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这个问题好大,也很现实, 确实不能一言尽数。我试试从不同角度抛准引玉:

1.BE studies:

•Usually two-way crossover, single-dose study (replicate cross over for high

variable drug )

•Normal volunteers

•Fasting –BE criteria: 90% CI between 80 and 125% (AUC, Cmax)

•Fed (point-estimate between 80 and 125)

2. Example BE results

3. Reasons for “Failure” of BE Studies

•Under-powered study

•Unusual study designs


•“Outlier” response from one or more subjects

•Assay issues

•Wrong reference

•Baseline-corrected vs. not corrected

•Incorrect statistical analysis

•Compliance issues

•Formulation that is not truly bioequivalent to the reference (配方只是 BE 失败其

中一个原因)

楼上英文版的关于 BE 失败的原因分析:制剂原因只是其中一个原因,这个非常赞同。我也

认为其实很多时候 BE 失败,都不一定能从制剂方面分析出原因或调整方向

好像我看了上面的回复多是调崩解、或改变粒径的方法

其实楼主的问题不用设前提,建议问题:作为判断 BE 合格的两个指标,Cmax 和 AUC 不

在标准范围内时,如何调整制剂处方工艺?

但就像上面提到的,制剂只是一个方面。所以如果有提到出现什么样的 BE 数据时,可以判

断绝对不是制剂原因,那是最好了

Cmax 和 Tmax 是相互影响的,Cmax 变化了 Tmax 一定也跟着变化,所以情况 1 和情况 2

在 BE 时一般不会出现。
确实,BE 时最不容易等效的是 Cmax。AUC 一般不会不等效性,但也会出现,比如受试制

剂在胃肠道内没有完全崩解。

BE 研究的是受试和参比的吸收速度和程度,Cmax 和吸收速度相关,对应的是安全性指标,

体外与制剂的溶出速率有关;AUC 和吸收程度有关,对应的是有效性指标,体外与制剂的

溶出程度有关。

会出现,当你给药量不足的情况下

BE 时,不存在给药剂量不足的情况,一般情况参比和受试的给药剂量是一致的。除非受试

制剂在胃肠道内溶出不完全,但现在这种情况也基本不会出现,没有人会不研究溶出曲线直

接上 BE 的,只要研究了 4 条溶出曲线,且 f2 都能大于 50,体内 AUC 基本上不会不等效,

最容易不等效的是 Cmax

是存在的,当药物的体内处置很快的时候就会出现,只是我们看到的相对较少。其次溶出跟

体内是否释放完全并无直接的关系,你所说的四条就基本不成立,我们已经遇到了类似的项

目,溶出曲线都一直,但是 BE 就不一致的,这个理论就是错的。

法规规定:自制制剂和参比制剂含量相差 5%以内,在统计分析中则不用进行剂量校正。一

般都会控制在 3%左右。我现在有一个问题:含量的测定一般都是很多片在一起测定的均值。

而在 BE 实验服药时,是以单个制剂的形式。与含量均匀度的方法类似。这样的话,单个制

剂含量就在 10%以内波动。这对 BE 的结果分析会有影响么?


"是存在的,当药物的体内处置很快的时候就会出现,只是我们看到的相对较少。"这句话不

太懂,请您指点。

我们现在进行的 BE 和看到的文献,受试和参比的给药剂量都是一致的,目前还没有发现给

药剂量不一致的 BE,不知这样设计的目的是什么?统计时也会造成麻烦

“其次溶出跟体内是否释放完全并无直接的关系,你所说的四条就基本不成立,我们已经遇

到了类似的项目,溶出曲线都一直,但是 BE 就不一致的,这个理论就是错的。”

请问不一致的是 AUC 吗?AUC 是否在 80-125 的范围内。如果 AUC 都不在 80-125 的范

围内,受试制剂和参比制剂在体外一定有的较大差异,应该没有找到有区分力的曲线。另外,

还要通过 PK 参数分析一下是制剂的原因、检测的原因还是临床操作过程中的原因

这个药什么类别,线性,非线性?变异咋样?这公式是用在最简单的单室线性药。极端例子,

横轴时间,纵轴 C,三个点。0,tmax,消除完了。AUC 就是个三角形的面积。AUC,tmax

一样,cmax 不一样,那消除相和横轴交点要不一样吧,否则怎么保证面积一样。如果不一

样就意味着 k 已经变了。

前辈,
“还要通过 PK 参数分析一下是制剂的原因、检测的原因还是临床操作过程中的原因”

这个通过 PK 参数分析原因的方法能否说的详细一点啊?我觉得您说的这个很有意思。还有

一个问题就是关于预试验,预实验的例数一般较少,结果可能有偏移。一般都会进行统计学

的推算。我想问如果按照推算的例数进行,风险会有多大?

假设其他因素均满足要求,只从制剂释放角度分析个人感觉应先搞清楚以下问题:1)药物

性质,药物的吸收是药物溶出速度限制还是肠道渗透限制,对于 bcs3 类药,由于溶解度高,

胃内一般可以以分子态存在,到肠道中直接吸收,这时增加制剂释放或溶出基本没有效果,
因为其限速步骤是渗透。对于 bcs2 类药,药物到达肠道的形态包括分子态和药物颗粒,分

子态被快速吸收,药物颗粒来不及溶出足够的分子态药物而降低其吸收,成为吸收的限速步

骤,此时增加药物的溶出速度将提高其生物利用度,比如固体分散(分子态药物)或减小粒

径(增加药物分子溶出)。2)药物胃排空时间,胃排空时间越长,药物在胃中滞留时间越

长,那么其到达吸收位点(肠道)的时间就越长,当然胃排空不是一下子的事情,他是以一

定的速度排空的,可能每次排空 3~5ml 内容物,对于速释制剂,其在胃内的 15~30 分钟

的溶出差异相对与后续的 2~3 小时的吸收是不显著的,而较长时间的差异将影响吸收,很

多上市制剂胶囊或片改剂型为冲剂或口崩片,生物等效也是这个道理,当然保证制剂在这

30 分钟能溶出或崩解成与参比制剂类似的情况是很关键的,因为这涉及到入肠道后药物的

溶出或药物与肠道的吸收面积。

有一个问题:假如处方里不含有改变细胞膜性质的辅料,如果药物吸收进入血液是被动扩散

的话,意味着膜两侧接近漏槽条件。这个时候释放速度与吸收速度直接相关(此处是否可以

直接关联 Cmax)
。如果药物吸收进入血液是通过主动转运,意味着膜上面的转运体才是吸

收速度的关键。这个时候,释放速度与吸收速度是否不直接相关?对于此类型的,是否溶出

快慢没那么大的意义?

确实是个好问题,如果 BE 不合格,该从哪些因素和环节分析原因?千万不要出现扯皮,推

诿和说不清的情况。

我们也遇到这个问题,体外溶出曲线比原研快,体内 Cmax,Tmax 比原研慢,怎么分析,找

出影响吸收的关键因素

飞翔 156
前辈,前段时间听群友讨论说很多品种都过了预 be。关于预 be 我有几个问题想请

教: 1、一般大家预 be 都做多少

例?

2、预 be 现在是不是餐前餐后都要

做?

3、预 be 过了是不是 be 就肯定能过

啊?

4、关于预 be 结果的判断及风险控制。有的预 be 结果是直接落在

80-125%范围内的,直接通过的。还有的结果可能不在范围内,但是经过软件推算,增加

一定例数后,结果是可以符合要求的。对于这种的,前辈您怎么看啊?如何规避 be 风险呢?

谢谢!

1 例数根据试验药物的变异情况、试验方案设计来定,高变异的要多一些,变异较低一般

4-8 例,高变异一般 8-16,当然还有更多,比如 FDA 公开的审评报告中预实验也有做 20

例以上的。

2 要看食物对关键的 PK 参数是否有影响,及影响有多大

3 预 BE 过了,正式不一定能过,尤其是高变异的药物

4 除了看范围,还要看几何均值的比值。预实验的比值非常重要,比值能分析出两个制剂

的差异有多少,这个通常在正式 BE 时是无法改变,预实验比值最好在 95-105%之间;范

围能分析出变异情况,范围是可以通过增加例数来变窄的。

要提高 BE 的成功率,体外溶出研究很重要,不要拘泥于常规的溶出条件
狼牙九纵

请问楼主,我们现在的品种 BCS 二类,Cmax 等效(GMR:100.1),但是 AUC 不等效,

应该从哪些方面分析

AUC 不等效的比较少见啊。自制与参比样品的含量差异大么?还有就是取样时间点的设置

是否合理啊?这些都会影响 AUC。如果排除以上的因素,BCS2 类的应该在体外能够找到

对应的溶出条件。重点关注一下溶出终点的差异。

有一个问题:假如处方里不含有改变细胞膜性质的辅料,如果药物吸收进入血液是被动扩散

的话,意味着膜两侧接近漏槽条件。这个时候释放速度与吸收速度直接相关(此处是否可以

直接关联 Cmax)。如果药物吸收进入血液是通过主动转运,意味着膜上面的转运体才是吸

收速度的关键。这个时候,释放速度与吸收速度是否不直接相关?对于此类型的,是否溶出

快慢没那么大的意义?

药物不溶出是不会被吸收的,不管哪种扩散方式,释放速度与吸收速度都是有关联性的!

zhushengsheng99

前辈,您好:

看了您的回复感觉受益匪浅,想请教您几个问题,请赐教。

1、一般什么样的药物的预 BE 会空腹和餐后都做? 是变异度比较大的,还是食物影响比较

大的会空腹餐后一起做?
一般药物的体内变异系数和食物对药物的吸收的影响等是从哪里查询? FDA 的网站上

还是?

2、如果预 BE 空腹餐后均做的话,通常的做法餐后的预 BE 需要餐前的结果出来后做餐后,

还是餐前做完直接做餐后?

3、正式实验的时候餐后 BE 是否一般等着餐前 BE 结果出来后再决定是否进行,是否修改方

案?

4、我们一般预 BE 空腹做的比较多,做餐后的不多,有的专家说预 BE 直接做餐后的预 BE,

根据餐后的结果推算出例数,然后餐前餐后的实验例数一样,这样就可以省做餐前 BE,您

觉得这种做法怎么样?

1、一般情况下预 BE 餐前、餐后都要做,主要目的是预估样本量和确认采血点。除非说明

书有明确的规定是餐前服用还是餐后服用。变异系数和食物影响可以看看药品的审评报

告。 2、预实

验一般都是做完一个再做另一个。因为一个不过,如果明确显示是处方工艺问题,另一个就

不用做了。

3、正式试验一般都是同时开展。也有人采用单独的方式进行。主要看你们和临床单位的沟

通。

4、这种方法有待商榷。主要原因是餐前和餐后的变异系数不一样,风险较

大。 以上是个人意见,有什么好的案

例大家可以一起交流。
Sorry for this question but I am totally new to the field of bioequivalence and I
have the following case:

A single dose, two sequence and two period- crossover bioequivalence study
with 32 subjects fails to show bioequivalence because the criteria for AUC 0-t
were not met (76.62-102.75%) but Cmax is clearly within the limits
(81.71-109.23%). T/R of Cmax was 94.47% and T/R of AUC 0-t was 88.73%.
CV% was 42.89% for Cmax and 46.99% for AUC 0-t of the test product.

The dissolution profiles have already revealed a tendency of slower dissolution


rates of the test formulation although statistically from the f2 values similarity
was concluded.

Since the test product fails to meet only the lower end of the criteria for AUC 0-t
it is not truely bioinequivalent. Could it be possible that bioinequivalence was
demonstrated accidentally although the two products are actually bioequivalent?
How could this be proven?

In the study protocol I have read: “A formal statistical calculation of the study’s
power was not carried out (given the scarce literature on intraindividual
variability and confidence intervals for ivermectin).” Is it therefore really only
possible to guess the sample size?

Would it be advisable to perform another bioequivalence study with the same


design?

Hi myy,

» The dissolution profiles have already revealed a tendency of slower


dissolution rates of the test formulation although statistically from
the f2 values similarity was concluded.

Unfortunately in vivo sometimes does not match in vitro.

» Since the test product fails to meet only the lower end of the criteria
for AUC 0-t it is not truely bioinequivalent. Could it be possible
that bioinequivalence was demonstrated accidentally although the two
products are actually bioequivalent? How could this be proven?

Don’t worry, it is too late. SCNR.


I’m not a friend of a posteriori power, but even Cmax passed by luck. With your
ratios and CVs power is just 32.2% for Cmax and 14.6% for AUC.

» In the study protocol I have read: “A formal statistical calculation


of the study’s power was not carried out (given the scarce literature
on intraindividual variability and confidence intervals for
ivermectin).” Is it therefore really only possible to guess the sample
size?

Well, to perform a study “out of the blue” is against the BE-GL Section
4.1.3 (“appropriate sample size calculation”) and ICH-E9. It is surprising that
both the IEC and the regulatory authority (may I ask which one?) approved the
protocol. If the CV is unknown, you should have performed a pilot study.

» Would it be advisable to perform another bioequivalence study with


the same design?

No. If I take your ratio and CV for AUC as “carved from stone” (cave: there is no
guarantee that you will be able to get exactly these numbers in the new study)
you would need 232 (!) subjects to show BE with 80% power.

ell, to perform a study “out of the blue” is against the BE-GL Section
4.1.3 (“appropriate sample size calculation”) and ICH-E9. It is
surprising that both the IEC and the regulatory authority (may I ask
which one?) approved the protocol.

The Spanish authority.

Hi myy,

» A single dose, two sequence and two period- crossover bioequivalence


study with 32 subjects fails to show bioequivalence because the
criteria for AUC 0-t were not met (76.62-102.75%) but Cmax is clearly
within the limits (81.71-109.23%). T/R of Cmax was 94.47% and T/R of
AUC 0-t was 88.73%. CV% was 42.89% for Cmax and 46.99% for AUC 0-t
of the test product.

The relevant CV is not for the T or R product but for the GMR. I assume that's
what you meant?
Anyways, a CV for Cmax lower than CV for AUCt is quite unusual and I always
question it. Please take a look at the production of data rather than just at the
data.

» Since the test product fails to meet only the lower end of the criteria
for AUC 0-t it is not truely bioinequivalent. Could it be possible
that bioinequivalence was demonstrated accidentally although the two
products are
actually bioequivalent? How could this be proven?
Careful with the terminology. Bioinequivalence was not shown. Your product
could be BE, it has just not been demonstrated. Bioinequivalence is only if the CI
is entirely outside the acceptance range.

» Would it be advisable to perform another bioequivalence study with


the same design?

Advisable? Perhaps.
Justifiable? Yes, probably.
But you might wish to take a new look at the sample size with your max
likelihood PEs and observed CVs..... after review of data production.

Ivermectin is kind of special compound, I guess (regarding chemical structure


etc.), look here

http://www.accessdata.fda.gov/drugsatfda_docs/nda/96/050742ap.pdf

According to p.191 and 198 CV% for AUC might well be higher than for Cmax,
at least in some cases...

Regards

» Since the test product fails to meet only the lower end of the criteria
for AUC 0-t it is not truely bioinequivalent. Could it be possible
that bioinequivalence was demonstrated accidentally although the two
products are
» actually bioequivalent? How could this be proven?
»
» Careful with the terminology. Bioinequivalence was not shown. Your
product could be BE, it has just not been demonstrated.
Bioinequivalence is only if the CI is entirely outside the acceptance
range.

Could this also be argued in front of regulatory authorities?

» Could this also be argued in front of regulatory authorities?


IMHO this will not be possible. For sample size calculation you assume a
formulation difference of <5%. In case of Cmax this holds true whereas in case
of AUC the T/R ratio is >10%. You could demonstrate bioequivalence but as
Helmut demonstrated you would need an unethical high number of subjects
since the study have to be overpowered to get the desired result.
Kind regards
Dr_Dan

Dear myy
In order to possibly give you some advice more information would be needed. I
guess the study was conducted in humans, right? And the AUC was truncated
due to the long terminal half life of the drug? Comparative dissolution showed f2
values >50 at all three pH levels (1.2, 4.5 and 6.8)? The high ANOVA CV was not
caused by outlying subjects? Before you start reformulating your product you
need to be sure that the study outcome is valid.
Kind regards
Dr_Dan

» In order to possibly give you some advice more information would


be needed. I guess the study was conducted in humans, right?

Yes.

» And the AUC was truncated due to the long terminal half life of the
drug?

AUC 0-i was measured as well. And the values were about the same as for AUC
0-t. (76.76-102.52)

» Comparative dissolution showed f2 values >50 at all three pH levels


(1.2, 4.5 and 6.8)?

Because of difficulties with degradation of ivermectin at acidic pH the drug


release rate was not measured at pH 1.2. But also at pH 7.0.

» The high ANOVA CV was not caused by outlying subjects?

I couldn't find any data about outlier detection. Maybe this was not carried out?

» Before you start reformulating your product you need to be sure that
the study outcome is valid.

I have to assess the study from a regulatory point of view and give a strategic
advice. But it seems to me that the study should be reviewed by a competent
statistician first...

Thank you very much for all your comments!

» Because of difficulties with degradation of ivermectin at acidic


pH the drug release rate was not measured at pH 1.2. But also at pH
7.0.
»
Degradation is a substance specific characteristic. Once the tablet disintegrates
and the drug dissolves the concentrations you measure both formulations
should be affected in the same way. But it is very important to see if the profiles
of test and reference are similar even if the shape of the curves are strange (no
100% dissolution, decline of curve etc.). In my opinion for IR formulations the
results of comparable dissolution at pH 1.2 are more predictive for in vivo
performance than the results of pH 6.8.
Kind regards
Dr_Dan