單劑量的奈韋拉平

1、單劑量的奈韋拉平第1頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二摘要：兩個隨機(jī)、單劑量、交叉的生物利用度的研究結(jié)果，描述了奈韋拉平（是一種新型的非核苷抗逆轉(zhuǎn)錄病毒的藥物）的藥代動力學(xué)和口服生物利用度。 ABSTRACT: The results of two randomized, single-dose, crossover bioavailability studies are presented which describe the pharmacokinetics and oral bioavailability of nevirapine, a novel nonnucl

2、eoside antiretroviral drug. 第2頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二在第一個研究中，向12名健康男性志愿者體內(nèi)短期靜脈注射15mg奈韋拉平，或者口服50mg的片劑，或者口服參比溶液（50 mg/200 mL）。靜脈注射完之后，奈韋拉平有一個較低的全身清除率(MeanS.D., Cl=1.40.3 L/h)和一個延長的消除相(t1/2=52.814.8 h; MRT =81.422.4 h). 。 In the first study 12 healthy male volunteers received nevirapine 15 mg via

3、short-term i.v. infusion or orally as a 50 mg tablet or reference solution (50 mg :200 mL). Following the i.v. dose,nevirapine had a low systemic clearance (MeanS.D., Cl=1.40.3 L/h) and a prolonged elimination phase (t1/2=52.814.8 h; MRT =81.422.4 h). 第3頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二奈韋拉平的絕對生物利用度分別為：注射

4、劑是939%，片劑和口服溶液是918%。在第二個研究中，24名健康男性志愿者服用200mg片劑奈韋拉平或者口服參比溶液（200 mg/200mL）。片劑和參比溶液的生物利用度沒有顯著的不同。 Nevirapine absolute bioavailability was 939% and918% for the tablet and oral solution, respectively. In the second study, 24 healthy male volunteers wereadministered nevirapine as a 200 mg production-line

5、 tablet or oral reference solution (200 mg/200 mL).There was no significant difference in bioavailability between the tablet and reference solution. 第4頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二總之，對50mg和200mg劑量的藥代動力學(xué)參數(shù)進(jìn)行比較，結(jié)果顯示，服用臨床相關(guān)劑量的奈韋拉平能夠被很好的吸收。使用解卷積法得到的吸收曲線表明，這兩種劑量或是每種劑量的給藥途徑?jīng)]有由特定的酶誘導(dǎo)。Overall,comparison of t

6、he pharmacokinetic parameters between the 50 and 200 mg doses indicates that nevirapine is well absorbed at clinically relevant doses. The absorption profiles using deconvolution revealed no evidence of differential enzyme induction between the two doses or routes of administration following a singl

7、e dose. 第5頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二介紹：奈韋拉平的結(jié)構(gòu)是二吡啶并二氮雜卓酮（如圖），它是第一類適用于治療人類免疫缺陷病毒（HIV）的非核甘類逆轉(zhuǎn)錄酶抑制劑。在細(xì)胞培養(yǎng)中，奈韋拉平通過與逆轉(zhuǎn)錄酶直接連接，抑制RNA依賴和DNA依賴的聚合酶活性。 Nevirapine, a dipyridodiaqepinone (Figure 1), was the first drug of the nonnucleoside reverse tran-scriptase inhibitor (NNRTIs) class to be approved for trea

8、ting the human immunodeficiency virus (HIV) infection in humans. By binding directly to reverse transcriptase, nevirapine inhibits the RNA-dependent and DNA-dependent polymerase activi-ties in cell culture第6頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二在臨床試驗(yàn)中，當(dāng)奈韋拉平與核苷類和蛋白酶類藥物用于聯(lián)合治療時，能夠證明奈韋拉平是強(qiáng)效的、持久的抗病毒藥物。In clinical

9、trials, nevirapine has demonstrated potent and sustained antiviral activity when used in triple combination therapy with drugs of the nucleoside and protease inhibitor classes 第7頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二口服給藥后，人體能夠迅速的吸收奈韋拉平達(dá)到400mg。服用200mg劑量的奈韋拉平，給藥4小時后，血漿濃度峰值達(dá)到大約2g/mL，盡管之后多重峰的次級峰值濃度也能被監(jiān)測出。劑量達(dá)到200m

10、g時，血藥濃度-時間曲線下面積和最大濃度呈線性關(guān)系。 In humans, nevirapine appears to be readily ab-sorbed following oral administration of doses up to 400 mg 7,8. Following a single 200 mg dose nevi-rapine peak plasma concentrations of approxi-mately 2g/mL are achieved by 4 h postdose,although subsequent multiple secondary

11、peak concentrations are also observed. Area under the plasma concentration time curve (AUC) and Cmax both exhibit dose linearity at doses up to 200 mg.第8頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二奈韋拉平的藥代動力學(xué)特征是服用單一劑量后，有持續(xù)很長時間的藥代動力學(xué)作用時期(t1/245h）奈韋拉平經(jīng)過P450酶的代謝形成羥基葡糖苷酸它作為無活性代謝物主要被排泄到尿中。單劑量中不到3%作為原藥排到尿中。 The pharmacoki

12、netics of nevirapine are also charac-terized by a prolonged pharmacokinetic dispositionphase (t1/245h)following a single dose. Nevirap-ine undergoes extensive P450 metabolism to hydroxylated glucuronides, which are largely excreted into the urine as inactive metabolites. Less than 3% of a dose is ex

13、creted in urine as parent compound. 第9頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二加倍劑量的藥代動力學(xué)特征是，當(dāng)從單劑量到200mg/day或更高劑量持續(xù)治療兩周時，細(xì)胞色素P450同工酶3A (CYP3A) 和 2B6 (CYP2B6)代謝的自身誘導(dǎo)，導(dǎo)致全身清除率明顯增加1.5-2倍。自身誘導(dǎo)也會導(dǎo)致奈韋拉平末期半衰期的減少，使其在血漿中從單一劑量的45小時減少到多劑量的25-30小時。 The multiple dose pharmacokinetics are charac-terized by metabolic autoinduct

14、ion of cytochrome P450 isozymes 3A (CYP3A) and 2B6 (CYP2B6) re-sulting in a 1.5- to 2-fold increase in nevirapine apparent systemic clearance as treatment continues from a single dose to 2 weeks of dosing with 200mg/day or higher 8. Autoinduction also results ina decrease in the nevirapine terminal

15、phase half-life in plasma from 45 h following a single dose to 25 30 h with multiple dosing.第10頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二憑借它的弱堿性和電離(pKa=2.8)，奈韋拉平的溶解度與PH相關(guān)。當(dāng)PH值小于酸度系數(shù)時，奈韋拉平在緩沖溶液中的溶解度很高。隨著PH值的升高，奈韋拉平自由堿在水中的溶解度會逐漸降低到0.1 mg/mL。盡管奈韋拉平口服容易吸收，但是尤其是服用50mg或是更高的劑量時，顯示溶解度限制了吸收的速率（延遲了到達(dá)峰值的時間，加倍了峰值濃度），并且生物利用度也

16、有稍微的下降。 By virtue of its weakly basic character and ionization (pKa=2.8)nevirapine exhibits pH dependent solubility. At pH values less than the pKa nevirapine is highly soluble in aqueous buffer. At higher pH values nevirapine free-base solubility in water decreases asymptotically to approximately.

17、0.1 mg :mL. Although the drug appears to be readily absorbed orally, nevirapine, particularly at doses of 50 mg and higher, exhibits characteristics of solubil-ity rate-limited absorption (delayed time-to-peak,multiple peak concentrations) and a slight fall-off in bioavailability.第11頁，共45頁，2022年，5月2

18、0日，2點(diǎn)14分，星期二本文描述了兩個研究的結(jié)果，這兩個研究旨在表明奈韋拉平在人體內(nèi)絕對和相對生物利用度的特征。在這兩個研究中，將片劑和口服參比溶液作比較，確定是否是藥物的劑型或是物理特性或是兩者皆有，導(dǎo)致了奈韋拉平在吸收的速率或程度上有所不同。另外，由于長時間的藥代動力學(xué)作用時期和假設(shè)在不同的靜脈注射和口服劑量之間藥代動力學(xué)的線性關(guān)系，我們利用解卷積法來更好的評價奈韋拉平的口服吸收特性。 This report describes the results of two studies aimed at characterizing the absolute and relative bioa

19、vailability of nevirapine in humans. In both studies a tablet formulation was compared to an oral reference solution to determine whether any differences in the rate or extent of nevirapine ab-sorption could be attributed to either the formula-tion or the physical characteristics of the drug, or bot

20、h. Additionally, because of the prolonged phar-macokinetic disposition phase and the assumption of pharmacokinetic linearity between different i.v.and oral doses, deconvolution was utilized to fur-ther assess the characteristics of nevirapine oral absorption.第12頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二實(shí)驗(yàn)對象和方法這兩個

21、研究都是在Quintiles公司進(jìn)行的（以前在Innovex公司），每一個研究用的納入與排除的標(biāo)準(zhǔn)都一樣。實(shí)驗(yàn)對象是不吸煙的健康的男性志愿者，年齡范圍是從18歲到50歲。在研究過程中，志愿者不能服用其他藥物，要戒除煙草制品、酒精、含咖啡因的飲料。要求志愿者的身高體重比在大城市人壽保險(xiǎn)公司表定義的正常范圍內(nèi)占10%。志愿者是由相當(dāng)好的健康狀況決定的，它包括病史、外部身體檢查和實(shí)驗(yàn)室檢查（血液學(xué)、血液化學(xué)和尿液分析）。 Both studies were conducted at Quintiles, Inc. (for-merly Innovex, Inc.), Lenexa, KS, USA.

22、 The same inclusion and exclusion criteria were used for each study. Subjects were nonsmoking, healthy male vol-unteers, ranging in age from 18 to 50 years. No concomitant medications were allowed and subjects were required to abstain from tobacco products,alcohol or caffeine containing beverages du

23、ring the study. Subjects were required to have a height:weight ratio within 10% of normal as definedby the Metropolitan Life Insurance Company Ta-bles. Subjects were determined to be in reasonably good health based on medical history, physical ex-amination and a laboratory screen (hematology, blood

24、chemistry and urinalysis)第13頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二試驗(yàn)設(shè)計(jì)第一個研究通過服用片劑和參比溶液與靜脈注射顯示的(血藥濃度時間)曲線下面積作比較，評估奈韋拉平的絕對生物利用度。這個實(shí)驗(yàn)根據(jù)一個公開的、單一劑量、隨機(jī)的對12個健康的男性志愿者進(jìn)行交叉實(shí)驗(yàn)。在進(jìn)行藥代動力學(xué)實(shí)驗(yàn)之前，我們在另一個實(shí)驗(yàn)中評估了12個志愿者（三個志愿者每劑量水平加上四倍的安慰劑）對三種靜脈注射劑量（5、15和30mg）的奈韋拉平的安全性和耐藥性。 The first study was designed to assess the absolute bioavai

25、lability of nevirapine from tablets and an oral reference solution by comparison of the extent of systemic exposure to the AUC from an intra-venous dose. The study was conducted according to an open label, single dose, randomized, crossover design in 12 healthy male volunteers. Before the pharmacoki

26、netic study, the safety and tolerance of three i.v. doses (5, 15 and 30 mg) of nevirapine were assessed in 12 subjects (three subjects per dose level plus four placebos) in a separate study. 第14頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二因?yàn)榻邮?0mg劑量的志愿者有關(guān)節(jié)痛、頭疼等癥狀，并且增加的肝功能檢測表明，這些癥狀很可能由試驗(yàn)藥物導(dǎo)致的，因此在目前的實(shí)驗(yàn)中，確定15mg是使用靜脈注射的

27、最高耐受劑量。為了確定奈韋拉平的絕對生物利用度，十二個志愿者接收單一劑量的奈韋拉平，分別是靜脈注射15mg，口服片劑50mg，口服溶液50mg。片劑用250mL的水送服，口服溶液（在1.5%的檸檬酸水溶液中每200mL含50mg奈韋拉平，PH3）用50mL水送服，靜脈注射是通過手臂表面靜脈注射37.5分鐘（15 mg/18.75 mL）。不同的劑量由兩周的清除時間分隔開。Because one of subjects receiving the 30 mg dose experience symptoms (e.g. arthralgia, headache) and increased li

28、ver function tests that were possibly attributed to the study drug, it was determined that 15 mg wasthe highest tolerable i.v. dose for use in the present study. For determination of absolute nevirapine bioavailability 12 subjects received single doses ofnevirapine as an intravenous injection (15mg)

29、, an oral tablet (50 mg), and an oral solution (50 mg).The tablet was administered with 250 mL of water,the oral solution (50 mg in 200 mL of 1.5% citric acid aqueous solution, pH B3) with 50 mL of water,and the i.v. injection was administered in a periph-eral arm vein as an i.v. infusion (15 mg :18

30、.75 mL)over 37.5 min. Doses were separated by a 2-week washout period.第15頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二在奈韋拉平的臨床研究中進(jìn)行的第二個實(shí)驗(yàn)，設(shè)計(jì)用來對200mg的片劑奈韋拉平與200mg的參比溶液的口服生物利用度進(jìn)行比較，作為維樂命注冊要求的一部分。這是一個在24個成年男性志愿者中進(jìn)行的隨機(jī)的、單一劑量的交叉實(shí)驗(yàn)。志愿者用250mL水送服一片200mg的奈韋拉平（在商業(yè)批量的條件下生產(chǎn)），50mL水送服參比溶液（每200mL3%檸檬酸水溶液中含奈韋拉平200mg，PH3）。24個志愿者中18個

31、完成了實(shí)驗(yàn)。不同的劑量由三周的清除時間分隔開。The second study, occurring later in the clinical development of nevirapine, was designed to assess the oral bioavailability of nevirapine 200 mg tablets compared to a 200 mg oral reference solution as part of the registration requirements for Viramune.This was a randomized, s

32、ingle dose, crossover study in 24 adult male volunteers. Subjects wereadministered nevirapine as a 200 mg tablet (manu-factured under commercial batch conditions) with 250 mL of water and as an oral reference solution(200 mg in 200 mL of 3% citric acid aqueous solu-tion, pH B3) with 50 mL of water.

33、Eighteen of the 24 enrolled subjects completed the study. Doses were separated by a 3-week washout period.第16頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二過程每種單一劑量都前一天晚上十點(diǎn)快速開始，服藥后持續(xù)四小時，奈韋拉平大約在早上八點(diǎn)給藥。在口服50mg劑量和靜脈注射15mg劑量奈韋拉平五分鐘之后開始計(jì)時，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

34、, 96和168小時的時候，抽取一系列用于藥代動力學(xué)分析的靜脈血樣。 Each single dose was preceded by an overnight fastbeginning at 22:00 h and lasting until 4 h after dosing. Nevirapine was administered at approxi-mately 08:00 h. Serial sampling of venous blood(5 mL) for pharmacokinetic analysis was done 5 min before (0 h) and at 0

35、.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, 96and 168 h following the 50 mg oral and 15 mg i.v.doses. 第17頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二在第二個實(shí)驗(yàn)中，在200mg劑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小時收集血漿樣品。血液被收集在肝素真空管中，然后在相對離心力10000的作用下離心十分

36、鐘。血漿被收集起來后轉(zhuǎn)移到螺旋蓋凍存管儲存在-20，然后用色譜法對奈韋拉平進(jìn)行含量測定。In the second study plasma samples were collected prior to and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, 96, 120, 144 and 168 h following the 200 mg doses. Blood was collected in heparinized evacuated tubes, which were then centrifuged at 10 000g for 10 min.

37、 Aliquots of plasma were collected, transferred to screw-top cryotubes and stored at 20C until they were chromatographically assayed for nevirapine at Boehringer Ingelheim Pharmaceuticals, Inc.第18頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二分析方法使用高效液相色譜法和紫外檢測法(=280 nm)測定奈韋拉平（相對分子質(zhì)量266.3）在人體血漿中的含量。定量檢測的下限是25 ng/mL，上限

38、是10000 ng/mL。通過每種分析方法對樣品進(jìn)行分析表明，這種含量檢測方法的精確度（%變異系數(shù)）和準(zhǔn)確度（%偏差）在15%以內(nèi)。Nevirapine (MW 266.3) was quantitated in human plasma using a high performance liquid chromato-graphic (HPLC) assay with ultraviolet (UV) detection (=280 nm) 13. The assay limits of quantitation were 25 ng :mL and 10 000 ng:mL.Quality

39、 control samples analysed with each analyti-cal run demonstrated that the assay had a precision(% coefficient of variation (C.V.) and an accuracy(% bias) within 15%.第19頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二藥代動力學(xué)分析 對于口服數(shù)據(jù)，藥代動力學(xué)分析是利用數(shù)據(jù)分析軟件SAS6.22版進(jìn)行的。最高觀察濃度值和相關(guān)的時間點(diǎn)被定義為峰濃度（Cmax）和達(dá)峰時間（Tmax）。檢測血藥濃度-時間數(shù)據(jù)的半對數(shù)曲線圖被用于確

40、定合適的初始數(shù)據(jù)點(diǎn)（24h），用來推測最終的消除速率常數(shù)(z)?？梢岳镁€性梯形積分法計(jì)算奈韋拉平血漿濃度-時間曲線下面的從時間0到最終可計(jì)量的濃度時間的區(qū)域的面積（AUCt）。 For the oral data pharmacokinetic analyses were performed using the statistical analysis software program SASVersion 6.11 (SAS Institute, Cary,NC). The highest observable concentration and as-sociated time poin

41、t were defined as the peak concentration ( Cmax) and time-to-peak concentration(Tmax). Semilogarithmic plots of the plasma concentration time data were examined to determine the appropriate initial data point (24 h) for estimating the terminal elimination rate constant (z). The areas under the nevir

42、apine plasma concentration time curve from time zero to the last quantifiable concen-tration (AUCt) were calculated using the linear trapezoidal rule. 第20頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二總的AUC可以看成是AUCT和Ct/z，這里Ct代表最終可計(jì)量濃度。另外，還計(jì)算了奈韋拉平的一些藥代動力學(xué)參數(shù)表觀全身清除率(Cl/F)、末期半衰期（t1/2）、平均停留時間（MRT）、表觀分布容積（Vss/F）。絕對生物利用度（F）可

43、以這樣計(jì)算，標(biāo)準(zhǔn)化給藥的AUCoral/AUCi.v.的比率。相對生物利用度（Frel）可以當(dāng)成相同給藥劑量的AUC片劑/AUC溶液的比率來計(jì)算。Total AUC was calculated as the sum of AUCTand Ct/z, where Ct represents the last quantifiable concentration. Additionally, the pharmacokinetic parameters of nevirapine apparent systemic clearance(Cl/F ), terminal-phase half-li

44、fe (t1/2),mean residence time (MRT), apparent volume of distribution (Vss/F ) were calculated . Absolute bioavailability (F ) was calculated as the dose-normalized ratio of AUCoral divided by AUCi.v. Relative bioavailability (Frel) was calculated as the same dose ratio of AUC tablet divided by AUC s

45、oln第21頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二血管內(nèi)給藥的藥代動力學(xué)的特點(diǎn)是通過非線性回歸分析（SAS NLIN）把觀察的i.v.濃度數(shù)據(jù)擬合成一個零級吸收和一級消除的二室模型：The pharmacokinetics of the intravenous dose were characterized by fitting a two-compartmentmodel with a zero-order input and first-order elimination to the observed i.v. concentration data using nonl

46、inear regression analysis (SAS NLIN)：第22頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二這里公式(1)中C(t)表示血漿濃度，Ai和i分別表示二室模型的系數(shù)和速度常數(shù)，在注射時等于時間(=t），在注射之后等于注射時間（=tinf）。非線性回歸分析用到一個濃度的倒數(shù)的加權(quán)函數(shù)（1/Yi1.4)，這里i是指第i個受試對象的估計(jì)濃度。擬合度是通過求加權(quán)平方和的最小值來評價的，同時還要檢查預(yù)測值和殘差圖的離散度。where C (t ) in Equation (1) represents the plasma concentration, Ai and

47、 ai represent the coefficients and rate constants for a two-compartment model, respectively, and equals time during the infusion(=t ) and equals the infusion time following the end of infusion (=tinf). An inverse concentration weighting function (1/Yi1.4) was used for the nonlinear regression analys

48、is where i is the predicted concentration for the ith subject. Goodness of fit was evaluated by minimizing the weighted sums of squares and by examining the randomness of scatter of the predicted values and residual plots.第23頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二我們進(jìn)行了成對的口服和靜脈注射數(shù)據(jù)的數(shù)值解卷積來評價奈韋拉平隨著時間吸收的速度和積累的程度。描

49、述任意藥物給藥和導(dǎo)致的濃度分布曲線圖之間的關(guān)系的表達(dá)由公式（2）解卷積積分給出。 Numerical deconvolution of the paired oral and intravenous data was performed to assess the rate and cumulative extent of nevirapine absorption over time. The expression that describes the rela-tionship between drug administration and the re-sulting concentra

50、tion profile for any drug is given by the convolution integral in Equation (2)第24頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二這里的C（t）表示觀察到的藥物濃度，f(t)表示吸收速率，C(t)表示單位脈沖響應(yīng)，符號“*”表示卷積。假設(shè)線性藥代動力學(xué)和時間變量C(t)代表瞬間注入藥物后的藥物的藥動學(xué)處置，C(t)是從靜注濃度-時間數(shù)據(jù)擬合公式（1）得到的靜脈注射藥動學(xué)參數(shù)建立的： where C (t ) represents the observed drug concentration, f (t )

51、 the input rate, c (t ) is the unit impulse response, and the symbol * denotes convolution. Assuming linear pharmacokinetics and time invariance c (t ) represents the pharmacokinetic disposition of the drug following instantaneous input, and was constructed from the i.v. pharmacokinetic parameters d

52、erived by fitting Equation (1) to the i.v.concentration time data:第25頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二然后利用PC軟件程序PCDCON提供的標(biāo)準(zhǔn)數(shù)值解卷積算法以觀察的口服濃度數(shù)據(jù)（C(t)）評估口服吸收速率（f(t)）。The rate of oral absorption ( f (t ) was then assessed on the observed oral concentration data (C (t ) using standard numerical deconvolution al

53、gorithms pro-vided with the PC software program PCDCON 18.第26頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二數(shù)據(jù)分析為了評價相對生物利用度，我們對AUC和Cmax的log轉(zhuǎn)化比值進(jìn)行了誤差分析（ANOVA），分析時利用了SAS6.11中的GLM程序。模型考慮了下列誤差來源：順序、嵌入順序的志愿者、周期和治療。我們檢驗(yàn)了AUC和Cmax的兩個片面假設(shè)，適用于建立的90%置信區(qū)間的片劑和口服參比溶液之間的比率。For purposes of evaluating relative bioavailability,an analy

54、sis of variance (ANOVA) was performed on the log-transformed ratios for AUC and Cmax using the GLM procedure in SAS 6.11. The following sources of variation were accounted for in the model: sequence, subjects nested within sequence, period, and treatment. The two one-sided hypothesis (p=0.05) was te

55、sted for AUC and for Cmax where applicable by constructing the 90% confidence intervals for the ratio between the tablet formulations and the oral reference solution.第27頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二結(jié)果實(shí)驗(yàn)對象參加絕對生物利用度實(shí)驗(yàn)的12名健康成年男性志愿者沒有事故全部完成了實(shí)驗(yàn)。志愿者的平均年齡是29.8歲（范圍是20-49歲）。他們的平均體重是80.6千克（范圍是千克）。沒有嚴(yán)重的不良反應(yīng)的報(bào)道，

56、在生命特征和實(shí)驗(yàn)試驗(yàn)中也沒有重大的臨床變化。 All 12 healthy adult men enrolled in the absolute bioavailability study completed the study without incident. Subjects mean age was 29.8 years (range20 49 years). Their mean body weight was 80.6 kg(range 67.7 96.8 kg). There were no reported seri-ous adverse events and no clin

57、ically important changes in vital signs or laboratory tests. 第28頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二有24個成年男性志愿者參加了相對生物利用度的實(shí)驗(yàn)。他們的平均年齡和體重分別是26.9歲（范圍是18-43歲）和78.5千克（范圍是千克）。十八個志愿者完成了實(shí)驗(yàn)。在中斷實(shí)驗(yàn)的六個人中，有五個是因?yàn)閷?shí)驗(yàn)時間太長退出，一個是因?yàn)楦喂z查升高而停止。其他人都有很好的耐受性，并且沒有嚴(yán)重的不良反應(yīng)。For the relative bioavailability study, 24 adult men were enro

58、lled. Their mean age and weight were 26.9 years (range 18 43 years) and 78.5 kg (range 58.8 95.5 kg), respectively. Eighteen subjects completed the study. Of the six subjects who discontinued the study, five dropped out due to the length of the study and one was discontinued due to an elevation in h

59、is liver function tests. Otherwise, the treatments were well tolerated and there were no reported serious adverse events第29頁，共45頁，2022年，5月20日，2點(diǎn)14分，星期二奈韋拉平的藥代動力學(xué)和生物利用度血漿中奈韋拉平靜脈注射和口服劑量的濃度-時間曲線圖見圖2。靜脈注射后，平均藥代動力學(xué)的各項(xiàng)參數(shù)見表1。經(jīng)過37.5分鐘的注射后，奈韋拉平的血漿濃度呈雙指數(shù)下降。平均停留時間（81.4h）、分布和末期半衰期(0.38 h對52.8 h)表明奈韋拉平在人體內(nèi)有一個持續(xù)很

60、久的藥代動力學(xué)作用時期。奈韋拉平的全身清除率(1.41 L/h)與報(bào)道的奈韋拉平作為單一劑量服用的其它單劑量的實(shí)驗(yàn)一致。 The plasma concentration time profiles of nevirapine i.v. and oral dosing are shown in Figure 2. The mean pharmacokinetic disposition parameters afteri.v. dosing are presented in Table 1. Following the 37.5 min infusion nevirapine plasma c