Pharmacokinetic Study Of Benfotiamine Tablets In Healthy Volunteers

Objective:The study aims to use modern analytical technology to research pharmacokinetic characteristics of benfotiamine tablets.Based on analysis method in the existed literature,establish accurate and sensitive analysis methods for determination of benfotiamine metabolite in human whole blood,design the experimental scheme of benfotiamine tablets pharmacokinetic study in human body according to the relevant guidelines,evaluate the pharmacokinetic characteristics in Chinese healthy human by the calculation and analysis of the measured blood drug concentration.This subject provides support for safety and tolerability of benfotiamine tablets in Chinese healthy volunteers and its rules of absorption,distribution,metabolism and excretion in human body,also provide evidence for formulating a reasonable dosing regimen on its Phase II clinic.Methods:1?The establishment for determination of concentration in whole bloodCombining with the reported literature and pre-experiments results,Respectively establish a HPLC method for determination of the metabolite of TDP and a LC-MS/MS method for determination of the metabolite of vitamin B₁,and study the methodology of two determinations respectively.2?Design of human pharmacokinetic experimentAccording to the“guiding principles of chemical medicine clinical pharmacokinetic study”and reported clinical pharmacological data ofbenfotiamine tablets in foreign human body,formulate a scientific and rational experiment scheme of benfotiamine pharmacokinetic study in Chinese healthy volunteers.3?Pharmacokinetic study on human bodyRespectively determining the concentrations of two metabolites by the established methods,using software WinNonlin 6.3 to calculate pharmacokinetic parameters,eventually,investigating the influence of dose,administration,food,sex to benfotiamine pharmacokinetic parameters by statistical analysis.Results:1?A HPLC method was developed and validated for determination of TDP in whole blood.LLOQ was15ng/mL,the intra-and inter-day precisions?RSD?for both were less than 15%,and the accuracy?RE?were between-4.80%⁴.11%.A LC-MS/MS method was developed and validated for determination of vitamin B₁ in whole blood.LLOQ was1ng/mL,the intra-and inter-day precisions?RSD?for both were less than 15%,and the accuracy?RE?were between-9.31%¹.09%.2?All subjects signed informed consent form before test,after a series of tests of demographic data registration,history demand,physical examination and laboratory examination,30qualified healthy subjects?19to 31 years old,half male and half female?were randomly divided into three groups,group 1 were given a single oral dose 25 mg of benfotiamine,group 2 were given single oral dose 50 mg of benfotiamine on an empty stomach or after meal,wash out period was 2 weeks,group 3were given a single oral dose 100 mg of benfotiamine,24h later,entered multiple dose period,administrated once a day for 7 days.Single and multiple dose groups respectively collected blood samples on the basis of their collection points,and then stored in-80?refrigerator.3?There was not a linear pharmacokinetic characteristics of TDP after healthy subjects took benfotiamine tablets,there was no significant differences between male and female;there was no accumulation tendency in multiple dose,the administration method that every 24h a time,once administrated 100mg could get higher steady-state concentration faster and maintain to the end of administration;food had no effect on the pharmacokinetic parameters.There was a linear pharmacokinetic characteristics of vitamin B₁ after healthy subjects took benfotiamine tablets,there was no significant differences between male and female;there was no accumulation tendency in multiple dose,the administration method that every 24h a time,once administrated 100mg could get higher steady-state concentration?On the third day?faster and maintain to the end of administration;food had no effect on the pharmacokinetic parameters.Conclusion:The topic adopted blood drug concentration method to study pharmacokinetic characteristics of benfotiamine in Chinese healthy volunteers.A HPLC method for determination of TDP in whole blood and a LC-MS/MS method for determination of vitamin B₁ in whole blood were established respectively,the established method was highly sensitive,simple,and suitable for the pharmacokinetic study of benfotiamine tablets.Pharmacokinetic study showed that there was not a linear pharmacokinetic characteristics of TDP after healthy subjects took benfotiamine tablets,there was no significant differences between male and female;there was no accumulation tendency in multiple dose,food had no effect on the pharmacokinetic parameters.There was a linear pharmacokinetic characteristics of vitamin B₁ after healthy subjects took benfotiamine tablets,there was no significant differences between male and female;there was no accumulation tendency in multiple dose,food had no effect on the pharmacokinetic parameters.