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1.BE studies:
•Usually two-way crossover, single-dose study (replicate cross over for high
variable drug )
•Normal volunteers
2. Example BE results
•Under-powered study
•Assay issues
•Wrong reference
•Compliance issues
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
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
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
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
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。”
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,
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
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
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。
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?
啊?
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
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
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
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
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。
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?
还是餐前做完直接做餐后?
案?
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.
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?
Hi myy,
» 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?
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.
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.
Hi myy,
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.
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.
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.
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
—
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)
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...