仿制药一致性评价的背景、实施及结局

我国是仿制药大国,开展仿制药质量和疗效一致性评价是国际惯例,也是我国经济、技术水平进步的必然结果。仿制药一致性评价适应国家新政,选择合适终点指标进行研究,目的是提高社会认可、实现仿制药与原研药的真正互换。仿制药一致性评价从简单的体外溶出度试验到系统的药学评价再到生物等效性评价,评价方法正在逐步完善,同时明确化学仿制药参比制剂遴选原则以减少仿制过程中的质量差异。仿制药一致性评价不仅能够提升我国制药行业的整体发展水平,促进医药产业升级和结构调整,同时可以节约医疗费用,保证患者用药安全。     

生物等效性试验健康受试者筛选流程的优化

目的 探讨如何提高生物等效性试验健康受试者筛选期的工作效率.方法 试验甲给予受试者根据各个检查项目等待人数自由分流的筛选方法;试验乙给予对部分检查项目进行先后顺序限定,并要求研究者在发现受试者某项检查结果异常后,应及时终止其继续参加其他检查的筛选方法.比较2个试验中受试者在某项检查不合格时合并有其他项目检查的情况.结果...     

Defining extended half‐life rFVIII—A critical review of the evidence

Introduction

Recent haemophilia treatment advances include new recombinant FVIII (rFVIII) products with improved pharmacokinetic (PK) properties that aim to reduce the burden of prophylaxis. These treatments are commonly referred to as extended half‐life rFVIII products (EHL rFVIII). There is no uniform definition of what constitutes an EHL rFVIII. Such a definition would help physicians, patients and funders understand the properties of standard and EHL rFVIIIs and thus provide clarity when selecting an EHL in clinical settings.

Aim

To critically assess the published evidence on new and emerging rFVIII products in order to propose a definition to classify EHL rFVIIIs.

Methods

We systematically searched PubMed, EMBASE and regulatory authorities (FDA/EMA/Health Canada) websites for publications and regulatory submissions describing prospective crossover PK studies evaluating rFVIIIs that demonstrate improved PK parameters in adults and adolescents with severe haemophilia A.

Results

Following critical analyses of the published data, we developed a holistic approach to defining rFVIIIs as EHLs, which requires all of the following: (i) using technology designed to extend rFVIII half‐life; (ii) lacking bioequivalence with a standard rFVIII comparator—above the FDA/EMA cut‐off of 125% for the 90% confidence intervals for area under the curve ratio; and (iii) having an extended half‐life ratio measured in a PK comparator crossover study.

Conclusion

In this systematic review, a pragmatic definition of EHL rFVIII has been proposed that should provide better clarity in clinical discussions surrounding the appropriate use of rFVIII products. At present, only products using PEGylation or Fc fusion half‐life extension technology meet the proposed criteria for definition of EHL rFVIII.     

国产盐酸特拉唑嗪片在人体内的药动学研究及生物等效性评价

目的对两种盐酸特拉唑嗪片在健康青年志愿者体内的药代动力学和相对生物利用度进行研究,并评价其生物等效性。方法单剂量口服盐酸特拉唑嗪片剂2 mg后,用HPLC法测定血药浓度,所得数据用BECS软件计算药动力学参数并进行等效性评价。结果两种盐酸特拉唑嗪片剂的药动学参数分别为:T1/213.39±1.89和13.00±2.32 h,Tmax 1.33±0.30和1.36±0.29 h,Cmax27.83±5.34μg.L-1,和28.62±5.35μg.L-1,AUC0→t342.31±61.18和334.93±73.08μg.h.L。两种特拉唑嗪片剂的相对生物利用度F1(AUC0→t)=96.92%±0.21,F2(AUC0→∞)=96.41%±0.21。结论经统计学分析,两种特拉唑嗪片剂的药动学参数之间差异均无显著性(P>0.05),两种制剂生物等效。     

吡仑帕奈片在健康受试者中的生物等效性研究

目的 考察在空腹、餐后条件下健康受试者口服吡仑帕奈片受试制剂和参比制剂体内吡仑帕奈的血药浓度和药动学参数,评价吡仑帕奈片的生物等效性和安全性。方法 采用健康受试者在空腹、餐后的单中心、单剂量、两制剂、随机、开放、两周期、自身交叉对照试验设计的人体生物等效性研究。空腹和餐后组健康受试者分别口服4 mg吡仑帕奈片受试制剂或参比制剂,采用HPLC-MS/MS法测定血浆中吡仑帕奈的浓度,药动学使用Phoenix Win Nonlin 8.1软件的非房室模型计算各受试者的药动学参数,使用SAS 9.4软件进行临床安全性统计分析。结果 空腹、餐后试验吡仑帕奈片受试试剂和参比试剂的最大血药浓度(C_max)分别为(181.20±46.14)、(168.60±47.98),(130.44±28.59)、(139.15±39.99)ng/m L,药时曲线面积(AUC_0-t)分别为(7 587.46±2 975.40)、(7 485.88±2 910.03),(7 820.54±3 229.68)、(7 528.88±2 325.94)h·ng/m L。两组吡仑帕...     

RELATIVE BIOAVAILABILITY OF FOUR CLOMIPRAMINE HYDROCHLORIDE TABLET PRODUCTS

The relative bioavailability of clomipramine was determined in two single-blind, single-dose, randomized, crossover studies. In the first study, the relative bioavailability of the test product, 2×25 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil^® 2×25 mg tablets (clomipramine HCl; Ciba—Geigy (Pty) Ltd.) was determined. In the second study, the relative bioavailability of the test product, 5×10 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil^® 5×10 mg tablets (clomipramine HCl; Ciba—Geigy (Pty) Ltd.), was determined. The geometric mean values for the variable C_max were 31·.3 ng mL⁻¹ for the reference and 31·.6 ng mL⁻¹ for the test product in study 1. The geometric mean values for the variable AUC were 736 ng h mL⁻¹ and 753 ng h mL⁻¹ for the reference and test, respectively. In study 2, the geometric mean C_max values were 25·.8 ng mL⁻¹ and 23·.9 ng mL⁻¹ for the reference and test respectively; the geometric mean AUC values were 569 ng h mL⁻¹ and 547 ng h mL⁻¹. The 90% confidence intervals for the ‘test/reference’ mean ratios of the plasma clomipramine pharmacokinetic variables C_max and AUC_(0–∞) (as measures of the rate and extent of absorption of clomipramine, respectively) fall within the conventional bioequivalence range of 80–125% for both studies. The test products (clomipramine HCl) are therefore bioequivalent to the reference products (Anafranil^®) with respect to the rate and the extent of absorption of clomipramine in both 10 mg and 25 mg strengths.     

盐酸特比萘芬片在中国健康受试者体内的生物等效性研究

目的 研究盐酸特比萘芬片在中国健康受试者中的药代动力学,评价国产受试制剂与原研参比制剂的生物等效性.方法 采用空腹/餐后、随机、开放、单剂量、两周期、两序列、双交叉试验设计.空腹试验和餐后试验各入组36例健康受试者,随机分为2组,每周期单次空腹或餐后口服盐酸特比萘芬片受试制剂或参比制剂125 mg.用液相色谱-串联质谱...     

阿比朵尔片剂与胶囊剂的人体生物等效性比较

 目的评价阿比朵尔片与参比制剂(阿比朵尔胶囊)是否等效。方法20名男性健康受试者随机分为2组,交叉口服受试制剂(阿比朵尔片)和参比制剂各200 mg后,以高效液相色谱法测定血浆中药物浓度。所得数据用3P87统计软件进行处理。结果阿比朵尔受试制剂和参比制剂的t_max分别为(1.08±0.61)和(1.63±1.06)h;ρ_max分别为(408.5±167.4)和(417.8±240.7)μg·L^-1;t_1/2分别为(11.77±5.01)和(10.55±4.01)h;用梯形法计算,AUC_0-48分别为(2 641.2±1 024.0)和(2 725.8±1 181.0)μg·h·L^-1;AUC_0-∞分别为(2 751.5±1 197.6)和(2 857.4±1 311.3)μg·h·L^-1。以AUC_0-48计算,盐酸阿比朵尔片的相对生物利用度平均为(96.9±42.3)%。结论2种制剂具有生物等效性。     

盐酸金刚乙胺颗粒人体生物等效性研究

 目的用高效液相色谱-质谱法(LC-MS)测定受试者口服盐酸金刚乙胺制剂后的血药浓度,估算受试制剂和参比制剂的药动学参数,评价两种制剂的生物等效性和相对生物利用度。方法采用随机二交叉设计试验,20例男性健康志愿受试者,单剂量口服受试制剂盐酸金刚乙胺颗粒和参比制剂盐酸金刚乙胺片。以LC-MS测定血浆中金刚乙胺的浓度。采用BAPP3.0软件处理计算主要药动学参数。结果受试制剂和参比制剂血浆中金刚乙胺的t_1/2分别为(26.46±4.48)和(27.41±4.42)h;ρ_max分别为(84.5±17.7)和(93.1±17.8)μg·L^-1;t_max分别为(4.08±2.86)和(4.70±3.59)h;AUC_0-120h分别为(3204±691)和(3450±724)μg·h·L^-1;AUC_0-∞分别为(3395±767)和(3661±820)μg·h·L^-1;人体相对生物利用度为(93.4±10.8)%。结论2种制剂在健康人体内具有生物等效性。     

Generic antiepileptic drugs—Safe or harmful in patients with epilepsy?

Generic antiepileptic drugs (AED) are significantly cheaper than brand name drugs, and may reduce overall health care expenditures. Regulatory bodies in Europe and North America require bioequivalence between generic and innovator drugs with regard to area under the plasma concentration–time curve (AUC) and peak plasma concentration (C_max); strict cutoff values have been defined. The main issue is if bioequivalence ensures therapeutic equivalence. Are switches from brand to generic, or between generic AEDs entirely safe or potentially harmful in patients with epilepsy? We summarized and evaluated the available evidence from bioequivalence, health care utilization, and clinical studies on safety of generic AEDs. In most cases, variations in AUC and C_max were negligible when comparing innovator and generic AEDs. Due to interindividual pharmacokinetic and pharmacodynamic variability, measured differences between innovator and generic drugs may be the same as differences between different lots of the same brand. Studies from several countries based on insurance data have reported an increase in health care usage after switch from brand to generic AEDs; switchback rates are significantly higher for AEDs compared to other compounds. Patients may be confused, and nonadherence may increase, when AEDs are switched between manufacturers, perhaps due to changes in medication shape and color. But clinical studies do not report changes in seizure frequency and tolerability attributable to generics. Sufficient evidence indicates that most generics are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. We recommend administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.