单剂量的奈韦拉平

单剂量奈韦拉平健康志愿者体内药代动力学和生物利用度的研究SingleDosePharmacokineticsandBioavailabilityofNevirapineinHealthyVolunteers1摘要：两个随机、单剂量、交叉的生物利用度的研究结果，描述了奈韦拉平（是一种新型的非核苷抗逆转录病毒的药物）的药代动力学和口服生物利用度。ABSTRACT:Theresultsoftworandomized,single-dose,crossoverbioavailabilitystudiesarepresentedwhichdescribethepharmacokineticsandoralbioavailabilityofnevirapine,anovelnonnucleosideantiretroviraldrug.2在第一个研究中，向12名健康男性志愿者体内短期静脉注射15mg奈韦拉平，或者口服50mg的片剂，或者口服参比溶液（50mg/200mL）。静脉注射完之后，奈韦拉平有一个较低的全身清除率(Mean±S.D.,Cl=1.4±0.3L/h)和一个延长的消除相(t1/2β=52.8±14.8h;MRT=81.4±22.4h).

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Inthefirststudy12healthymalevolunteersreceivednevirapine15mgviashort-termi.v.infusionororallyasa50mgtabletorreferencesolution(50mg:200mL).Followingthei.v.dose,nevirapinehadalowsystemicclearance(Mean±S.D.,Cl=1.4±0.3L/h)andaprolongedeliminationphase(t1/2β=52.8±14.8h;MRT=81.4±22.4h).3奈韦拉平的绝对生物利用度分别为：注射剂是93±9%，片剂和口服溶液是91±8%。在第二个研究中，24名健康男性志愿者服用200mg片剂奈韦拉平或者口服参比溶液（200mg/200mL）。片剂和参比溶液的生物利用度没有显著的不同。Nevirapineabsolutebioavailabilitywas93±9%and91±8%forthetabletandoralsolution,respectively.Inthesecondstudy,24healthymalevolunteerswereadministerednevirapineasa200mgproduction-linetabletororalreferencesolution(200mg/200mL).Therewasnosignificantdifferenceinbioavailabilitybetweenthetabletandreferencesolution.4总之，对50mg和200mg剂量的药代动力学参数进行比较，结果显示，服用临床相关剂量的奈韦拉平能够被很好的吸收。使用解卷积法得到的吸收曲线表明，这两种剂量或是每种剂量的给药途径没有由特定的酶诱导。Overall,comparisonofthepharmacokineticparametersbetweenthe50and200mgdosesindicatesthatnevirapineiswellabsorbedatclinicallyrelevantdoses.Theabsorptionprofilesusingdeconvolutionrevealednoevidenceofdifferentialenzymeinductionbetweenthetwodosesorroutesofadministrationfollowingasingledose.5介绍：奈韦拉平的结构是二吡啶并二氮杂卓酮（如图），它是第一类适用于治疗人类免疫缺陷病毒（HIV）的非核甘类逆转录酶抑制剂。在细胞培养中，奈韦拉平通过与逆转录酶直接连接，抑制RNA依赖和DNA依赖的聚合酶活性。Nevirapine,adipyridodiaqepinone(Figure1),wasthefirstdrugofthenonnucleosidereversetran-scriptaseinhibitor(NNRTIs)classtobeapprovedfortreatingthehumanimmunodeficiencyvirus(HIV)infectioninhumans.Bybindingdirectlytoreversetranscriptase,nevirapineinhibitstheRNA-dependentandDNA-dependentpolymeraseactivi-tiesincellculture6在临床试验中，当奈韦拉平与核苷类和蛋白酶类药物用于联合治疗时，能够证明奈韦拉平是强效的、持久的抗病毒药物。Inclinicaltrials,nevirapinehasdemonstratedpotentandsustainedantiviralactivitywhenusedintriplecombinationtherapywithdrugsofthenucleosideandproteaseinhibitorclasses7口服给药后，人体能够迅速的吸收奈韦拉平达到400mg。服用200mg剂量的奈韦拉平，给药4小时后，血浆浓度峰值达到大约2μg/mL，尽管之后多重峰的次级峰值浓度也能被监测出。剂量达到200mg时，血药浓度-时间曲线下面积和最大浓度呈线性关系。Inhumans,nevirapineappearstobereadilyab-sorbedfollowingoraladministrationofdosesupto400mg[7,8].Followingasingle200mgdosenevi-rapinepeakplasmaconcentrationsofapproxi-mately2μg/mLareachievedby4hpostdose,althoughsubsequentmultiplesecondarypeakconcentrationsarealsoobserved.Areaundertheplasmaconcentration–timecurve(AUC)andCmaxbothexhibitdoselinearityatdosesupto200mg.8奈韦拉平的药代动力学特征是服用单一剂量后，有持续很长时间的药代动力学作用时期(t1/2>45h）奈韦拉平经过P450酶的代谢形成羟基葡糖苷酸它作为无活性代谢物主要被排泄到尿中。单剂量中不到3%作为原药排到尿中。Thepharmacokineticsofnevirapinearealsocharac-terizedbyaprolongedpharmacokineticdispositionphase(t1/2>45h)followingasingledose.Nevirap-ineundergoesextensiveP450metabolismtohydroxylatedglucuronides,whicharelargelyexcretedintotheurineasinactivemetabolites.Lessthan3%ofadoseisexcretedinurineasparentcompound.9加倍剂量的药代动力学特征是，当从单剂量到200mg/day或更高剂量持续治疗两周时，细胞色素P450同工酶3A(CYP3A)和2B6(CYP2B6)代谢的自身诱导，导致全身清除率明显增加1.5-2倍。自身诱导也会导致奈韦拉平末期半衰期的减少，使其在血浆中从单一剂量的45小时减少到多剂量的25-30小时。Themultipledosepharmacokineticsarecharac-terizedbymetabolicautoinductionofcytochromeP450isozymes3A(CYP3A)and2B6(CYP2B6)re-sultingina1.5-to2-foldincreaseinnevirapineapparentsystemicclearanceastreatmentcontinuesfromasingledoseto2weeksofdosingwith200mg/dayorhigher[8].Autoinductionalsoresultsinadecreaseinthenevirapineterminalphasehalf-lifeinplasmafrom45hfollowingasingledoseto25–30hwithmultipledosing.10凭借它的弱碱性和电离(pKa=2.8)，奈韦拉平的溶解度与PH相关。当PH值小于酸度系数时，奈韦拉平在缓冲溶液中的溶解度很高。随着PH值的升高，奈韦拉平自由碱在水中的溶解度会逐渐降低到0.1mg/mL。尽管奈韦拉平口服容易吸收，但是尤其是服用50mg或是更高的剂量时，显示溶解度限制了吸收的速率（延迟了到达峰值的时间，加倍了峰值浓度），并且生物利用度也有稍微的下降。Byvirtueofitsweaklybasiccharacterandionization(pKa=2.8)nevirapineexhibitspHdependentsolubility.AtpHvalueslessthanthepKanevirapineishighlysolubleinaqueousbuffer.AthigherpHvaluesnevirapinefree-basesolubilityinwaterdecreasesasymptoticallytoapproximately.0.1mg:mL.Althoughthedrugappearstobereadilyabsorbedorally,nevirapine,particularlyatdosesof50mgandhigher,exhibitscharacteristicsofsolubil-ityrate-limitedabsorption(delayedtime-to-peak,multiplepeakconcentrations)andaslightfall-offinbioavailability.11本文描述了两个研究的结果，这两个研究旨在表明奈韦拉平在人体内绝对和相对生物利用度的特征。在这两个研究中，将片剂和口服参比溶液作比较，确定是否是药物的剂型或是物理特性或是两者皆有，导致了奈韦拉平在吸收的速率或程度上有所不同。另外，由于长时间的药代动力学作用时期和假设在不同的静脉注射和口服剂量之间药代动力学的线性关系，我们利用解卷积法来更好的评价奈韦拉平的口服吸收特性。Thisreportdescribestheresultsoftwostudiesaimedatcharacterizingtheabsoluteandrelativebioavailabilityofnevirapineinhumans.Inbothstudiesatabletformulationwascomparedtoanoralreferencesolutiontodeterminewhetheranydifferencesintherateorextentofnevirapineab-sorptioncouldbeattributedtoeithertheformula-tionorthephysicalcharacteristicsofthedrug,orboth.Additionally,becauseoftheprolongedphar-macokineticdispositionphaseandtheassumptionofpharmacokineticlinearitybetweendifferenti.v.andoraldoses,deconvolutionwasutilizedtofur-therassessthecharacteristicsofnevirapineoralabsorption.12实验对象和方法

这两个研究都是在Quintiles公司进行的（以前在Innovex公司），每一个研究用的纳入与排除的标准都一样。实验对象是不吸烟的健康的男性志愿者，年龄范围是从18岁到50岁。在研究过程中，志愿者不能服用其他药物，要戒除烟草制品、酒精、含咖啡因的饮料。要求志愿者的身高体重比在大城市人寿保险公司表定义的正常范围内占10%。志愿者是由相当好的健康状况决定的，它包括病史、外部身体检查和实验室检查（血液学、血液化学和尿液分析）。BothstudieswereconductedatQuintiles,Inc.(for-merlyInnovex,Inc.),Lenexa,KS,USA.Thesameinclusionandexclusioncriteriawereusedforeachstudy.Subjectswerenonsmoking,healthymalevol-unteers,ranginginagefrom18to50years.Noconcomitantmedicationswereallowedandsubjectswererequiredtoabstainfromtobaccoproducts,alcoholorcaffeinecontainingbeveragesduringthestudy.Subjectswererequiredtohaveaheight:weightratiowithin10%ofnormalasdefinedbytheMetropolitanLifeInsuranceCompanyTa-bles.Subjectsweredeterminedtobeinreasonablygoodhealthbasedonmedicalhistory,physicalex-aminationandalaboratoryscreen(hematology,bloodchemistryandurinalysis)13试验设计

第一个研究通过服用片剂和参比溶液与静脉注射显示的(血药浓度时间)曲线下面积作比较，评估奈韦拉平的绝对生物利用度。这个实验根据一个公开的、单一剂量、随机的对12个健康的男性志愿者进行交叉实验。在进行药代动力学实验之前，我们在另一个实验中评估了12个志愿者（三个志愿者每剂量水平加上四倍的安慰剂）对三种静脉注射剂量（5、15和30mg）的奈韦拉平的安全性和耐药性。ThefirststudywasdesignedtoassesstheabsolutebioavailabilityofnevirapinefromtabletsandanoralreferencesolutionbycomparisonoftheextentofsystemicexposuretotheAUCfromanintra-venousdose.Thestudywasconductedaccordingtoanopenlabel,singledose,randomized,crossoverdesignin12healthymalevolunteers.Beforethepharmacokineticstudy,thesafetyandtoleranceofthreei.v.doses(5,15and30mg)ofnevirapinewereassessedin12subjects(threesubjectsperdoselevelplusfourplacebos)inaseparatestudy.14因为接受30mg剂量的志愿者有关节痛、头疼等症状，并且增加的肝功能检测表明，这些症状很可能由试验药物导致的，因此在目前的实验中，确定15mg是使用静脉注射的最高耐受剂量。为了确定奈韦拉平的绝对生物利用度，十二个志愿者接收单一剂量的奈韦拉平，分别是静脉注射15mg，口服片剂50mg，口服溶液50mg。片剂用250mL的水送服，口服溶液（在1.5%的柠檬酸水溶液中每200mL含50mg奈韦拉平，PH<3）用50mL水送服，静脉注射是通过手臂表面静脉注射37.5分钟（15mg/18.75mL）。不同的剂量由两周的清除时间分隔开。Becauseoneofsubjectsreceivingthe30mgdoseexperiencesymptoms(e.g.arthralgia,headache)andincreasedliverfunctionteststhatwerepossiblyattributedtothestudydrug,itwasdeterminedthat15mgwasthehighesttolerablei.v.doseforuseinthepresentstudy.Fordeterminationofabsolutenevirapinebioavailability12subjectsreceivedsingledosesofnevirapineasanintravenousinjection(15mg),anoraltablet(50mg),andanoralsolution(50mg).Thetabletwasadministeredwith250mLofwater,theoralsolution(50mgin200mLof1.5%citricacidaqueoussolution,pHB3)with50mLofwater,andthei.v.injectionwasadministeredinaperiph-eralarmveinasani.v.infusion(15mg:18.75mL)over37.5min.Doseswereseparatedbya2-weekwashoutperiod.15在奈韦拉平的临床研究中进行的第二个实验，设计用来对200mg的片剂奈韦拉平与200mg的参比溶液的口服生物利用度进行比较，作为维乐命注册要求的一部分。这是一个在24个成年男性志愿者中进行的随机的、单一剂量的交叉实验。志愿者用250mL水送服一片200mg的奈韦拉平（在商业批量的条件下生产），50mL水送服参比溶液（每200mL3%柠檬酸水溶液中含奈韦拉平200mg，PH<3）。24个志愿者中18个完成了实验。不同的剂量由三周的清除时间分隔开。Thesecondstudy,occurringlaterintheclinicaldevelopmentofnevirapine,wasdesignedtoassesstheoralbioavailabilityofnevirapine200mgtabletscomparedtoa200mgoralreferencesolutionaspartoftheregistrationrequirementsforViramune®.Thiswasarandomized,singledose,crossoverstudyin24adultmalevolunteers.Subjectswereadministerednevirapineasa200mgtablet(manu-facturedundercommercialbatchconditions)with250mLofwaterandasanoralreferencesolution(200mgin200mLof3%citricacidaqueoussolu-tion,pHB3)with50mLofwater.Eighteenofthe24enrolledsubjectscompletedthestudy.Doseswereseparatedbya3-weekwashoutperiod.16过程

每种单一剂量都前一天晚上十点快速开始，服药后持续四小时，奈韦拉平大约在早上八点给药。在口服50mg剂量和静脉注射15mg剂量奈韦拉平五分钟之后开始计时，在0.17,0.33,0.5,0.63,0.75,0.83,1,1.25,1.5,1.75,2,3,4,8,12,16,24,48,72,96和168小时的时候，抽取一系列用于药代动力学分析的静脉血样。Eachsingledosewasprecededbyanovernightfastbeginningat22:00handlastinguntil4hafterdosing.Nevirapinewasadministeredatapproxi-mately08:00h.Serialsamplingofvenousblood(5mL)forpharmacokineticanalysiswasdone5minbefore(0h)andat0.17,0.33,0.5,0.63,0.75,0.83,1,1.25,1.5,1.75,2,3,4,8,12,16,24,48,72,96and168hfollowingthe50mgoraland15mgi.v.doses.17在第二个实验中，在200mg剂量服用之前和服用之后的0.5,1,2,4,6,8,12,16,24,48,72,96,120,144和168小时收集血浆样品。血液被收集在肝素真空管中，然后在相对离心力10000的作用下离心十分钟。血浆被收集起来后转移到螺旋盖冻存管储存在-20℃，然后用色谱法对奈韦拉平进行含量测定。Inthesecondstudyplasmasampleswerecollectedpriortoand0.5,1,2,4,6,8,12,16,24,48,72,96,120,144and168hfollowingthe200mgdoses.Bloodwascollectedinheparinizedevacuatedtubes,whichwerethencentrifugedat10000gfor10min.Aliquotsofplasmawerecollected,transferredtoscrew-topcryotubesandstoredat20°CuntiltheywerechromatographicallyassayedfornevirapineatBoehringerIngelheimPharmaceuticals,Inc.18分析方法

使用高效液相色谱法和紫外检测法(λ=280nm)测定奈韦拉平（相对分子质量266.3）在人体血浆中的含量。定量检测的下限是25ng/mL，上限是10000ng/mL。通过每种分析方法对样品进行分析表明，这种含量检测方法的精确度（%变异系数）和准确度（%偏差）在15%以内。Nevirapine(MW266.3)wasquantitatedinhumanplasmausingahighperformanceliquidchromato-graphic(HPLC)assaywithultraviolet(UV)detection(λ=280nm)[13].Theassaylimitsofquantitationwere25ng:mLand10000ng:mL.Qualitycontrolsamplesanalysedwitheachanalyti-calrundemonstratedthattheassayhadaprecision(%coefficientofvariation(C.V.)andanaccuracy(%bias)within15%.19药代动力学分析

对于口服数据，药代动力学分析是利用数据分析软件SAS6.22版进行的。最高观察浓度值和相关的时间点被定义为峰浓度（Cmax）和达峰时间（Tmax）。检测血药浓度-时间数据的半对数曲线图被用于确定合适的初始数据点（24h），用来推测最终的消除速率常数(λz)。可以利用线性梯形积分法计算奈韦拉平血浆浓度-时间曲线下面的从时间0到最终可计量的浓度时间的区域的面积（AUCt）。FortheoraldatapharmacokineticanalyseswereperformedusingthestatisticalanalysissoftwareprogramSAS®Version6.11(SASInstitute,Cary,NC).Thehighestobservableconcentrationandas-sociatedtimepointweredefinedasthepeakconcentration(Cmax)andtime-to-peakconcentration(Tmax).Semilogarithmicplotsoftheplasmaconcentration–timedatawereexaminedtodeterminetheappropriateinitialdatapoint(24h)forestimatingtheterminaleliminationrateconstant(λz).Theareasunderthenevirapineplasmaconcentration–timecurvefromtimezerotothelastquantifiableconcen-tration(AUCt)werecalculatedusingthelineartrapezoidalrule.20总的AUC可以看成是AUCT和Ct/λz，这里Ct代表最终可计量浓度。另外，还计算了奈韦拉平的一些药代动力学参数表观全身清除率(Cl/F)、末期半衰期（t1/2）、平均停留时间（MRT）、表观分布容积（Vss/F）。绝对生物利用度（F）可以这样计算，标准化给药的AUCoral/AUCi.v.的比率。相对生物利用度（Frel）可以当成相同给药剂量的AUC片剂/AUC溶液的比率来计算。TotalAUCwascalculatedasthesumofAUCTandCt/λz,whereCtrepresentsthelastquantifiableconcentration.Additionally,thepharmacokineticparametersofnevirapineapparentsystemicclearance(Cl/F),terminal-phasehalf-life(t1/2),meanresidencetime(MRT),apparentvolumeofdistribution(Vss/F)werecalculated.Absolutebioavailability(F)wascalculatedasthedose-normalizedratioofAUCoral

dividedbyAUCi.v..Relativebioavailability(Frel)wascalculatedasthesamedoseratioofAUCtabletdividedbyAUCsoln21血管内给药的药代动力学的特点是通过非线性回归分析（SASNLIN）把观察的i.v.浓度数据拟合成一个零级吸收和一级消除的二室模型：

Thepharmacokineticsoftheintravenousdosewerecharacterizedbyfittingatwo-compartmentmodelwithazero-orderinputandfirst-ordereliminationtotheobservedi.v.concentrationdatausingnonlinearregressionanalysis(SASNLIN)：22这里公式(1)中C(t)表示血浆浓度，Ai和αi分别表示二室模型的系数和速度常数，τ在注射时等于时间(τ=t），在注射之后等于注射时间（τ=tinf）。非线性回归分析用到一个浓度的倒数的加权函数（1/Yi1.4)，这里γi是指第i个受试对象的估计浓度。拟合度是通过求加权平方和的最小值来评价的，同时还要检查预测值和残差图的离散度。whereC(t)inEquation(1)representstheplasmaconcentration,Aiandairepresentthecoefficientsandrateconstantsforatwo-compartmentmodel,respectively,andτequalstimeduringtheinfusion(τ=t)andequalstheinfusiontimefollowingtheendofinfusion(τ=tinf).Aninverseconcentrationweightingfunction(1/Yi1.4)wasusedforthenonlinearregressionanalysiswhereγiisthepredictedconcentrationfortheithsubject.Goodnessoffitwasevaluatedbyminimizingtheweightedsumsofsquaresandbyexaminingtherandomnessofscatterofthepredictedvaluesandresidualplots.23我们进行了成对的口服和静脉注射数据的数值解卷积来评价奈韦拉平随着时间吸收的速度和积累的程度。描述任意药物给药和导致的浓度分布曲线图之间的关系的表达由公式（2）解卷积积分给出。Numericaldeconvolutionofthepairedoralandintravenousdatawasperformedtoassesstherateandcumulativeextentofnevirapineabsorptionovertime.Theexpressionthatdescribestherela-tionshipbetweendrugadministrationandthere-sultingconcentrationproanydrugisgivenbytheconvolutionintegralinEquation(2)24这里的C（t）表示观察到的药物浓度，f(t)表示吸收速率，Cδ(t)表示单位脉冲响应，符号“*”表示卷积。假设线性药代动力学和时间变量Cδ(t)代表瞬间注入药物后的药物的药动学处置，Cδ(t)是从静注浓度-时间数据拟合公式（1）得到的静脉注射药动学参数建立的：whereC(t)representstheobserveddrugconcentration,f(t)theinputrate,cδ(t)istheunitimpulseresponse,andthesymbol‘*’denotesconvolution.Assuminglinearpharmacokineticsandtimeinvariancecδ(t)representsthepharmacokineticdispositionofthedrugfollowinginstantaneousinput,andwasconstructedfromthei.v.pharmacokineticparametersderivedbyfittingEquation(1)tothei.v.concentration–timedata:25然后利用PC软件程序PCDCON提供的标准数值解卷积算法以观察的口服浓度数据（C(t)）评估口服吸收速率（f(t)）。Therateoforalabsorption(f(t))wasthenassessedontheobservedoralconcentrationdata(C(t))usingstandardnumericaldeconvolutionalgorithmspro-videdwiththePCsoftwareprogramPCDCON[18].26数据分析

为了评价相对生物利用度，我们对AUC和Cmax的log转化比值进行了误差分析（ANOVA），分析时利用了SAS6.11中的GLM程序。模型考虑了下列误差来源：顺序、嵌入顺序的志愿者、周期和治疗。我们检验了AUC和Cmax的两个片面假设，适用于建立的90%置信区间的片剂和口服参比溶液之间的比率。Forpurposesofevaluatingrelativebioavailability,ananalysisofvariance(ANOVA)wasperformedonthelog-transformedratiosforAUCandCmaxusingtheGLMprocedureinSAS6.11.Thefollowingsourcesofvariationwereaccountedforinthemodel:sequence,subjectsnestedwithinsequence,period,andtreatment.Thetwoone-sidedhypothesis(p=0.05)wastestedforAUCandforCmaxwhereapplicablebyconstructingthe90%confidenceintervalsfortheratiobetweenthetabletformulationsandtheoralreferencesolution.27结果

实验对象

参加绝对生物利用度实验的12名健康成年男性志愿者没有事故全部完成了实验。志愿者的平均年龄是29.8岁（范围是20-49岁）。他们的平均体重是80.6千克（范围是67.7-96.8千克）。没有严重的不良反应的报道，在生命特征和实验试验中也没有重大的临床变化。All12healthyadultmenenrolledintheabsolutebioavailabilitystudycompletedthestudywithoutincident.Subjectsmeanagewas29.8years(range20–49years).Theirmeanbodyweightwas80.6kg(range67.7–96.8kg).Therewerenoreportedseri-ousadverseeventsandnoclinicallyimportantchangesinvitalsignsorlaboratorytests.28有24个成年男性志愿者参加了相对生物利用度的实验。他们的平均年龄和体重分别是26.9岁（范围是18-43岁）和78.5千克（范围是58.8-95.5千克）。十八个志愿者完成了实验。在中断实验的六个人中，有五个是因为实验时间太长退出，一个是因为肝功检查升高而停止。其他人都有很好的耐受性，并且没有严重的不良反应。Fortherelativebioavailabilitystudy,24adultmenwereenrolled.Theirmeanageandweightwere26.9years(range18–43years)and78.5kg(range58.8–95.5kg),respectively.Eighteensubjectscompletedthestudy.Ofthesixsubjectswhodiscontinuedthestudy,fivedroppedoutduetothelengthofthestudyandonewasdiscontinuedduetoanelevationinhisliverfunctiontests.Otherwise,thetreatmentswerewelltoleratedandtherewerenoreportedseriousadverseevents29奈韦拉平的药代动力学和生物利用度

血浆中奈韦拉平静脉注射和口服剂量的浓度-时间曲线图见图2。静脉注射后，平均药代动力学的各项参数见表1。经过37.5分钟的注射后，奈韦拉平的血浆浓度呈双指数下降。平均停留时间（81.4h）、分布和末期半衰期(0.38h对52.8h)表明奈韦拉平在人体内有一个持续很久的药代动力学作用时期。奈韦拉平的全身清除率(1.41L/h)与报道的奈韦拉平作为单一剂量服用的其它单剂量的实验一致。Theplasmaconcentration–timeprofilesofnevirapinei.v.andoraldosingareshowninFigure2.Themeanpharmacokineticdispositionparametersafteri.v.dosingarepresentedinTable1.Followingthe37.5mininfusionnevirapineplasmaconcentrationsdeclinedbiexponentially.Themeanresidencetime(81.4h)anddistributionandterminalphasehalf-lives(0.38hversus52.8h)indicatethatnevirapinehasaprolongedpharmacokineticdispositionphaseinhumans.Nevirapinesystemicclearance(1.41L:h)wasconsistentwithvaluesreportedinothersingledosetrialsinwhichnevirapinewasadministeredasasingledose.30口服50mg片剂和50mg参比溶液后，奈韦拉平的药代动力学参数（MRT和t1/2）与静脉注射后观察到的结果一致(见表二）。口服参比溶液(0.98–1.07%)和片剂的AUC比率的90%置信区间表明这两种形式在吸收程度上是等价的。奈韦拉平绝对生物利用度的点估计值，口服溶液是91%片剂是93%。平均奈韦拉平的生物利用度参数Cmax和Tmax表明奈韦拉平片剂比口服溶液吸收的更快。Thenevirapinepharmacokineticdispositionparameters(MRTandt1/2)followingthe50mgoraltabletand50mgoralreferencesolutionwereconsistentwiththeresultsobservedfollowingthei.v.dose(Table2).The90%confidenceintervalfortheratioofAUCbetweenthetabletcomparedtotheoralreferencesolution(0.98–1.07%)indicatedthatthetwooralformationswereequivalentwithrespecttoextentofabsorption.Thepointestimatesofnevirapineabsolutebioavailabilitywere91%fortheoralsolutionand93%forthetablet.OnaveragethenevirapinebioavailabilityparametersCmaxandTmaxsuggestthatnevirapinewasabsorbedmorerapidlyfromthetabletormulationthanfromtheoralsolution.31通过使用解卷积方法对成对的静脉注射和口服数据对奈韦拉平的口服吸收速率进行评估，这些数据是通过静脉注射的药代动力学参数构建的理论单位脉冲响应(Cδ(t))。积累的口服吸收曲线图见图3。他们表明在服用6小时后奈韦拉平几乎完全被吸收。Assessmentoftherateofnevirapineoralabsorptionwasdonebyapplyingtechniquesofdeconvolutiontothepairedi.v.andoraldatausingthei.v.pharmacokineticparameterstoconstructthetheo-reticalunitimpulseresponse(cδ(t)).ThecumulativeoralabsorptionprofilesareillustratedinFigure3.Theyshowthatnevirapinewasgenerallynearlycompletelyabsorbedwithin6hofdosing.32在给药后最初的48小时期间，在奈韦拉平血浆浓度-时间曲线图上观察到的二次极大值，在图3的吸收曲线图中作为多个振荡出现。然而48小时后，去、解卷积图的斜率没有明显的从零偏离，这表明，奈韦拉平的这两种剂量或是给药途径的药代动力学分布检测不出不同。Thesecondarymaximaobservedinthenevirapineplasmaconcentration–timeprofilesduringtheinitial48hafterdosingappearedasmultipleoscilla-tionsontheabsorptionprofiles(Figure3,inserts).However,after48htheslopesofthedeconvolutionplotsdidnotdeviatemarkedlyfromzero,indicat-ingthattherewasnodetectablediscrepancyinthepharmacokineticdispositionofnevirapinebetweenthetwodosesorroutesofadministration.33口服200mg奈韦拉平片剂和200mg参比溶液的血药浓度-时间曲线图见图2。从24到168小时，奈韦拉平的血浆浓度呈单指数下降，并且末期半衰期为38.4±8.1h。Theplasmaconcentration–timeprofilesofnevi-rapinefollowingthe200mgnevirapinetabletand200mgoralreferencesolutionareshowninFigure2.From24to168hplasmaconcentrationsofnevirapinedeclinedmonoexponentiallywithanappar-entterminalphasehalf-lifeof38.4±8.1h.34使用生物等效性标准，在奈韦拉平溶液和片剂的AUC(119±30对123±29μg·h/L)，峰浓度（2.1±0.4对1.8±0.4μg/mL）和达峰时间（3.0±1.2对3.7±2.0h）上没有明显的不同。总的来说，50mg和200mg剂量的药代动力学参数的比较表明，奈韦拉平的剂量在200mg时能够被很好的吸收Usingthebioequivalencecriteria,therewasnosignificantdifferencebetweenthesolutionandtabletwithrespecttonevirapineAUC(119±30versus123±29μg·h/L）,peakconcentration(2.1±0.4versus1.8±0.4μg/mL)orTmax(3.01±1.2versus3.7±2.0h).Over-all,comparisonofthepharmacokineticparametersbetweenthe50and200mgdosesindicatesthatnevirapineiswellabsorbedatthe200mgdose.35结论

绝对和相对生物利用度的研究结果证明，口服50mg和200mg剂量的奈韦拉平能够被很好的吸收。静脉注射给药，奈韦拉平表现出低的全身清除率(1.41L/h)和比全身体液总量都大的表观分布容积(108L)，这表明奈韦拉平广泛的分布到血管外组织。一个单独的研究表明奈韦拉平通过血脑屏障到达脑髓液中的浓度与血浆中未结合的浓度相等（血浆蛋白的结合浓度是60%）。Theresultsoftheabsoluteandrelativebioavailabilitystudiesdemonstratethatnevirapineiswellabsorbedfollowingoraladministrationof50and200mgdoses.Followingi.v.administration,nevirapineexhibitedalowsystemicclearance(1.41L:h)andasteady-statevolumeofdistribution(108L)largerthantotalbodywaterindicatingthatnevirapinedistributesextensivelyintoextravasculartissues.Inaseparatestudynevirapinealsohasbeenshowntocrosstheblood–brainbarrierachievingconcentrationsincerebrospinalfluid(CSF)thatareequivalenttounboundconcentrationsinplasma(plasmaproteinbinding60%)36绝对生物利用度（F~90%）和药代动力学参数(MRT,t1/2)表明奈韦拉平口服吸收好，并且在人体内的作用时间长。假设肝的血流量（QH）是90L/h并且忽略了原药的肾清除率，估算的奈韦拉平的肝提取率(ER=1-F)大约是0.1L/h，奈韦拉平的肝脏血液清除率（ClH=QH·ER）大约是9L/h。Theabsolutebioavailability(F~90%)andpharmacokineticdispositionparameters(MRT,t1/2)indicatethatnevirapineiswellabsorbedorallyandhasaprolongeddispositionphaseinhumans.Assuminganhepaticbloodflow(QH)of90L/handnegligiblerenalclearanceofparentdrug[8,9],theestimatedhepaticextractionratio(ER=1-F)ofnevirapineisapproximately0.1L/h,andthehepaticbloodclearance(ClH=QH·ER)ofnevirapineisapproximately9L/h.37这些数据表明奈韦拉平是一种低清除率的药物，推测甚至在酶诱导的情况下，我们能够观察到全身清除率明显的增加两倍。

因为奈韦拉平吸收迅速并且药代动力学作用时间长，因此实验中血浆的取样时间特别选择了在口服吸收时大量的数据点。Thesedataindicatethatnevirapineisalowclearancedrug,presumablyevenunderconditionsofenzymeinductionwhereina2-foldincreaseinapparentsystemicclearancehasbeenobserved.Becauseofnevirapine’srapidabsorptionandprolongedpharmacokineticdispositionphase,theplasmasamplingtimesinthisstudywerechosenspecificallytogivealargernumberofdatapointsoverthetimeperiodoforalabsorption.38片剂和口服溶液的累加吸收曲线和估算的绝对生物利用度的相似性表明片剂的生物利用度对病人来说是存在的。早期研究证明奈韦拉平能够与食物、抗酸药和地达诺新（由一种碱性缓冲液制成）同服，而在生物利用度上却没有显著变化。Thesimilarityofthecumulativeabsorptionprofilesandestimatesofabsolutebioavailabilitybetweenthetabletsandoralsolutionsuggestthatbioavailabilityfromthetabletshouldnotbeaproblemforpatients.Earlierstudieshavedemonstratedthatnevirapinecanbeadministeredwithfood,antacid[19],ordidanosine[20],whichisformulatedwithanalkalinebuffer,withoutanysignificantchangeinbioavailability.39对任何受试者来说，在吸收阶段的第二个极大值与生物利用度的下降无关，也不是只有片剂或是液体制剂有。在第24小时的二次极大值不只是液体制剂和片剂（50mg和200mg）有，静脉注射中也能观察到。通常，次级峰值的可能机制包括：两相溶解、胃排空、特定位点的吸收、肝肠循环和其它生理现象。Thesecondarymaximaduringtheabsorptionphasewerenotassociatedwithafall-offinbioavailabilityforanyofthesubjects,andwerenotuniquetoeitherthetableto