Single-dose pharmacokinetics of levetiracetam in healthy Chinese male subjects

Single-dose pharmacokinetics of levetiracetam in healthy Chinese male subjectsQian Zhao,Ji Jiang,XiaoMing Li,Zhihong (Sarah)Lu 1&Pei HuClinicalPharmacology Research Centre,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College,Beijing,China and 1UCB Pharma,Inc.,Smyrna,GA,USAWhat is already known about this subject•Levetiracetam has been evaluated for epilepsy since 1992.•Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers,in adults,children and elderly patients with epilepsy,and in patients with renal and hepatic impairment.•Although this antiepileptic has been well studied inWestern countries,this paper describes the first such trial of the drug in a Chinese population.What this study adds•Information is given on the pharmacokinetics,doseproportionality,safety and tolerability profile of levetiracetam in healthy male Chinese volunteers,and the results are compared with published data obtained in White subjects.•The pharmacokinetics and the pattern of adverse events of levetiracetam in Chinese subjects are similar to the data reported in White subjects.CorrespondencePei Hu MD,Clinical Pharmacology Research Centre,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College,no.1Shuai Fu Yuan,Dongcheng District,Beijing,China 100730.Tel./Fax:+861065296573E-mail:peihu@.............................................................................................................................KeywordsChinese subjects,epilepsy,Keppra,levetiracetam,pharmacokinetics,ucb L059.............................................................................................................................Received 13April 2006Accepted 20July 2006Published OnlineEarly 26February 2007AimsThe main aims of this study were to evaluate the pharmacokinetics of levetiracetam in healthy male Chinese volunteers and to assess the dose proportionality between the 500-mg and 1500-mg single doses.MethodsThis was a randomized,single-centre,single-dose,two-way crossover study.Twenty-six healthy male Chinese subjects were enrolled.All subjects received a single dose of 500mg or 1500mg levetiracetam tablet(s)on the dosing day,and the wash-out period was 7days.Blood was obtained for a 36-h pharmacokinetic evaluation.ResultsFollowing single-dose administration of 500mg and 1500mg of levetiracetam,the median t max was 0.5and 0.5h;t 1/2was 7.3Ϯ0.8and 7.3Ϯ0.7h;C max was 13.6Ϯ3.2and 47.1Ϯ12.1m g ml -1;AUC 0–•was 109.3Ϯ14.1and 340.4Ϯ50.6m g h -1ml -1;and AUC 0–t was 105.7Ϯ13.3and 329.0Ϯ47.9m g h -1ml -1,respectively.ConclusionsBoth C max and AUCs were dose-proportional over the range of 500–1500mg.The pharmacokinetic data obtained in these Chinese subjects were similar to the historical data from a matched group of White subjects.British Journal of Clinical PharmacologyDOI:10.1111/j.1365-2125.2006.02782.x©2006The AuthorsJournal compilation ©2006Blackwell Publishing LtdBr J Clin Pharmacol 63:5614–617614IntroductionLevetiracetam[(S)-a-ethyl-2-oxo-1-pyrrolidine aceta-mide]is a novel antiepileptic drug with a unique mecha-nism of action.It was found to be well tolerated and effective when used as an adjunctive treatment in adults and children with partial-onset seizures[1–6].One major advantage of levetiracetam is that it has minimal potential for pharmacokinetic drug interactions.This is due to the minimal metabolism that does not utilize hepatic cytochrome P450enzymes,and low protein binding[7].Neither levetiracetam nor its major metabo-lite formed via hydrolysis is bound significantly to plasma proteins(<10%)[8].White pharmacokinetic data show that levetiracetam is rapidly and almost completely absorbed after oral administration.The oral bioavailability of levetiracetam tablets is close to100%.The maximal plasma concen-tration(C max)is generally reached within1h after administration in fasting subjects.After single-dose oral administration,C max and area under the curve(AUC)are proportional to the dose given(range500–5000mg)[9]. The apparent volume of distribution(V z/F)is in the range of0.5–0.7l kg-1.The major route of levetiracetam excretion is via the urine,accounting for a mean of95% of the administered dose.The renal clearance(CL R)is approximately0.6ml min-1kg-1.The half-life(t1/2)of the compound is7.2Ϯ1.1h in young healthy volun-teers,with a slightly shorter half-life in females.The longer t1/2(10–11h)in elderly subjects is due to an age-related decline in renal function[10].The apparent clearance(CL/F)is0.96ml min-1kg-1in healthy adults. Although coadministration with food results in a delayed absorption[the time to reach C max(t max)2.1–2.3h],the decreased extent of absorption(by approxi-mately8–10%)is not of clinical significance[11]. The pharmacokinetic,efficacy and safety profiles of levetiracetam have been well established in White popu-lations but have never been studied in Chinese subjects. The present study was designed to(i)investigate the pharmacokinetics of levetiracetam and assess dose pro-portionality between the500-mg and1500-mg single dose in healthy male Chinese volunteers;(ii)compare the results with published data obtained in Whites;(iii) gain information on the safety and tolerability profile of levetiracetam in Chinese subjects.MethodsStudy populationsTwenty-six healthy male Chinese subjects between 20and36years of age were included following regular medical assessments,including laboratory safety screens.Subjects were nonsmokers or able to stop smoking throughout the study period.Subjects testing positive for HIV,hepatitis B surface antigen,hepatitis C virus or drugs of abuse(including alcohol)were excluded.Subjects with a history of frequent and severe headache were also excluded.All subjects provided written informed consent.The study protocol was approved by Peking Union Medical College Hospital(PUMC Hospital)Ethics Committee, Beijing,China.Study designThis was a randomized,single-centre,single-dose,two-way crossover study of500-mg and1500-mg levetirac-etamin tablet(s)in healthy,adult male Chinese subjects after an overnight fast.In each study period,the subjects received1¥500mg or3¥500mgfilm-coated tablets of levetiracetam.These two treatments were separated by a7-day wash-out period.All subjects were not allowed to take food until4h postdose on the dosing days.Blood samples for determination of levetiracetam plasma concentrations were taken predose and at0.25, 0.5,0.75,1,1.25,1.5,2,3,4,6,9,12,24and36h postdose.Safety was evaluated by monitoring adverse events, vital signs,physical examinations,clinical laboratory tests and electrocardiograms(ECGs).Analytic assaysPlasma samples were analysed by a liquid chromatography–tandem mass spectrometry(LC-MS/ MS)method,which was fully validated according to the Standard Operation Procedure of PUMC Hospital and Good Laboratory Practice guidelines.The calibration curve ranged from0.10to50m g ml-1.Plasma samples (100m l)were mixed with50m l of internal standard solution(ucb17025,5m g ml-1)and350m l acetonitrile. After centrifugation,100m l of the supernatant was diluted with300m l of water.Following plasma sample preparation,injection(20m l)was made onto an Alltech C18column(4.6¥100mm,3m m)using60%2m m ammonia acetate,30%acetonitrile,30%0.1%formic acid as mobile phase.Pharmacokinetic analysisPharmacokinetic parameters resulting from the plasma concentrations of levetiracetam were calculated with WinNonlin(Pharsight4.0.1;SCI software,Cary,NC, USA)by noncompartmental methods.The C max and t max were obtained directly from the concentration–time data.AUC0–t was calculated using the trapezoidal rule and extrapolated to infinite time for AUC0–•.The CL/F, V z/F and terminal phase t1/2were also calculated.Short reportBr J ClinPharmacol63:5615ResultsPharmacokineticsTwenty-six healthy male Chinese subjects were included.The demographic details were as follows (mean ϮSD):age was 24.0Ϯ4.3years,weight 64.3Ϯ6.8kg,height 1.72Ϯ0.06m and body mass index 21.74Ϯ1.69kg m -2.Figure 1shows the mean concentration–time profile of levetiracetam following single oral doses of 500mg and 1500mg.Levetiracetam was rapidly absorbed after administration.C max was reached within 1h after dosing.The pharmacokinetic parameters are shown in Table 1.C max and AUCs were proportional to the administrated dose,since the 90%CIs of 1500mg/500mg for dose-normalized C max ,AUC 0–t and AUC 0–•were within the established acceptable ranges.The pharmacokinetics of levetiracetam in 26Chinese and in 19matched White subjects were evaluated by a bioequivalence approach.The geometric mean ratios between the two populations were as follows:for the 500-mg group,the geometric mean ratios (90%CIs)of C max ,AUC 0–t ,AUC 0–•and weight-adjusted C max ,AUC 0–t ,AUC 0–•were 96.1%(84.5,109.3),102.8%(95.8,110.4),92.1%(85.4,99.3)and 96.1%(84.4,109.5),102.8%(96.2,109.9),92.1%(86.1,98.4),respectively;for the 1500-mg group,the geometric mean ratios (90%CIs)were 120.6%(105.9,137.4),89.5%(83.2,96.4),89.5%(83.1,96.4)and 120.6%(105.8,137.4),89.5%(84.0,95.5),89.5%(83.7,95.7),respectively.The comparison demonstrated similar pharmacokinetic data between the two populations,since the 90%CIs of geometric means ratios for either the original or weight-adjusted parameters were entirely within reference boundaries of 0.80–1.25for AUC 0–•,AUC 0–t and within 0.70–1.43for C max .Adverse eventsAdverse events observed in the study included somno-lence,dizziness and nausea.All adverse events were considered treatment related,mild or moderate in sever-ity,and transient and resolved without treatment.The incidence and profile of adverse events between the 500-mg and 1500-mg groups were comparable and not dose-related.61663:5Br J Clin PharmacolDiscussionThis study showed that the pharmacokinetic data of levetiracetam in healthy adult male Chinese subjects were similar to historical data in White subjects.The t max of levetiracetam in Chinese subjects was 0.5h,com-pared with the within 1h found in White subjects.The t 1/2,CL/F equated for weight and V z /F equated for weight were comparable in Chinese and White subjects (t 1/2-7.2h,CL/F ~1.43ml min -1kg -1and V z /F ~0.5–0.8l kg -1).Because different dietary conditions in this comparison with historical data could have affected the absorption rate,while the clinical efficacy of levetirac-etam was likely to be related to absorption and overall exposure rather than to absorption rate and peak expo-sure,a broader range of acceptance (0.70–1.43)was selected for C max .The results of this study indicated that both C max and AUCs could be considered to be dose proportional over the tested dose range of 500–1500mg in Chinese subjects,which is in line with previously published results on levetiracetam linear pharmacokinet-ics (range 500–5000mg)in White subjects [11].The authors gratefully acknowledge the volunteers who took part in this study.We also thank the staff at PUMC Hospital for providing the medical care to the subjects.References1Glauser TA,Pellock JM,Bebin EM,Fountain NB,Ritter FJ,Jensen CM,Shields WD.Efficacy and safety of levetiracetam in children with partial seizures.Epilepsia 2002;43:518–24.2Ben-Menachem E,Falter U.Efficacy and tolerability oflevetiracetam 3000mg/day in patients with refractory partial seizures.Epilepsia 2000;41:1276–83.3Grant R,Shorvon SD.Efficacy and tolerability of 1000–4000mg per day of levetiracetam as add-on therapy in patients with refractory epilepsy.Epilepsy Res 2000;42:89–95.4French J,Edrich P,Cramer JA.A systematic review of the safety profile of levetiracetam.Epilepsy Res 2001;4:77–90.5Beran RG,Berkovic SF,Black AB,Danta G,Hiersemenzel R,Schapel GJ,Vajda FJ.Efficacy and safety of levetiracetam 1000–3000mg/day in patients with refractory partial-onset seizures.Epilepsy Res 2005;63:1–9.6Harden C.Safety profile of levetiracetam.Epilepsia 2001;42:36–9.7Benedetti MS,Whomsley R,Nicolas JM,Young C,Baltes E.Pharmacokinetics and metabolism of 14C-levetiracetam,a new antiepileptic agent,in healthy volunteers.Eur J Clin Pharmacol 2003;59:621–30.8Doheny HC,Ratnaraj N,Whittington MA,Jefferys JG,Patsalos PN.Blood and cerebrospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam in the rat.Epilepsy Res 1999;34:161–8.9Patsalos PN.Clinical pharmacokinetics of levetiracetam.Clin Pharmacokinet 2004;43:707–24.10Radtke RA.Pharmacokinetics of levetiracetam.Epilepsia 2001;42:24–7.11Patsalos PN.Pharmacokinetic profile of levetiracetam.PharmacolTher 2000;85:77–85.Table 1Pharmacokinetic parameters of levetiracetam after a single-dose administration of a 500-mg oral tablet or a 1500-mg oral tablet (3¥500-mg tablets)in 26healthy male Chinese subjects*Values are arithmetic mean ϮSD except for t max ,where values are median (range).†Intra-individual CV (%).‡Point estimate and 90%CI for the adjusted 1500-mg/500-mg geometric least squares mean ratio (%),derived from anova for continuous parameters.NA,Not applicable.Short reportBr J Clin Pharmacol63:5617。