Sec. 320.26  Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study

 

单剂量体内生物利用度或生物等效性研究指南

 

（a）Basic principles.

 

（a）基本原则：

 

(1) An in vivo bioavailability or bioequivalence study should be a single-dose comparison of the drug product to be tested and the appropriate reference material conducted in normal adults.

 

（1）体内生物利用度或生物等效性研究应在正常成人体内将待测药品与参比制剂进行单剂量比较。

 

(2) The test product and the reference material should be administered to subjects in the fasting state, unless some other approach is more appropriate for valid scientific reasons.

 

（2）受试者应在禁食状态下服用测试产品与参比制剂，除非有其他更有效的科学依据。

 

（b） Study design.

 

（b）研究设计。

 

(1) A single-dose study should be crossover in design, unless a parallel design or other design is more appropriate for valid scientific reasons, and should provide for a drug elimination period.

 

（1）单剂量研究应进行交叉试验设计，除非平行试验设计或有其他设计更合适，并应有药物的清洗期。

 

(2) Unless some other approach is appropriate for valid scientific reasons, the drug elimination period should be either:

 

除非有其他适用的有效的科学依据，否则药物清洗期应为：

 

(i) At least three times the half-life of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured in the blood or urine; or

 

（i）至少为血液或尿液中测定的药物活性成分或治疗结构或其代谢物半衰期的三倍；或

 

(ii) At least three times the half-life of decay of the acute pharmacological effect.

 

（ii）至少是急性药理作用半衰期的三倍。

 

(c) Collection of blood samples.

 

（c）血液样品收集。

 

(1) When comparison of the test product and the reference material is to be based on blood concentration time curves, unless some other approach is more appropriate for valid scientific reasons, blood samples should be taken with sufficient frequency to permit an estimate of both:

 

（1）当测试样品与参比制剂进行比较时，以血药浓度-时间曲线为基础，除非有其他更合适有效的科学依据，否则应以足够的频率采集血液样品，以便对二者进行评估。

 

(i) The peak concentration in the blood of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured; and

 

（i）测定活性药物成分或治疗结构或其代谢物在血液中峰浓度；和

 

(ii) The total area under the curve for a time period at least three times the half-life of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured.

 

（ii）至少测定药物活性成分或治疗结构或其代谢产物半衰期的三倍时间的曲线下总面积。

 

(2) In a study comparing oral dosage forms, the sampling times should be identical.

 

（2）在比较口服剂型时，取样时间应相同。

 

(3) In a study comparing an intravenous dosage form and an oral dosage form, the sampling times should be those needed to describe both:

 

（3）在比较静脉注射剂型和口服剂型时，取样时间应满足二者的需要。

 

(i) The distribution and elimination phase of the intravenous dosage form; and

 

（i）静脉注射剂型的分布和消除阶段；和

 

(ii) The absorption and elimination phase of the oral dosage form.

 

（ii）口服剂型的吸收和消除阶段。

 

(4) In a study comparing drug delivery systems other than oral or intravenous dosage forms with an appropriate reference standard, the sampling times should be based on valid scientific reasons.

 

（4）在比较有适当参比制剂、口服或静脉注射剂型以外给药方式的研究中，取样时间应按照有效的科学依据。

 

(d) Collection of urine samples. When comparison of the test product and the reference material is to be based on cumulative urinary excretion-time curves, unless some other approach is more appropriate for valid scientific reasons, samples of the urine should be collected with sufficient frequency to permit an estimate of the rate and extent of urinary excretion of the active drug ingredient or therapeutic moiety, or its metabolite(s), measured.

 

（d）尿样收集。当测试产品和参比制剂的比较是基于尿药累积排泄量曲线时，除非有其他更合适的有效的科学依据，否则应以足够的频率收集尿样，以便对活性药物成分或治疗结构或其代谢产物的尿液排泄率和排泄量进行估计。

 

(e) Measurement of an acute pharmacological effect.

 

（e）急性药理作用的测定

 

(1) When comparison of the test product and the reference material is to be based on acute pharmacological effect-time curves, measurements of this effect should be made with sufficient frequency to permit a reasonable estimate of the total area under the curve for a time period at least three times the half-life of decay of the pharmacological effect, unless some other approach is more appropriate for valid scientific reasons.

 

（1）当试验产品和参比制剂的比较是基于急性药理作用-时间曲线时，应有足够的频率去测定该效应，至少为药理学半衰期的三倍时间对曲线下总面积进行合理估计，除非有其他更合适的科学依据。

 

(2) The use of an acute pharmacological effect to determine bioavailability may further require demonstration of dose-related response. In such a case, bioavailability may be determined by comparison of the dose-response curves as well as the total area under the acute pharmacological effect-time curves for any given dose.

 

（2）使用急性药理作用来确定生物利用度可能需要进一步证明剂量相关的反应。在此情况下，可以比较剂量-反应曲线以及任何给定剂量的急性药理作用-时间曲线下总面积来确定生物利用度。

 

Sec. 320.27  Guidelines on the design of a multiple-dose in vivo bioavailability study

 

多剂量体内生物利用度研究指南

 

(a) Basic principles.

 

基本原则。

 

(1) In selected circumstances it may be necessary for the test product and the reference material to be compared after repeated administration to determine steady-state levels of the active drug ingredient or therapeutic moiety in the body.

 

（1）在一些情况下，可能需要在重复给药后比较试验产品与参比制剂，以确定活性成分或治疗结构在体内的稳态水平。

 

(2) The test product and the reference material should be administered to subjects in the fasting or nonfasting state, depending upon the conditions reflected in the proposed labeling of the test product.

 

（2）受试者应按照测试产品说明中的条件空腹或非空腹状态下服用测试产品和参比制剂。

 

（3）A multiple-dose study may be required to determine the bioavailability of a drug product in the following circumstances:

 

（3）以下情况可能需要进行多剂量研究试验来确定药品的生物利用度：

 

(i) There is a difference in the rate of absorption but not in the extent of absorption.

 

（i）吸收速率有差异，吸收程度不同。

 

(ii) There is excessive variability in bioavailability from subject to subject.

 

（ii）受试者之间的生物利用度变异过大。

 

(iii) The concentration of the active drug ingredient or therapeutic moiety, or its metabolite(s), in the blood resulting from a single dose is too low for accurate determination by the analytical method.

 

（iii）单剂量给药后血液中药物成分或治疗结构或其代谢产物的浓度太低，分析方法无法准确定量。

 

(iv) The drug product is an extended release dosage form.

 

（iv）药品是缓释剂型。

 

(b) Study design.

 

（b）研究设计。

 

(1) A multiple-dose study should be crossover in design, unless a parallel design or other design is more appropriate for valid scientific reasons, and should provide for a drug elimination period if steady-state conditions are not achieved.

 

（1）多剂量生物利用度研究应该进行交叉试验设计，除非平行试验设计或其他设计更合适，如果没有实现稳态条件，应该提供药物的清洗期。

 

(2) A multiple-dose study is not required to be of crossover design if the study is to establish dose proportionality under a multiple-dose regimen or to establish the pharmacokinetic profile of a new drug product, a new drug delivery system,

 

or an extended release dosage form.

 

（2）如果多剂量研究是为了建立剂量比例关系或研究新药、新的药物剂型或缓释剂型的药代动力学，则不需要进行交叉试验设计。

 

(3) If a drug elimination period is required, unless some other approach is more appropriate for valid scientific reasons, the drug elimination period should be either:

 

（3）如果需要药物的清洗期，除非有其他更合适的科学方法，否则药物的清洗期应为：

 

(i) At least five times the half-life of the active drug ingredient or therapeutic moiety, or its active metabolite(s), measured in the blood or urine; or

 

（i）至少为血液或尿液中活性药物成分或治疗结构或其代谢产物半衰期的5倍；或

 

(ii) At least five times the half-life of decay of the acute pharmacological effect.

 

（ii）至少为急性药理作用半衰期的5倍。

 

(c) Achievement of steady-state conditions. Whenever a multiple-dose study is conducted, unless some other approach is more appropriate for valid scientific reasons, sufficient doses of the test product and reference material should be administered in accordance with the labeling to achieve steady-state conditions.

 

（c）实现稳态。当进行多剂量研究时，除非有其他更适合的科学原因，否则应按照说明给予足够剂量的试验药品和参比制剂以达到稳态。

 

(d) Collection of blood or urine samples.

 

（d）收集血样或尿样。

 

(1) Whenever comparison of the test product and the reference material is to be based on blood concentration-time curves at steady state, appropriate dosage administration and sampling should be carried out to document attainment of steady state.

 

（1）当以稳态条件下血药浓度-时间曲线来比较测试样品与参比制剂时，应给予适当剂量药物和取样，证明达到稳态。

 

(2) Whenever comparison of the test product and the reference material is to be based on cumulative urinary excretion-time curves at steady state, appropriate dosage administration and sampling should be carried out to document attainment of steady state.

 

（2）当以稳态条件下尿药累积排泄-时间曲线来比较测试产品与参比制剂时，应给予适当剂量和取样，证明达到稳态。

 

(3) A more complete characterization of the blood concentration or urinary excretion rate during the absorption and elimination phases of a single dose administered at steady-state is encouraged to permit estimation of the total area under concentration-time curves or cumulative urinary excretion-time curves and to obtain pharmacokinetic information, e.g., half-life or blood clearance, that is essential in preparing adequate labeling for the drug product.

 

（3）稳态时服用单一剂量后，获得血药浓度或尿排泄率更完整的信息，可以估算浓度-时间曲线或尿药累积排泄-时间曲线下总面积，以获得更多的药代动力学信息，如半衰期或血液清除率，这是药品说明书需要的。

 

(e) Steady-state parameters.

 

（e）稳态参数。

 

(1) In certain instances, e.g., in a study involving a new drug entity, blood clearances at steady-state obtained in a multiple-dose study should be compared to blood clearances obtained in a single-dose study to support adequate dosage recommendations.

 

（1）在某些情况下，例如在设计新药物实体的研究中，应在多剂量研究中获得稳态血液清除率与单剂量研究中的血液清除率进行比较，来支持合适的服用剂量。

 

(2) In a linear system, the area under the blood concentration-time curve during a dosing interval in a multiple-dose steady-state study is directly proportional to the fraction of the dose absorbed and is equal to the corresponding "zero to infinity" area under the curve for a single-dose study. Therefore, when steady-state conditions are achieved, a comparison of blood concentrations during a dosing interval may be used to define the fraction of the active drug ingredient or therapeutic moiety absorbed.

 

（2）在线性系统下，在多剂量稳态研究中给药间隔期间血药浓度-时间曲线下面积与吸收量的分数成正比，且等于单剂量研究曲线下相应的“零到无穷”面积，因此，当达到稳态时，比较给药间隔期间的血药浓度可以确定吸收的药物活性成分或治疗结构的分数。

 

(3) Other methods based on valid scientific reasons should be used to determine the bioavailability of a drug product having dose-dependent kinetics (non-linear system).

 

（3）基于有效科学依据的其他方法用于确定具有剂量依赖性动力学（非线性系统）药物的生物利用度。

 

(f) Measurement of an acute pharmacological effect. When comparison of the test product and the reference material is to be based on acute pharmacological effect-time curves, measurements of this effect should be made with sufficient frequency to demonstrate a maximum effect and a lack of significant difference between the test product and the reference material.

 

（f）急性药理作用的测定。当比较测试产品与参比制剂的急性药理作用-时间曲线时，应有足够的频率测量该效应，来证明最大效果和测试产品与参比制剂之间无显著性差异。