国内奥美拉唑(盐)口服制剂人体生物等效性试验的问题和对策

奥美拉唑是质子泵抑制剂类代表药物,临床上应用广泛.文中通过对国内26篇奥美拉唑(盐)12服制剂人体生物等效性试验文献进行分析,探讨了试验内容、参比制剂、受试者、生物样品采集及分析、药动学参数、上市后生物等效性再评价或监测等方面的问题和对策,以期为奥美拉唑(盐)口服制剂人体生物等效性研究和临床应用提供参考信息,并基于现有...     

浅谈高变异药物的生物等效性研究

高变异药物的生物等效性研究是一个引人关注的现实课题，本文分析和介绍了高变异药物生物等效性研究的困难及其主要解决方法，希望能够有助于国内临床研究单位加强对高变异药物生物等效性研究问题的重视，从而更加科学可靠地评价高变异药物的生物等效性。     

吸入剂生物等效性评价方法介绍与比较

吸入剂相较于普通制剂在剂型、装置及作用方式等方面有其特殊性,吸入剂生物等效性评价若按照普通制剂的评价方法进行,可能导致所得结果的准确度降低,故吸入剂的生物等效性评价具有挑战性。目前,随着市场需求的不断增加,国内对于吸入制剂的研究也呈现上升趋势,但国内尚未正式出台吸入剂生物等效性评价的相关指南,这给相关研究带来一定局限。本文主要通过对美国、欧洲以及加拿大药品管理机构关于吸入制剂生物等效性评价的指南及修订稿进行介绍,并与我国国家药品监督管理局药品审评中心于2019年8月发布的关于公开征求《经口吸入制剂仿制药药学和人体生物等效性研究指导原则》征求意见稿进行比较的基础上,结合具体案例进行分析,以期为国内相关吸入制剂生物等效性研究提供科学参考。     

两阶段生物等效性研究的试验设计及关注要点

两阶段生物等效性研究目前已得到多个国家生物等效性指南的认可,但在实施两阶段生物等效性研究时如何在控制I类错误的基础上保证目标把握度是很大的挑战。对目前国内外文献发表的两阶段设计生物等效性研究方法加以综述,详细介绍了文献方法的研究策略、检验水准的校正方法、样本量再估算等,为国内药品申办者在开展两阶段生物等效性研究提供参考。     

中国鼓励仿制药品目录（第二批）品种特征及生物等效性研究要求

为及时满足国内临床用药需求，国家卫生健康委员会分别于2019年10月、2021年2月发布2批《鼓励仿制药品目录清单》。检索并整理了《鼓励仿制药品目录（第二批）》纳入品种的适应证、批准文号数量、临床试验登记等信息，结合美国食品药品监督管理局（FDA）发布的生物等效性研究个药指南，对目录中涉及的相关品种生物等效性研究要求进行梳理，结合品种特征与生物等效性研究要求进行了初步分析，以期为国内研究机构及企业开展相关研究提供科学依据与参考。     

我国鼓励仿制药品目录清单（第一批）品种特征及口服固体制剂生物等效性研究要求分析

为及时满足国内临床用药需求，2019年10月，国家卫生健康委员会正式发布《关于印发第一批鼓励仿制药品目录的通知》。检索并整理了全部纳入品种的适应症、批准文号数量、临床试验登记等信息，结合美国食品药品管理局（FDA）发布的生物等效性研究个药指南，对目录中涉及的固体口服制剂生物等效性研究要求进行梳理，并结合涉及品种的相关特征与生物等效性研究要求进行分析，以期为国内研究机构及原研企业开展相关研究提供科学依据与参考。     

浅谈世界卫生组织的药品生物等效性豁免

介绍世界卫生组织(WHO)有关药品生物等效性实验豁免(以下简称生物豁免)的政策指南,使国内制药行业对其有所了解。就WHO的生物豁免政策而言,更多的药品可以避免进行体内生物等效性研究,这对于以仿制药为主的药品研发更具节约时间和开发成本的效益,也为国内的有关生物等效性豁免提供借鉴。     

等效性评价方法研究现状

目的：阐明生物等效性与临床等效性的研究现状及发展方向。方法：介绍新药等效性评价方法的原理，生物等效性分析方法的新进展包括总体或(和)个体生物等效性和多变量生物等效性检验的方法，以及临床等效性中等效界值、目标参数及有待解决的问题，并结合实例进行论述。结论：等效性评价的基本方法已得到推广使用，但在应用上还存在很大的可塑性，不利于新药审评标准的把握，应加强等效性评价方法的正确应用与发展。     

对含盐酸二甲双胍制剂生物等效性试验若干问题的探讨

通过分析盐酸二甲双胍制剂生物等效性试验文献资料,结合我们的相关研究,探讨了目前国内药物制剂生物等效性试验存在的问题,并提出相应对策。荟萃分析表明,我国在盐酸二甲双胍制剂生物等效性试验的生物样品分析测定、试验管理、设计与实施、试验结果及讨论分析方面均存在一定问题,提示应进一步规范生物等效性试验,通过药物上市后再评价以提高我国上市药品的有效性、安全性和经济性。     

等效性研究的常用统计分析方法及其评价

等效性研究在新药开发和新药评价过程中发挥非常重要的作用。生物等效性研究选用和试验药及参比药都有关的药代动力学参数作等效性分析 ,临床等效性研究选用能反映药物疗效的临床目标参数作等效性分析。两种等效性研究的试验设计与统计学方法有所不同。     

药物代谢物在生物等效性评价中的意义

关于药物代谢物在生物等效性评价中的地位已经争论数十年,目前对于达到最后统一的意见还有相当的距离。一部分人认为检测母体药物就足以反映药物制剂间的性能差异,而另一部分人则认为建立一个能反映所有药物制剂有效性和安全性的生物等效性标准是保证药物间相互替代的可靠方法,而且在实际应用中也存在着很多需要探讨的问题。通过相关情况的综述使我们意识到,对于在生物等效性评价中是否使用代谢物资料没有简单的规则,而众多争议问题的解决必须更多地依赖于以后对于影响药物和代谢物浓度因素的全面了解,药物代谢相关模拟试验的完善和药物基因组学的研究必将大大推动这一问题的解决。     

Pharmacokinetics and pharmacodynamics of a new reformulated microemulsion and the long-chain triglyceride emulsion of propofol in beagle dogs

Background and purpose:

Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations.

Experimental approach:

The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg·kg⁻¹·min⁻¹) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling.

Key results:

Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUC_last and AUC_inf between both formulations were acceptable for bioequivalence, whereas that of C_max was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E₀ (baseline ApEn)–E_max (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V₁ of both formulations and sex for k₂₁ of microemulsion propofol. The blood-brain equilibration rate constants (k_e0, min⁻¹) were 0.476 and 0.696 for microemulsion and LCT propofol respectively.

Conclusions and implications:

Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges.     

A comparative analysis of biopharmaceutics classification system and biopharmaceutics drug disposition classification system: A cross-sectional survey with 500 bioequivalence studies

Although policies of waiving bioequivalence studies are part of the legal framework of various regulatory agencies, there is no harmonization with regard to extension of the biowaiver to drugs other than those with high solubility and high permeability, nor is there any consensus or official endorsement of the biopharmaceutics drug disposition classification system (BDDCS). To better understand the applicability of the biowaiver, we carried out a cross-sectional survey to estimate the relative risk of obtaining nonbioequivalent (non-BE) or bioinequivalent (BIE) results for drug products containing drugs belonging to each of the biopharmaceutics classification system (BCS) and BDDCS classes. Five hundred bioequivalence studies were randomly sampled from a database of the Brazilian Health Surveillance Agency (ANVISA). The drugs were classified according to the BCS and BDDCS, to evaluate how characteristics related to drug and dosage form influence the outcome of bioequivalence studies. The relative risk of obtaining a non-BE result was approximately four times lower for drugs in classes 1 and 3 of BCS or BDDCS when compared with class 2 drugs. Thus, it seems that the final outcome of a bioequivalence study is strongly influenced by the solubility of the drug, but not by its intestinal permeability or extent of metabolism.     

Bioavailability of carbamazepine from four different products and the occurrence of side effects

The relative bioavailability of four different carbamazepine products, showing large differences in in vitro dissolution profiles, was studied in healthy volunteers to correlate the occurrence of side effects with a measure of the rate of absorption in vivo for bioequivalence testing. Two of the three generic products investigated showed bioequivalence with respect to the extent of absorption with Tegretol. In vivo, the differences found in absorption rate were reflected in the occurrence of side effects, especially dizziness. As a measure for the rate of absorption, the partial AUC did not seem to be a good characteristic to test bioequivalence, as the variability is very high and dependent on the AUC taken. The Cmax/AUCpart seems more promising, especially the partial AUC directly after completion of the absorption process. The variability is low in the case of carbamazepine after a single dose. However, as long as no consensus on the use of other metrics and the objective (clinical or quality control aspects) of bioequivalence testing is reached, and no other pharmacokinetic characteristic is validated, Cmax should be the characteristic of choice for the rate of absorption in single-dose studies with carbamazepine products.     

Metabolites and bioequivalence: past and present

Although it is widely recognised that measurement of metabolite concentrations is crucial to understanding the clinical pharmacology characteristics of a new molecular entity, a clear consensus on the role of metabolites in the assessment of bioequivalence has never been achieved within the scientific community. However, a regulatory policy for the role of metabolites in bioavailability and bioequivalence has been established by the US FDA. One school of thought believes that the parent drug alone is sensitive to picking up formulation differences, whereas another school of thought believes that establishing bioequivalence criteria on all the species that contribute to safety and efficacy is the only way to ensure the switchability of two products.In this paper, a brief review of the pharmacokinetics of metabolites under different scenarios is presented and the history of the role of metabolites in the assessment of bioequivalence is summarised. Relevant examples from the literature illustrating conflicting opinions on the need for the measurement of metabolites in bioequivalence studies are given. Cases from the literature in which the parent drug is able to meet the 90% confidence intervals while the metabolite(s) fail to do so, and vice versa, are presented to illustrate the difficulty in choosing the pertinent entity to measure. The relevant current US FDA policy and guidelines related to bioavailability and bioequivalence are discussed and contrasted with the rules and regulations applicable in Canada and Europe.     

Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Conference report.

This is a summary report of the conference on Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies. The conference was held from December 3 to 5, 1990 in the Washington, DC area and was sponsored by the American Association of Pharmaceutical Scientists, US Food and Drug Administration, Federation International Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists. The purpose of the report is to represent our assessment of the major agreements and issues discussed at the conference. The report is also intended to provide guiding principles for validation of analytical methods employed in bioavailability, bioequivalence and pharmacokinetic studies in man and animals. The objectives of the conference were: 1. To reach a consensus on what should be required in analytical methods validation and the procedures to establish validation; 2. To determine processes of application of the validation procedures in the bioavailability, bioequivalence and pharmacokinetic studies; 3. To develop a report on analytical methods validation (which may be referred to in developing future formal guidelines). Acceptable standards for documenting and validating analytical methods with regard to processes, parameters or data treatments were discussed because of their importance in assessment of pharmacokinetic, bioavailability and bioequivalence studies. Other topics which were considered essential in the conduct of pharmacokinetic studies or in establishing bioequivalency criteria, including measurement of drug metabolites and stereoselective determinations, were also deliberated.     

Pharmacokinetics and pharmacodynamics of a single bolus of propofol 2% in healthy volunteers

This study was undertaken to assess the bioequivalence between a new formulation of propofol 2% and the commercially available product Diprivan. Secondary objectives were to compare the times to onset of and emergence from hypnosis, the hemodynamic effects, and the safety profiles. Twelve healthy male volunteers were included in a randomized crossover study. Subjects were administered a 2-mg/kg single bolus injection of each formulation separated by a 7- to 10-day washout period. Plasma propofol was determined by reversed-phase liquid chromatography with fluorescence detection. Eleven subjects completed the study, and both formulations were considered bioequivalent. There were no serious or severe adverse events. The concentration-time profiles of all the subjects could adequately be described using a three-compartment model. The mean times to cessation of counting out loud (17 vs. 18 s) and to eye opening (245 vs. 244 s) were not statistically different between treatment groups. Moreover, they seem to show some degree of pharmacodynamic bioequivalence, although a higher number of subjects are necessary to unequivocally demonstrate it.     

Recommendations for bioequivalence testing of cyclosporine generics revisited

The immunosuppressant cyclosporine is generally considered a critical-dose drug. The validity of standard criteria to establish bioequivalence between cyclosporine formulations has recently been challenged. Recommendations included establishment of individual bioequivalence rather than average bioequivalence, establishment of bioequivalence in transplant patients and in subgroups known to be poor absorbers, as well as long-term efficacy and safety studies in transplant patients. However, at the moment individual bioequivalence is a theoretical concept, the practical benefits of which have not statistically been proven. The proposed patient pharmacodynamic studies can be expected to require an unrealistically high number of subjects to achieve sufficient statistical power. It is well established that the common practice of blood-concentration-guided dosing of cyclosporine efficiently compensates for interindividual and intraindividual variability and allows for safely switching cyclosporine formulations as bioinequivalent as Sandimmune and Neoral. Recent studies comparing the generic cyclosporine formulation SangCya with Neoral, including individual bioequivalence, bioequivalence in transplant patients, and long-term safety after switching from Sandimmune to SangCya, confirmed that it was valid to conclude bioequivalence of both cyclosporine formulations based on standard average bioequivalence criteria. Present FDA guidelines for approving bioequivalence can be considered adequate and sufficient for generic cyclosporine formulations.     

高变异药物的生物等效性研究进展

高变异药物的生物等效性研究困扰着众多药学工作者。为此本文阐述了高变异药物等效性研究的难点,并总结了目前对高变异药物进行生物等效性研究的可行性方法:对Cmax进行特殊处理;合理界定生物等效;更改试验设计;更改统计方法;更改均值生物等效性方法的接受标准;在稳态下,研究药物及其生物代谢产物的生物等效性。本文比较了这些方法各自的优缺点,希望能对高变异药物的生物等效性研究起到启发作用。     

Understanding the scientific issues embedded in the generic drug approval process.

OBJECTIVE: To review the major scientific issues embedded in the generic drug approval process. DATA SOURCES: Articles indexed initially under terms such as generic medications, generic drugs, bioequivalence, and bioinequivalence. These terms were used to search indexing services such as MEDLINE, International Pharmaceutical Abstracts, CINAHL (a database of nursing and allied health literature), and Science Citation Index. Additional data sources included the Code of Federal Regulations and regulatory guidances from the Food and Drug Administration (FDA) Center for Drug Evaluation and Research. STUDY SELECTION: Performed by the authors. DATA EXTRACTION: Not applicable. DATA SYNTHESIS: Despite the fact that regulations regarding bioequivalence have been in place for more than 20 years, controversies over bioequivalence continue to arise. Consensus on many of these issues is driving the development of new FDA guidances regarding bioequivalence. Still, despite the issuance of new guidance and consensus building among scientists, many clinicians and consumers remain uninformed regarding the scientific basis for establishing bioequivalence and the generic drug approval process in general. Although some have suggested that the generic drug approval process is flawed, overall, it appears that the process works. CONCLUSION: Understanding the generic drug approval process and the issues surrounding bioequivalence is of paramount importance to both clinicians and scientists.