Mehul Patel
☆

India,
2021-08-17 12:00
(589 d 03:10 ago)

Posting: # 22520
Views: 1,782

## Significant difference in Cmax of Reference drug product [Study As­sess­ment]

Hi,

Can anybody please tell what may be the probable reasons behind significant (more than 20%) difference in mean Cmax concentration of Reference product of a same batch number in two different studies conducted at same CRO and on the similar kind of population but different sample size?

Is it correct to compare and expect Reference product's behavior same for all repeated studies?

Moreover, Can 6 months old (frozen) samples yield significant different results as compared to freshly analyzed study samples?
Helmut
★★★

Vienna, Austria,
2021-08-17 13:57
(589 d 01:14 ago)

@ Mehul Patel
Posting: # 22521
Views: 1,576

## Significant difference in Cmax of Reference drug product

Hi Mehul,

❝ Can anybody please tell what may be the probable reasons behind significant (more than 20%) difference in mean Cmax concentration of Reference product of a same batch number in two different studies conducted at same CRO and on the similar kind of population but different sample size?

I guess you had also the same batch of the test? Was the AUC different as well?

❝ Is it correct to compare and expect Reference product's behavior same for all repeated studies?

A few reference products (dasatinib is an infamous example) show extreme batch-to-batch variability. However, generally batches are expected to be similar.
You could compare the references of the two studies as a paired design (assuming to period effects). For a quick estimate calculate $$\small{\widehat{PE}=PE_1/PE_2}$$, with $$\small{PE_1=\frac{T}{R_1}}$$ and $$\small{PE_2=\frac{T}{R_2}}$$, where $$\small{R_1}$$ and $$\small{PE_1=\frac{T}{R_2}}$$ are the reference batches of the two studies.

❝ […] Can 6 months old (frozen) samples yield significant different results as compared to freshly analyzed study samples?

If long term storage was validated for this duration, no.

Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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Mehul Patel
☆

India,
2021-08-17 14:02
(589 d 01:08 ago)

@ Helmut
Posting: # 22522
Views: 1,613

## Significant difference in Cmax of Reference drug product

❝ I guess you had also the same batch of the test? Was the AUC different as well?

Both the tests were different but Reference were same. AUC of Reference was similar for both the studies, only Cmax varied by 22%. What may be the reasons for this?

❝ ❝ […] Can 6 months old (frozen) samples yield significant different results as compared to freshly analyzed study samples?

❝ If long term storage was validated for this duration, no.

Ok. Thanks

Helmut
★★★

Vienna, Austria,
2021-08-17 17:36
(588 d 21:34 ago)

@ Mehul Patel
Posting: # 22523
Views: 1,515

## Different products → different BA

Hi Mehul,

❝ ❝ I guess you had also the same batch of the test? Was the AUC different as well?

❝ Both the tests were different but Reference were same. AUC of Reference was similar for both the studies, only Cmax varied by 22%.

OK, that’s another cup of tea. If you had different test products (not batches of the same one) in the studies, it’s not uncommon they differ. Were these modified release products? For them similar AUC and different Cmax is much more common than for IR products.

❝ What may be the reasons for this?

Different products, different bioavailability… Business as usual.

Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
dshah
★★

India/United Kingdom,
2021-08-21 12:48
(585 d 02:23 ago)

@ Mehul Patel
Posting: # 22530
Views: 1,400

## Significant difference in Cmax of Reference drug product

Dear Méhul!
There can be multiple reasons for the same.
1. Same subjects? With subject changes- concentration also changes a bit.
2. Same BA method?
3. Same Internal standard batch? Change in internal standard changes height and thus ultimately concentration.
Regards,
Dshah
Helmut
★★★

Vienna, Austria,
2021-08-21 23:43
(584 d 15:27 ago)

@ dshah
Posting: # 22531
Views: 1,382

## Reasons?

Hi Dshah,

❝ 1. Same subjects? With subject changes- concentration also changes a bit.

Agree. However, each study stands on its own since the T vs R comparison is done within subjects. Imagine: One study is performed in ballerinas and the other in Sumo wrestlers. Likely different volume of distributions and hence, concentrations in the first study will by higher than in the second. Nevertheless, the T/R-ratios will be similar.

❝ 2. Same BA method?

Even if different ones are used (unlikely cause Mehul mentioned the same CRO) and if both methods are validated, different Cmax and similar AUC are unlikely as well.

❝ 3. Same Internal standard batch? Change in internal standard changes height and thus ultimately concentration.

Given, the IS response might be different. However, even if calibrators and QC samples are prepared with, say, an IS of just 50% of the declared content in one of the studies, the back-calculated concentrations should be similar and therefore, the T/R-ratios.

Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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dshah
★★

India/United Kingdom,
2021-08-24 14:06
(582 d 01:04 ago)

@ Helmut
Posting: # 22538
Views: 1,287

## Reasons?

Hi Helmut

I have following thoughts w.r.t. to my points.

1. Change in subject will cause change in concentration. Even MVR of many regulatory and ISR also permits ~15% variation at Cmax point. The Cmax is generally variable than AUC. So if the ratio difference is +/- 15%, the discussion shall be of no point. But still may point out that there is difference.

2. BA method and same instrument needs to be mentioned. It could have impact.

❝ ❝ 3. Same Internal standard batch? Change in internal standard changes height and thus ultimately concentration.

❝ Given, the IS response might be different. However, even if calibrators and QC samples are prepared with, say, an IS of just 50% of the declared content in one of the studies, the back-calculated concentrations should be similar and therefore, the T/R-ratios.

Although, it sounds odd, Even for NTI- with same CRO- Method-Instrument; I have witnessed change in concentration with just change in IS batch. It may have similar T/R but even there was difference in T/R.

I hope this may help.
Regards,
Dshah