hirenpharm
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Ahmedabad,
2007-01-20 11:05
(6355 d 06:25 ago)

Posting: # 476
Views: 14,065
 

 SR formulations [General Sta­tis­tics]

Dear all,

Please suggest.
If a single dose BE study of a SR product Vs SR product... we find AUC0-last failing but AUC0-T(Tau)(say 0-24 hrs) passing and Cmax and AUC0-inf is also passing (fast and fed) and no need for steady state.

Can be seek TGA approval for the study?

Which objections are anticipated?

regards..

Dr. Hiren Mehta
Helmut
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Vienna, Austria,
2007-01-22 20:09
(6352 d 21:21 ago)

@ hirenpharm
Posting: # 479
Views: 12,520
 

 SR formulations - no MD study?

Dear hirenpharm!

❝ If a single dose BE study of a SR product Vs SR product...we find AUC0-last failing but AUC 0-T(Tau)(say 0-24 hrs) passing and Cmax and AUC0-inf is also passing.(fast and fed)…


First of all have a look at Imran's post about metrics in steady state.
Single dose parameters are AUClast, AUCinf, and Cmax (although depending on the drug and the type of formulation other parameters like Cmax/AUC, HVD, and MRT may be of interest).

Do I get you right:
AUClast and AUCinf passed, whereas AUC truncated at 24 h did not? This is an interesting phenomenon I never came across before!

❝ …and no need for steady state.


Based on what?
Do you mean that if you do not expect any accumulation, there is no need for such a study?

❝ Can be seek TGA approval for the study?


Yes, but I strongly would suggest a scientific advisory meeting beforehand.

Just to give you an example, we tried to get around a multiple dose study for a formulation with following properties:
  • MR mimicking two IR doses with tau = 4 h
  • half life of the drug 3 h
  • no drug above LOQ in the majority of subjects at 12 h
  • no drug above at LLOQ in any subject at 24 h
  • SPC states OAD administration only
  • no accumulation reported in the literature both for IR (tau = 4 h), and another MR formulation
We had 5 years of development time, a lot of single dose data (vs. solution, IR, fasting, fed, different types of food...), two scientific advisory meetings, a couple of deficiency letters, and finally an approval in 15 European members states. Retrospectively I'm not sure whether it was worth the trouble.

❝ Which objections are anticipated?


OK, the simple one: it's against the guidelines - at least in many countries.
The rationale for a multiple dose study is not only to show BE in steady state, but to get information about potential problems (i.e., even if you have demonstrated no food effect in single dose, and dose dumping is a rare event, you have a higher chance to 'see something' in steady state).

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hirenpharm
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Ahmedabad,
2007-01-23 19:13
(6351 d 22:17 ago)

@ Helmut
Posting: # 483
Views: 12,252
 

 SR formulations - no MD study?

Dear HS,

I did not get me right by misfortune.
I meant to say that the AUC(0-last) failing and AUC(0-24) passing.

Please let me be adviced by you.

regards..
:-(


EDIT: Full Quote removed. [Helmut]

Dr. Hiren Mehta
Helmut
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Vienna, Austria,
2007-01-23 19:32
(6351 d 21:58 ago)

@ hirenpharm
Posting: # 484
Views: 12,309
 

 SR formulations - no MD study?

Dear hirenpharm!

❝ I did not get me right by misfortune.

❝ I meant to say that the AUC(0-last) failing and AUC(0-24)passing.


Hhm, that's bad luck...
One possible reason: your last sampling points are close to LOQ, combined with a relatively long sampling interval (e.g., 16, 24, 36 h). In such a case it happens quite often that in the same subject t(last) will be 24 h for one formulation, and 36 h for the other. Such a difference mainly influences the intra-subject variability--which I would expect to be higher for AUC(last) than for AUC(24). The point estimate should not be influenced as much (differences will mean out).
Unfortunatelly you have to follow your statistical protocol; regulators do not like any kind of 'data dredging' / 'cherry picking'. :cherry picking:

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velupharm
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2007-01-23 13:38
(6352 d 03:52 ago)

@ hirenpharm
Posting: # 481
Views: 12,290
 

 SR formulations

❝ If a single dose BE study of a SR product Vs SR product...we find AUC0-last failing but AUC 0-T(Tau)(say 0-24 hrs) passing and C max and AUC0-inf is also passing.(fast and fed)and no need for steady state.


Dear Hiren, here you are forgetting one important point that calculation of AUC tau has to be done only AFTER THE DRUG REACHES STEADY STATE.
If it is calculated with a single dose study, it does not solve the purpose, because the idea of taking the AUC tau after steady state is to show that the drug concentration shows consistent level in blood/plasma and fluctuating minimally between a Maximum and Minimum concentration.
Also I would like to know with regard to AUC (0-last) that you have mentioned - Is this up to last quantifiable concentration or last concentration that you have measured. I have seen many people getting confused at this point.
Also if you can give the exact details about halflife of the drug and about your last time point, we can give better suggestions
Helmut
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Vienna, Austria,
2007-01-23 20:59
(6351 d 20:31 ago)

@ velupharm
Posting: # 485
Views: 12,379
 

 bioanalytics (LLOQ)

Dear velupharm!

❝ Also I would like to know with regard to AUC (0-last) that you have mentioned - Is this upto last quantifiable concentration or last concentration that you have measured. I have seen many people getting confused at this point.


Me too!
What's the difference between a measured and a quantified concentration? :-D

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velupharm
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2007-01-24 06:36
(6351 d 10:54 ago)

@ Helmut
Posting: # 486
Views: 12,296
 

 bioanalytics (LLOQ)

❝ ❝ Also I would like to know with regard to AUC (0-last) that you have mentioned -Is this upto last quantifiable concentration or last concentration that you have measured.I have seen many people getting confused at this point.


❝ Me too!

❝ What's the difference between a measured and a quantified concentration? :-D


Dear HS
What actually I meant is the difference between measured and quantifiable concentration not quantified concentration.

Especially for longer halflife drugs, sometimes we may not capture adequately say 4-5 halflives (considering a non-truncated approach),despite a highly sensitive bio analytical method and in such cases whatever concentration we have captured with the last may not actually represent in AUC(0-last). In that case the last measured concentration shall not represent last quantifiable concentration
Also I would like to make it clear, whatever words I have used (Confused), shall not mean to criticise or comment particular person. If somebodies feelings have been hurted, kinly pardon me. :-)
Helmut
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Vienna, Austria,
2007-01-24 13:40
(6351 d 03:50 ago)

@ velupharm
Posting: # 487
Views: 13,021
 

 bioanalytics (LLOQ)

Dear velupharm!

❝ What actually I meant is the difference between measured and quantifiable concentration not quantified concentration.


Especially for longer halflife drugs, sometimes we may not capture adequately say 4-5 halflives (considering a non-truncated approach),despite a highly sensitive bio analytical method and in such cases whatever concentration we have captured with the last may not actually represent in AUC(0-last). In that case the last measured concentration shall not represent last quantifiable concentration


Perhaps I am a little bit slow-brained today (still not getting your point).
In my opinion to be measured (=quantified) a concentration of course has to be quantifiable (≥LLOQ and ≤ULOQ) = within the validation range of the method.
If you ‘see something’ in the chromatogram (≥LOD and <LLOQ) you cannot measure it within given limits of accuracy and precision.
Tlast is defined as the time point of the last quantified concentration (within a particular profile).
This is part of a never-ending debate between analysts and phamacokineticist. The former want to report data below the LLOQ simply as 'BLQ' (or if they are liberal even distinguish between 'BLQ' and 'BLD', but never come up with a numeric value), wheras the latter want all possible numbers, irrespective of accuracy/precision (‘we don't care about error - we model it’).
In the field of BA/BE regulators definitely expect us to follow the analyst’s viewpoints.

Have a look at Azim Karim’s plot from David Bourne's PK/PD-list (also giving an explanation of Pharsight's 'invention' AUCall, which sometimes > AUCinf). ;-)

[image]

❝ Also I would like to make it clear, whatever words I have used (Confused), shall not mean to criticise or comment particular person. If somebodies feelings have been hurted, kinly pardon me.


No, no; confusion is a very creative state of mind and highly appreciated!

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joyjac
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Philippines,
2007-05-22 04:13
(6233 d 14:18 ago)

@ Helmut
Posting: # 736
Views: 12,109
 

 bioanalytics (LLOQ)

While I think that values below LLOQ should be reported, may I know how do you handle the statistical analysis? Are these values included in the analysis of data or are they ignored? Thanks for the insight.
Ohlbe
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France,
2007-05-25 01:02
(6230 d 17:28 ago)

@ joyjac
Posting: # 739
Views: 12,052
 

 bioanalytics (LLOQ)

Dear joyjac,

The idea in HS' post was that values below LLOQ should not be reported as numeric values but as "BLQ" (or any other abbreviation. So no value to be included in the PK analysis.

LLOQ is the lowest concentration for which you have demonstrated that you meet the requirements for precision and accuracy. Meaning that any value below LLOQ should be considered as not meeting these requirements and is therefore not reportable.

Even if you see a very nice-looking peak on your chromatogram. And even if you feel that you could achieve a lower LLOQ (which may indeed happen if you have selected your LLOQ based on what you really need for your trial, not on what your instrument can achieve, which can be significantly lower).

Regards
Ohlbe
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