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

 

單劑量體內(nèi)生物利用度或生物等效性研究指南

 

（a）Basic principles.

 

（a）基本原則：

 

(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）體內(nèi)生物利用度或生物等效性研究應(yīng)在正常成人體內(nèi)將待測(cè)藥品與參比制劑進(jìn)行單劑量比較。

 

(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）受試者應(yīng)在禁食狀態(tài)下服用測(cè)試產(chǎn)品與參比制劑，除非有其他更有效的科學(xué)依據(jù)。

 

（b） Study design.

 

（b）研究設(shè)計(jì)。

 

(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）單劑量研究應(yīng)進(jìn)行交叉試驗(yàn)設(shè)計(jì)，除非平行試驗(yàn)設(shè)計(jì)或有其他設(shè)計(jì)更合適，并應(yīng)有藥物的清洗期。

 

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

 

除非有其他適用的有效的科學(xué)依據(jù)，否則藥物清洗期應(yīng)為：

 

(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）至少為血液或尿液中測(cè)定的藥物活性成分或治療結(jié)構(gòu)或其代謝物半衰期的三倍；或

 

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

 

（ii）至少是急性藥理作用半衰期的三倍。

 

(c) Collection of blood samples.

 

（c）血液樣品收集。

 

(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）當(dāng)測(cè)試樣品與參比制劑進(jìn)行比較時(shí)，以血藥濃度-時(shí)間曲線為基礎(chǔ)，除非有其他更合適有效的科學(xué)依據(jù)，否則應(yīng)以足夠的頻率采集血液樣品，以便對(duì)二者進(jìn)行評(píng)估。

 

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

 

（i）測(cè)定活性藥物成分或治療結(jié)構(gòu)或其代謝物在血液中峰濃度；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）至少測(cè)定藥物活性成分或治療結(jié)構(gòu)或其代謝產(chǎn)物半衰期的三倍時(shí)間的曲線下總面積。

 

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

 

（2）在比較口服劑型時(shí)，取樣時(shí)間應(yīng)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）在比較靜脈注射劑型和口服劑型時(shí)，取樣時(shí)間應(yīng)滿足二者的需要。

 

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

 

（i）靜脈注射劑型的分布和消除階段；和

 

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

 

（ii）口服劑型的吸收和消除階段。

 

(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）在比較有適當(dāng)參比制劑、口服或靜脈注射劑型以外給藥方式的研究中，取樣時(shí)間應(yīng)按照有效的科學(xué)依據(jù)。

 

(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）尿樣收集。當(dāng)測(cè)試產(chǎn)品和參比制劑的比較是基于尿藥累積排泄量曲線時(shí)，除非有其他更合適的有效的科學(xué)依據(jù)，否則應(yīng)以足夠的頻率收集尿樣，以便對(duì)活性藥物成分或治療結(jié)構(gòu)或其代謝產(chǎn)物的尿液排泄率和排泄量進(jìn)行估計(jì)。

 

(e) Measurement of an acute pharmacological effect.

 

（e）急性藥理作用的測(cè)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）當(dāng)試驗(yàn)產(chǎn)品和參比制劑的比較是基于急性藥理作用-時(shí)間曲線時(shí)，應(yīng)有足夠的頻率去測(cè)定該效應(yīng)，至少為藥理學(xué)半衰期的三倍時(shí)間對(duì)曲線下總面積進(jìn)行合理估計(jì)，除非有其他更合適的科學(xué)依據(jù)。

 

(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）使用急性藥理作用來(lái)確定生物利用度可能需要進(jìn)一步證明劑量相關(guān)的反應(yīng)。在此情況下，可以比較劑量-反應(yīng)曲線以及任何給定劑量的急性藥理作用-時(shí)間曲線下總面積來(lái)確定生物利用度。

 

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

 

多劑量體內(nèi)生物利用度研究指南

 

(a) Basic principles.

 

基本原則。

 

(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）在一些情況下，可能需要在重復(fù)給藥后比較試驗(yàn)產(chǎn)品與參比制劑，以確定活性成分或治療結(jié)構(gòu)在體內(nèi)的穩(wěn)態(tài)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）受試者應(yīng)按照測(cè)試產(chǎn)品說(shuō)明中的條件空腹或非空腹?fàn)顟B(tài)下服用測(cè)試產(chǎn)品和參比制劑。

 

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

 

（3）以下情況可能需要進(jìn)行多劑量研究試驗(yàn)來(lái)確定藥品的生物利用度：

 

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

 

（i）吸收速率有差異，吸收程度不同。

 

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

 

（ii）受試者之間的生物利用度變異過(guò)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）單劑量給藥后血液中藥物成分或治療結(jié)構(gòu)或其代謝產(chǎn)物的濃度太低，分析方法無(wú)法準(zhǔn)確定量。

 

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

 

（iv）藥品是緩釋劑型。

 

(b) Study design.

 

（b）研究設(shè)計(jì)。

 

(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）多劑量生物利用度研究應(yīng)該進(jìn)行交叉試驗(yàn)設(shè)計(jì)，除非平行試驗(yàn)設(shè)計(jì)或其他設(shè)計(jì)更合適，如果沒有實(shí)現(xiàn)穩(wěn)態(tài)條件，應(yīng)該提供藥物的清洗期。

 

(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）如果多劑量研究是為了建立劑量比例關(guān)系或研究新藥、新的藥物劑型或緩釋劑型的藥代動(dòng)力學(xué)，則不需要進(jìn)行交叉試驗(yàn)設(shè)計(jì)。

 

(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）如果需要藥物的清洗期，除非有其他更合適的科學(xué)方法，否則藥物的清洗期應(yīng)為：

 

(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）至少為血液或尿液中活性藥物成分或治療結(jié)構(gòu)或其代謝產(chǎn)物半衰期的5倍；或

 

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

 

（ii）至少為急性藥理作用半衰期的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）實(shí)現(xiàn)穩(wěn)態(tài)。當(dāng)進(jìn)行多劑量研究時(shí)，除非有其他更適合的科學(xué)原因，否則應(yīng)按照說(shuō)明給予足夠劑量的試驗(yàn)藥品和參比制劑以達(dá)到穩(wěn)態(tài)。

 

(d) Collection of blood or urine samples.

 

（d）收集血樣或尿樣。

 

(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）當(dāng)以穩(wěn)態(tài)條件下血藥濃度-時(shí)間曲線來(lái)比較測(cè)試樣品與參比制劑時(shí)，應(yīng)給予適當(dāng)劑量藥物和取樣，證明達(dá)到穩(wěn)態(tài)。

 

(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）當(dāng)以穩(wěn)態(tài)條件下尿藥累積排泄-時(shí)間曲線來(lái)比較測(cè)試產(chǎn)品與參比制劑時(shí)，應(yīng)給予適當(dāng)劑量和取樣，證明達(dá)到穩(wěn)態(tài)。

 

(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）穩(wěn)態(tài)時(shí)服用單一劑量后，獲得血藥濃度或尿排泄率更完整的信息，可以估算濃度-時(shí)間曲線或尿藥累積排泄-時(shí)間曲線下總面積，以獲得更多的藥代動(dòng)力學(xué)信息，如半衰期或血液清除率，這是藥品說(shuō)明書需要的。

 

(e) Steady-state parameters.

 

（e）穩(wěn)態(tài)參數(shù)。

 

(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）在某些情況下，例如在設(shè)計(jì)新藥物實(shí)體的研究中，應(yīng)在多劑量研究中獲得穩(wěn)態(tài)血液清除率與單劑量研究中的血液清除率進(jìn)行比較，來(lái)支持合適的服用劑量。

 

(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）在線性系統(tǒng)下，在多劑量穩(wěn)態(tài)研究中給藥間隔期間血藥濃度-時(shí)間曲線下面積與吸收量的分?jǐn)?shù)成正比，且等于單劑量研究曲線下相應(yīng)的“零到無(wú)窮”面積，因此，當(dāng)達(dá)到穩(wěn)態(tài)時(shí)，比較給藥間隔期間的血藥濃度可以確定吸收的藥物活性成分或治療結(jié)構(gòu)的分?jǐn)?shù)。

 

(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）基于有效科學(xué)依據(jù)的其他方法用于確定具有劑量依賴性動(dòng)力學(xué)（非線性系統(tǒng)）藥物的生物利用度。

 

(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）急性藥理作用的測(cè)定。當(dāng)比較測(cè)試產(chǎn)品與參比制劑的急性藥理作用-時(shí)間曲線時(shí)，應(yīng)有足夠的頻率測(cè)量該效應(yīng)，來(lái)證明最大效果和測(cè)試產(chǎn)品與參比制劑之間無(wú)顯著性差異。