Pharmacokinetics Study Of Levetiracetam Extended-release Tablets In Human

Objective:(1)To study relative bioavailability of levetiracetam extended-release tablets(XR)following single and multiple dosing.(2)To study single dose pharmacokinetics of levetiracetam XR tablets.(3)To compare the pharmacokinetics of levetiracetam XR tablets under fasted and fed states.To evaluate the food effects on pharmacokinetics of levetiracetam XR tablets.Methods:(1)Establish an LC-MS/MS method for the determination of levetiracetam in human plasma.The separation was achieved on the Waters Symmetry(?)C18(3.9 × 150 mm,5 ?m),and the mobile phase was acetonitrile/5 mmol·L-1 ammonium formate containing 0.3%formic acid(10/90,V/V)with a flow rate of 1000 ?L·min-1,Electrospray ionization(ESI)source was applied and operated under multiple reaction monitoring(MRM)mode using the transitions of m/z 171.1?126.land 172.1?154.1 for levetiracetam and internal standard gabapentin,respectively.Plasma samples were extracted by acetonitrile and analyzed by LC-MS/MS.(2)To study the relative bioavailability of levetiracetam XR tablets following single and multiple dosing.During the two treatment periods,each subject was given levetiracetam XR tablets/levetiracetam immediate release tables(IR)1000 mg under fasting conditions on Day1 followed by q.d.administration(levetiracetam XR tablets)or b.i.d.administration(levetiracetam IR tables)from Day3 to Day8.The wash-out between treatment periods was one week.Blood was sampled for levetiracetam determinations at pre-dose(0 h),and every sampling time post-dosing.The plasma was separated after sampling by centrifugation at 4?,4000 rpm for 5 min,and stored at-30?until analysis.The plasma concentrations of levetiracetam were measured by LC-MS/MS.DAS 3.2.9 was used for pharmacokinetic parameters evaluation.Statistic analysis was done by SPSS 19.0.(3)A single-dose,four-way crossover trial was done in 12 healthy subjects.12 healthy subjects were randomly picked from volunteers and divided into four treatments,which was single dose treatment of 500 mg and 2000 mg levetiracetam XR tablets,taken under fasting conditions respectively and 1000 mg levetiracetam XR tablets,taken both under fasting and fed conditions.The wash-out between treatment periods was one week.Blood was sampled for levetiracetam determinations at pre-dose(0 h),and every sampling time post-dosing.The plasma was separated after sampling by centrifugation at 4?,4000rpm for 5min,and stored at temperature of-30?until analysis.The plasma concentrations of levetiracetam were measured by LC-MS/MS.DAS 3.2.9 was used for pharmacokinetic parameters evaluation.Statistic analysis was done by SPSS 19.0.Results:(1)Endogenous substances dose not interfere with the measurement of levetiracetam and the internal standard gabapentin.The method is sensitive,accurate,and reproducible.The calibration curve of levetiracetam in human plasma was linear over the concentration rang of 0.1000-80.00 ?g·mL-1.The intra and inter day precisions were within the acceptable range and the means of the extraction recovery were 100%.Plasma samples were stable at-30? repeated freezing and thawing three times,frozen under-30? for 52 days and room temperature for 6 h,(2)Cmax was lower by 41.54%after single oral administration of 1000 mg levetiracetam XR tablets in comparison to single oral administration of 1000 mg IR tablets intake.Tmax is about 4 hours longer with levetiracetam XR tablets than with IR tablets.The 90%confidence interval(CI)of the XR/IR tablets ratios for AUC were contained within the 80-125%range of bioequivalence.Single oral administration of 1000 mg levetiracetam XR tablets once daily produced comparable Cmax and AUC as the oral administration of 1000 mg levetiracetam IR tablet twice daily in fasting state did.Css min was lower by 34.66%after multiple dose levetiracetam XR tablets in comparison to multiple dose levetiracetam IR tablets intake.The 90%CI of the XR/IR tablets ratios for Css max,Css av,AUCss(?=24h)and DF were contained within the 80%-125%range of bioequivalence.There was no significant difference in Tmax.After single-dose and multiple-dose oral administration of 1000 mg levetiracetam XR tablets,the RAUC and RCmax,were 1.275 ±0.146 and 1.243± 0.147,respectively.AUCss(?=24h)and Cmax were higher by 26.7%and 23.5%,respectively.The results indicate that accumulation phenomena exist in human.There was no significant difference in Tmax.(3)The pharmacokinetics(Cmax,AUC0-48h and AUC0-?)were shown to be dose proportional after single administration of 500 mg,1000 mg,and 2000 mg levetiracetam XR tablets.There was no significant difference in the pharmacokinetic parameters of MRT0-48h,MRT0-?,Kel,t1/2,Vd,CL/F,Tmax.A high fat,high calorie breakfast before the oral administration of 1000 mg levetiracetam XR tablets resulted in a higher Cmax by 14.18%without altering AUC.Tmax was 1.2 hours longer in the fed state than in the fasting state.There was no significant difference in MRT0-48h,MRT0-?,Kel,t1/2,Vd,CL/F.Conclusion:Cmax of levetiracetam XR tablets was lower than IR tablets.AUC of levetiracetam XR tablets was similar to that of the IR Tablets.The pharmacokinetics(Cmax,AUC0-48h and AUC0-?)were shown to be dose proportional after single administration of 500 mg,1000 mg,and 2000 mg levetiracetam XR tablets.A high fat,high calorie breakfast before the oral administration of 1000 mg levetiracetam XR tablets resulted in a higher Cmax without altering AUC.Tmax was longer in the fed state than in the fasting state.Levetiracetam IR tablets were dosed twice daily,therefore,levetiracetam XR tablets with a dose of once daily can decrease the frequency of dosing for drugs and improve convenience and adherence.