奥昔布宁缓释胶囊与普通片的药动学及生物等效性

目的 研究健康志愿者单剂量和多剂量口服奥昔布宁缓释胶囊后的药动学特征,并评价奥昔布宁缓释胶囊与奥昔布宁普通片是否生物等效,为临床合理用药提供参考依据.方法 20名健康志愿者分别单剂量、多剂量口服试验缓释胶囊和参比普通片剂,于规定时间点取血,以LC-MS联用法测定奥昔布宁血药浓度,采用3P97软件计算各制剂单剂量和多剂量给药后的药动学参数.结果 单剂量给药,奥昔布宁缓释胶囊和普通片的ρmax分别为(8.27±7.28)μg·L-1和(17.16±12.17)μg·L-1;tmax分别为(2.55±0.85)h和(0.82±0.35)h;t1/2分别为(6.23±2.78)h和(5.54±2.18)h;AUC0→t分别为(51.94±40.27)μg·h·L-1和(49.8±434.33)μg·h·L-1;AUC0→∞.分别为(57.25±40.78)μg·h·L-1和(54.68±36.44)μg·h·L-1.奥昔布宁缓释胶囊相对于普通片生物利用度F0→1为(104.15±15.47)%.多剂量给药,奥昔布宁缓释胶囊和普通片的ρss max分别为(24.00±10.41)μg·L-1和(15.37±8.00)μg·L-1;ρss min分别为(1.59±0.80)μg·L-1和(1.33±0.80)μg‘L-1;ρss av分别为(5.01±2.22)μg·L-1和(2.49±1.17)μg·L-1;AUCss分别为(120.19±53.24)μg·h·L-1和(59.85±28.01)μg·h·L-1;DF分别为(446.23±135.27)%和(579.75±148.10)%;奥昔布宁缓释胶囊波动度明显小于普通片.结论 试验制剂具有缓释作用.试验制剂与参比制剂的ρmax生物不等效,但AUC0→t生物等效.     

阿斯达莫缓释胶囊的人体生物等效性研究

目的比较阿斯达莫缓释胶囊在20名健康志愿者体内的药动学特征及相对生物利用度,评价其生物等效性.方法 20名健康男性志愿者采用随机交叉给药方案.单剂量试验中分别口服受试制剂--阿斯达莫缓释胶囊2粒(每粒含双嘧达莫100 mg和阿司匹林12.5 mg)或参比制剂--双嘧达莫片8片(25 mg·片-1)及阿司匹林肠溶片1片(25 mg·片-1).多剂量试验中,分别口服试验制剂阿斯达莫缓释胶囊,2次·d-1,1粒·次-1和参比制剂双嘧达莫片,3次·d-1,2片·次-1,连服5 d.采用高效液相色谱-质谱联用的方法测定双嘧达莫及水杨酸的血药浓度,计算两者的药物动力学参数,评价生物等效性.结果单剂量试验,受试制剂及参比制剂中水杨酸和双嘧达莫的药物动力学参数经统计学分析,两制剂生物等效.多剂量试验,受试制剂及参比制剂中双嘧达莫的药物动力学参数经折算后进行统计学分析,结果表明试验制剂Cmax、Cmin、Css、DF均符合缓释特点.结论口服试验制剂阿斯达莫缓释胶囊剂2次·d-1,与口服等剂量市售双嘧达莫普通片以及阿司匹林肠溶片3次·d-1,具有生物等效性.     

头孢克洛缓释片的研制及人体药物动力学研究

以HPMC为阻滞剂制备头孢克洛缓释片,并测定体外释放度和人体内血药浓度.结果表明,单剂量口服375mg头孢克洛自制缓释片和参比制剂(商品名Ceclor CD)后的tmax、Cmax、AUCo-τ和MRT分别为(1.42±0.20)和(1.25±0.27)h、(3.58±0.30)和(3.42±0.28)μg/ml、(12.31±1.8)和(11.65±1.26)μg·h·ml-1、(2.77±0.27)和(2.66±0.23)h.统计结果显示,AUC0-τ无显著性差异(P＞0.05),表明两制剂生物等效.     

盐酸二甲双胍片生物等效性及药物动力学研究

采用随机交叉、自身对照实验设计,比较了两种盐酸二甲双胍片在18名健康男性受试者体内的药动学情况.血药浓度采用高效液相色谱法测定.方差分析结果表明,两者主要药动学参数无显著差别,双单侧t检验表明两者生物等效.     

Confidence Interval Criteria for Assessment of Dose Proportionality

Purpose. The aim of this work was a pragmatic, statistically sound and clinically relevant approach to dose-proportionality analyses that is compatible with common study designs. Methods. Statistical estimation is used to derive a (1-)% confidence interval (CI) for the ratio of dose-normalized, geometric mean values (R_dnm) of a pharmacokinetic variable (PK). An acceptance interval for R_dnm defining the clinically relevant, dose-proportional region is established a priori. Proportionality is declared if the CI for R_dnm is completely contained within the critical region. The approach is illustrated with mixed-effects models based on a power function of the form PK = ₀ Dose¹; however, the logic holds for other functional forms. Results. It was observed that the dose-proportional region delineated by a power model depends only on the dose ratio. Furthermore, a dose ratio (₁) can be calculated such that the CI lies entirely within the pre-specified critical region. A larger ratio (₂) may exist such that the CI lies completely outside that region. The approach supports inferences about the PK response that are not constrained to the exact dose levels studied. Conclusion. The proposed method enhances the information from a clinical dose-proportionality study and helps to standardize decision rules.     

The Role of Metabolites in Bioequivalency Assessment. III. Highly Variable Drugs with Linear Kinetics and First-Pass Effect

Purpose. Simulated pharmacokinetic (PK) studies were done to determine the effect of intrinsic clearance (CL_INT) on the probability of meeting bioequivalence criteria for extent (AUC) and rate (Cmax) of drug absorption when the absorption rate and fraction absorbed (F) were formulated either to be equivalent or to differ by 25%. Methods. Simulated PK studies were done using a linear first-pass model with CL_INT values ranging from 15 L/HR to 900 L/HR. Test/Reference absorption rate constants (Ka) and fraction absorbed (Fa) ratios of 1.0 or 1.25 were used for all simulations. The impact of the value of CL_INT and its intrasubject variation upon the probability of concluding bioequivalence at the two different Ka and F ratios was studied. Additionally, the effect of fraction metabolized i.v., (Fm) on the probabilities of concluding equivalence was studied at values of 0.25 and 0.75. Results. When CL_INT values were raised above those for liver blood flow, the frequency of trials in which bioequivalence was correctly declared decreased when parent AUC was used as a bioequivalence criterion. Only when CL_INT exceeded liver blood flow did the metabolite become important in assessing extent of absorption. Conclusions. The Cmax for the parent drug provided the most accurate assessment of bioequivalence. The Cmax for the metabolite was insensitive to changes related to rate of input, and when CL_INT exceeded liver blood flow, evaluation of the metabolite Cmax data may lead to a conclusion of bioequivalence for products that were not.     

Pharmacokinetics and bioequivalence of a combined oral formulation of eniluracil, an inactivator of dihydropyrimidine dehydrogenase, and 5-fluorouracil in patients with advanced solid malignancies

Background:This study was performed to evaluate thepharmacokinetics, bioequivalence, and feasibility of a combined oralformulation of 5-flurouracil (5-FU) and eniluracil (Glaxo Wellcome Inc.,Research Triangle Park, North Carolina), an inactivator of dihydropyrimidinedehydrogenase (DPD). The rationale for developing a combined eniluracil/5-FUformulation oral dosing form is to simplify treatment with these agents, whichhas been performed using separate dosing forms, and decrease the probabilityof severe toxicity and/or suboptimal therapeutic results caused byinadvertently high or conversely insufficient 5-FU dosing. Patients and methods:The trial was a randomized, three-waycrossover bioequivalence study of three oral dosing forms of eniluracil/5-FUtablets in adults with solid malignancies. Each period consisted of two daysof treatment and a five- to seven-day washout phase. Eniluracil at a dose of20 mg, which results in maximal DPD inactivation, was administered twice dailyon the first day and in the evening on the second day of each of the threetreatments. On the morning of the second day, all patients received a totaleniluracil dose of 20 mg orally and a total 5-FU dose of 2 mg orally as eitherseparate tablets (treatment A) or combined eniluracil/5-FU tablets in twodifferent strengths (2 tablets of eniluracil/5-FU at a strength (mg/mg) of10/1 (treatment B) or 8 tablets at a strength of 2.5/0.25 (treatment C)). Thepharmacokinetics of plasma 5-FU, eniluracil, and uracil, and the urinaryexcretion of eniluracil, 5-FU, uracil, and -fluoro--alanine (FBAL),were studied. To determine the bioequivalence of the combined eniluracil/5-FUdosing forms compared to the separate tablets, an analysis of variance onpharmacokinetic parameters reflecting eniluracil and 5-FU exposure wasperformed. Results:Thirty-nine patients with advanced solid malignancies hadcomplete pharmacokinetic studies performed during treatments A, B, and C. Thepharmacokinetics of eniluracil and 5-FU were similar among the three types oftreatment. Both strengths of the combined eniluracil/5-FU dosing form and theseparate dosing forms were bioequivalent. Mean values for terminal half-life,systemic clearance, and apparent volume of distribution for oral 5-FU duringtreatments A/B/C were 5.5/5.6/5.6 hours, 6.6/6.6/6.5 liters/hour, and50.7/51.5/50.0 liters, respectively. The intersubject coefficient of variationfor pharmacokinetic variables reflecting 5-FU exposure and clearance intreatments ranged from 23% to 33%. The urinary excretion ofunchanged 5-FU over 24 hours following treatments A, B, and C averaged52.2%, 56.1%, and 50.8% of the administered dose of 5-FU,respectively. Parameters reflecting DPD inhibition, including plasma uraciland urinary FBAL excretion following treatments A, B, and C were similar.Toxicity was generally mild and similar following all three types oftreatments. Conclusions:The pharmacokinetics of 5-FU and eniluracil weresimilar and met bioequivalence criteria following treatment with the separateoral formulations of 5-FU and eniluracil and two strengths of the combinedformulation. The availability of a combined eniluracil/5-FU oral dosing formwill likely simplify dosing and decrease the probability of severe toxicityor suboptimal therapeutic results caused by an inadvertent 5-FU overdose orinsufficient 5-FU dosing in the case of separate oral formulations, therebyenhancing the overall feasibility and therapeutic index of oral 5-FU therapy.     

萘普生钠片的人体生物等效性研究

 目的：通过交叉试验比较两种萘普生钠制剂的生物等效性。方法：以8名男性志愿受试者按交叉试验方案以高效液相色谱法测定血浓度。进行两种制剂一次口服给药300 mg的药物动力学和生物利用度比较试验。结果：两种片剂药物动力学参数无显著差异。试验片的相对生物利用度为112.2%。结论：在8名受试者交叉试验证明两种制剂萘普生钠片生物利用度相当，证明两种片剂生物等效。     

盐酸特比萘芬片人体药动学和生物等效性研究

目的 研究盐酸特比萘芬片的人体药动学,并对试验制剂盐酸特比萘芬片和参比制剂盐酸特比萘芬片(兰美抒)的生物等效性进行评价.方法 按照两制剂两周期随机交叉设计,19名男性健康志愿者单剂量口服试验制剂盐酸特比萘芬片和参比制剂盐酸特比萘芬片(兰美抒)250 mg.采用HPLC-UV法测定血浆盐酸特比萘芬片浓度,并进行统计学分析.结果 单剂量口服250mg盐酸特比萘芬片试验和参比制剂,测定得主要药动学参数如下:Cmax分别为(1.66±0.62)μg·mL-1和(1.55±0.66)μg·mL-1,Tmax分别为(1.5±0.7)h和(1.4±0.6)h,t1/2(Kel)分别为(12.65±3.07)h和(14.24±3.65)h,MRT分别为(10.21±3.13)h和(11.56±3.62)h,AUC0-48分别为(5.98±2.45)μg·h·mL-1和(6.76±3.14)μg·h·mL-1,AUC0-∞分别为(6.32±2.58)μg·h·mL-1和(7.20±3.27)μg·h·mL-1.按AUC0-48估算,受试制剂的人体平均相对生物利用度为(95.1±22.5)%,按AUC0-∞估算,平均相对生物利用度为(93.9±21.6)%.结论 两制剂主要药动学参数经对数转换后进行方差分析及双单侧t检验,并计算90%置信区间,表明两种制剂生物等效.     

磷酸奥司他韦干混悬剂的人体药动学与生物等效性

目的:研究磷酸奥司他韦干混悬剂在健康受试者的人体药动学和生物等效性。方法:78例受试者分别空腹和餐后口服75 mg受试制剂或参比制剂。采用高效液相色谱-串联质谱(HPLC-MS/MS)检测奥司他韦和奥司他韦酸的全血浓度,用WinNonlin 8.2软件计算药动学参数,评价两制剂生物等效性。结果:空腹试验受试制剂和参比制剂的奥司他韦C_max、AUC_0-t、AUC_0-∞分别为(52.07±23.44)和(50.54±16.09)ng·mL^-1、(150.8±32.0)和(153.6±29.3)h·ng·mL^-1、(154.2±32.2)和(157.8±30.9)h·ng·mL^-1;奥司他韦羧酸盐C_max、AUC_0-t、AUC_0-∞分别为(259.66±42.65)和(267.10±44.06)ng·mL^-1、(3 235.1±549.9)和(3 321.6±567.5)h·...