50%of healthy children,the higher frequency of premature contractions may progress to severe arrhythmias and even cause heart failure or other diseases.Propafenone has been shown to inhibit up to 88%premature contractions in adult patients.However,its half-life and concentrations have large inter-individual variance,which can be tens of times between different individuals with the same dose.In vivo,propafenone is metabolized to 5hydroxypropafenone and N-depropylpropafenone mainly through CYP2D6,CYP3A4 and CYP1A2.The metabolites also have antiarrhythmic activity.CYP2D6 has gene polymorphism which may affects the metabolism of propafenone.Currently,the use of propafenone in pediatric patients with premature contractions is still off-label,and there is no clear administration regimen.Related studies have been conducted in children abroad.Due to the influence of ethnic differences and gene polymorphism,this study was conducted to evaluate the efficacy,safety and pharmacokinetics of propafenone in Chinese children with premature contractions.PurposesTo evaluate the efficacy and safety of propafenone in Chinese children with premature contractions,and promote the reasonable use of drugs.To explore the factors influencing individual pharmacokinetics of propafenone and its metabolite 5-hydroxypropafenone in pediatric patients with premature contractions,and establish the population pharmacokinetics model in Chinese children with premature contractions.MethodsThis is an open-label,observational clinical study.The study was approved by the Ethics Committee of Children’s Hospital of Hebei province.Children who diagnosed as premature contractions and treated with propafenone were included in this study.Collecting 24-hour premature contractions times,QTc intervals and heart rate during follow-up period and any adverse reactions during treatment to assess the efficacy and safety of propafenone.The plasma concentration of propafenone and 5-hydroxypropafenone were determined by liquid chromatography-tandem mass spectrometry.A population pharmacokinetics model of propafenone/5-hydroxypropafenone was established by nonlinear mixed-effect model(NONMEM)software.ResultsA total of 31 patients(16 females,15 males,median age 7.8 years)were enrolled in this study.Efficacy outcome was collected from 24 patients,and the average premature contractions inhibition rate was 74.2±35.1%,54.1%of patients had a premature contractions inhibition rate great than 90%,70.8%of patients had premature contractions inhibition rate great than 70%.Four patients had prolonged QTc intervals.Data from 31 patients and 60 plasma samples were used to establish a population pharmacokinetics model.Two-compartments for parent drug and one-compartment for metabolite model is able to describe the pharmacokinetics of propafenone/5-hydroxypropafenone in children with premature contractions accurately.Covariate analysis showed that body weight,age and biochemical test data had no significant influence on the model.The mean(range)of clearance of propafenone and 5hydroxypropafenoneis 1.14(0.19-7.17)L/kg/h and 1.29(0.44-2.98)L/kg/h,respectively.ConclusionsThis study preliminarily evaluated the efficacy of propafenone in Chinese children with premature contractions,and four patients had prolongation of QTc intervals.The population pharmacokinetics model of propafenone/5-hydroxypropafenone was established in Chinese children with premature contractions.Compared with the results of previous studies,there were no significant differences in the pharmacokinetics parameters of propafenone in this study.