共查询到17条相似文献,搜索用时 125 毫秒
1.
2.
3.
《中国新药与临床杂志》2019,(11)
仿制药一致性评价推动着生物等效性试验的开展,生物等效性试验的风险日益突出。本文基于临床试验管理者的视角,对生物等效性试验实施过程中的机构组织管理、受试者管理、试验药物和生物样品管理风险现状及存在问题进行剖析,提出加强对机构管理者及研究者生物等效性试验专业知识和法规的培训、关注受试者招募合规性及试验期间管理的合理性、规范试验药物和生物样品的管理流程和记录等相应的风险管控措施和策略。 相似文献
4.
5.
本文我们将着重讨论一些特殊的仿制药品的生物等效性试验方法.此类药品包括代谢物具有生物活性类的药物、对映异构体、内源性物质、高变异性药物和局部作用药物等仿制药品. 相似文献
6.
生物等效性在新药研究、非专利药开发和药品上市后评价中具有重要作用。本文从实验方法学、药剂因素、内源性物质、活性代谢物、立体异构药物和高变异性药物等方面对生物等效性研究在技术指南及实际应用中需要特别注意的问题进行了具体论述,同时对生物药剂学分类系统等生物等效性研究的相关进展做了初步介绍。 相似文献
7.
8.
摘要:目的:为保证新型冠状病毒肺炎(COVID-19)疫情防控常态化下,仿制药人体生物等效性试验的有序开展和试验质量,最大限度的保护受试者和研究者的安全,针对新常态下影响受试者管理的因素进行探讨。方法:以生物等效性试验流程中受试者管理关键环节为切入点,分别对COVID-19疫情防控新常态下受试者的招募、筛选、入住、出院、随访等阶段进行深入探讨。结果与结论:在保障受试者权益与安全的前提下,对COVID-19疫情后开展生物等效性试验受试者的管理流程和细节作出相应调整,从而有效的保证了受试者安全和试验质量,提高了特殊公共卫生事件下生物等效性试验受试者管理的水平。 相似文献
9.
目的以枸橼酸钾为例,介绍内源性药物的尿药生物等效性试验(BE)的设计和分析方法。方法根据FDA关于内源性药物BE研究相关指南及相关文献,以枸橼酸钾尿药BE研究为实例,探讨其研究流程、质量监控、剂量选择、样本采集以及数据分析等关键问题。结果在枸橼酸钾BE研究中,用单剂量、双交叉设计,对试验期间的饮食和活动进行标准化控制,用同一周期的给药前的内源性物质作为基线,校正尿药排泄量,最后用24 h尿药累积排泄量(Ae0-24h)、最大尿药排泄速率(Rmax)进行生物等效性分析。结论内源性药物BE研究,在设计上更为复杂,饮食和生理因素对结果影响大,需要基线校正,数据波动明显。尿药参数以Ae0-t和Rmax为主,而Tmax和T1/2没有实际意义。 相似文献
10.
参考国际上的相关指导原则,对《中国药典》2015年版药物制剂生物利用度和生物等效性指导原则提出了修改草案。包括前言,常释制剂生物等效性试验的设计、实施和评价,调释制剂和透皮吸收制剂的生物等效性试验,试验报告,与生物等效性试验相关的体外溶出度检查,对不同剂型的生物等效性要求,以及基于生物药剂学分类系统的生物豁免。与现行药典指导原则相比,把生物样品定量分析方法的内容分离出去,对试验药品的规格、参比制剂选取、测试原形药物还是代谢物、高变异性药品生物等效性等提供了新的建议,强调溶出度实验的意义,并引入了生物试验豁免的相关内容。 相似文献
11.
A Marzo 《Pharmacological research》1999,40(4):357-368
This paper focuses on some specific situations where bioequivalence requires careful attention and tailored protocols in order to overcome intrinsic difficulties either marginally covered or fully neglected by operating guidelines. Some problems congregate with serious difficulties, namely high variability, very poorly absorbed drugs and endogenous substances with their own baseline. With endogenous substances, the dilemma faced is whether to subtract baseline from post-dose values in assessing bioequivalence. Either approach has intrinsic problems and is somewhat puzzling. In an attempt to resolve other existing problems, the most appropriate approach should be selected on a case-by-case basis, ensuring that the adopted procedure does not conflict with operating guidelines and scientific literature on the matter. Problematic cases include the management of trials with a predominant active metabolite, the absence of a reliable analytical bioassay, the availability of various strengths of the same drug on the market, a wide acceptability titre range, the management of studies on topical drugs that are devoid of systemic activity, the management of drugs that cannot be given for ethical reasons to healthy subjects or that may cause adverse events, especially when a steady state design is required. The parallel group study design appears to be more appropriate than the cross-over or the individual bioequivalence design in assessing drugs with a long half-life. Some pharmacokinetic and statistical analysis-related issues are also discussed such as the sequence/period interaction sometimes encountered in these trials, which, in the absence of the carry-over effect, does not bias the bioequivalence results and the need to process data with non-compartmental pharmacokinetic analysis. 相似文献
12.
Oral administration of endogenous substances in most cases results in negligible net increases in baseline plasma concentrations, associated with high variability. This poses the problem of their bioequivalence. Using the data obtained from a bioequivalence investigation of potassium aspartate (test vs reference formulation), the authors demonstrate the inconsistency of bioequivalence based on plasma concentrations and standard methods. Potassium aspartate was given orally at a dose of 15.8 mmoles to 12 healthy volunteers as test and reference values according to a two-period, two-formulation, two-sequence design. The individual net values of the area under the curve of plasma concentration (AUC) and cumulative urinary excretion (CUE), both obtained with the test formulation as post-dose minus baseline, were multiplied by 2, 3, 4, 5 and 6 and added to the baseline in order to simulate the administration of increasing single doses of the test, assuming dose-linear kinetics. Data generated with the test formulation were compared with original data of the reference according to 90% confidence intervals. With AUC, bioequivalence of test and reference formulations was demonstrated with 1 : 1, 2 : 1 and 3 : 1 test to reference dose ratios. With CUE only the 1 : 1 dose ratio comparison produced bioequivalence. The authors conclude that bioequivalence of endogenous substances conducted with standard procedures in most cases is a useless exercise. With potassium and more generally with drugs cleared via urine, urinary excretion would reflect the extent of absorption more faithfully than AUC. 相似文献
13.
Zherdev VP Kolyvanov GB Litvin AA Sariev AK 《Eksperimental'naia i klinicheskaia farmakologiia》2003,66(2):60-64
Problems encountered in the testing for bioequivalence of reproduced drugs (generics) are discussed in the parts incompletely resolved in domestic methodological recommendations. There are special cases when such drugs significantly vary in concentration and dosage, contain endogenous substances, exhibit intensive metabolism with a genetically polymorphous component, belong to "long-lived" compounds, and are intended for local administration. Also mentioned are problems related to insufficient sensitivity of analytical methods and some ethical aspects of investigations. 相似文献
14.
Professor Antonio Marzo 《Pharmaceutical Development and Regulation》2003,1(3):179-189
This paper focuses on some unresolved issues in bioequivalence. In these cases, intrinsic difficulties not clearly considered in EU and US FDA operating guidelines are involved. Careful attention to these issues and wide experience is required for tailoring specific bioequivalence study protocols. The aim is to reach a bioequivalence or bioinequivalence conclusion on the basis of test versus reference performance, avoiding less definite, borderline conclusions attributable to intrinsic difficulties in the specific study. In discussing these unresolved issues, the author suggests potential solutions, where possible, on the basis of personal experience and specific bibliographic references. The difference in titer between test and reference would normally be in the range of 95–105%, but in some cases it would fall within the expanded range of 90–120%. This would call for a titer normalization in establishing bioequivalence. A long elimination half-life (t1/2) [e.g. 50 days with amiodarone] calls for decision making about study design, namely crossover or parallel group design, the latter design being more adequate for drugs cleared with a t1/2 >10 days. Ethical problems concerning drug administration in healthy individuals (e.g. cytostatic agents in single dose, and other drugs in a repeated-dose regimen) is another issue. Drugs that produce unacceptable side effects in a repeated-dose regimen should be studied in healthy volunteers only in single dose. Drugs characterized by high variability require a high number of participants in the trial. Endogenous substances, most of which are eliminated faster than they are absorbed, have plasma concentration-time behavior not predictive of bioavailability. When the endogenous substance is cleared via urine, cumulative urinary excretion is a better evaluation parameter than area under the plasma concentration curve. In other cases a repeated dose regimen to steady state can allow post-dose concentration without baseline subtraction to be considered in assessing bioequivalence. Drugs producing one or more active metabolite(s) raise different opinions on whether bioequivalence should be assessed for the drug, metabolite(s) or both. All active moiety, namely parent drug and metabolite(s) should be assayed. Bioequivalence, however, should be assessed on only one substance, preferably the parent drug. In the presence of a prevalent active metabolite, this metabolite should be preferred in assessing bioequivalence. Insufficient sensitivity of the bioassay often compels an alternative solution, such as working in steady state or assaying the compound in urine. Polymorphic metabolism calls for a preliminary classification of volunteers in order to exclude poor metabolizers from bioequivalence studies of repeated-dose regimens. Topical application of drugs for topical effect calls for a therapeutic bioequivalence; this is because circulating concentrations are not an expression of activity, but only of safety. When there are several strengths of a given drug on the market, the replicator can profit from a waiver allowing only one strength to be checked when some conditions hold. Reversible metabolites should be considered active metabolites. This is because they can revert into the parent compound. Reversibility of metabolites is very common with endogenous substances, but it is also present with several exogenous substances. The approaches selected to solve bioequivalence problems must not conflict with US FDA and EU operating guidelines, which, however, in some instances do not overlap. This would mean that it is mandatory to operate on a case-by-case basis. 相似文献
15.
16.
Sanjeeva Dissanayake 《British journal of clinical pharmacology》2010,69(3):238-244
BACKGROUND
Assessment of the bioequivalence of generic versions of certain reference drugs is complicated by the presence of endogenous levels of said compounds which cannot be distinguished from externally derived compound levels following drug administration. If unaccounted for, the presence of endogenous compound biases towards equivalence in bioequivalence studies of these drugs. Bioequivalence assessments may be complicated further as disposition of the exogenous analogue can be subject to various endogenous processes resulting in nonlinear pharmacokinetics. To overcome these inherent biases a number of different strategies have been employed.AIMS
To critically review methods used to overcome confounding biases in bioequivalence studies of ‘endogenous’ drugs.METHODS
A literature search of the EMBASE and PubMed databases was performed.RESULTS
The following strategies were identified: ablation/modulation of baseline endogenous substance levels; recruitment of ‘substance-deficient’ populations; restriction of dietary intake of the relevant substance; standardization of conditions with the potential to affect relevant homeostatic mechanisms; correction for baseline substance levels; and administration of supra-therapeutic drug doses.CONCLUSIONS
On the basis of this review key study design concepts, intended to optimize the design of future bioequivalence studies of these so-called ‘endogenous drugs’, are described. The dual stable isotope method, which could be used in a specific context, is also discussed. 相似文献17.
Marzo A 《Current Clinical Pharmacology》2007,2(2):179-189
During the last thirteen years, the author has investigated a relevant number of bioequivalence trials, for the approval of generics, which in the Mediterranean area show an increasing business trend. In his activity the author has faced several problems, most of them not considered in operating guidelines, defined "open questions on bioequivalence". They deal with the most appropriate procedures to adopt in case of studies on drugs with long half-lives, of ethics problems, high data dispersion, endogenous substances, presence of active metabolite(s), prevalent metabolites and reversible metabolism, very low plasma concentrations, multiple peak phenomenon, titre differences, polymorphic metabolism, stereogenic atoms. The relevance of a pilot trial, mainly for modified-release formulations, and the problem of frauds are discussed as well. These open questions are discussed in the present review taking into account EU and US FDA guidelines, current literature and personal experience. In most cases suitable approaches are suggested. Appropriate procedures should be planned and defined in the study protocol and extensively discussed in the final report. An appropriate approach to the "open questions" is a requisite to achieve a clearly defined bioequivalence/bioinequi-valence conclusion. 相似文献