NK
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India,
2024-08-05 08:07
(90 d 16:49 ago)

Posting: # 24128
Views: 1,542
 

 Predose concentration more than 5 % of Cmax [Regulatives / Guidelines]

Hello All,

Please provide your input for the following,

As per the FDA guideline

If the pre-dose concentration is ≤ 5 percent of the Cmax value in a subject with a pre-dose plasma concentration, applicants can include the subject’s data without any adjustments in all PK measurements and calculations. We recommend that if the pre-dose value is > 5 percent of the Cmax, applicants drop the subject from all BE study evaluations.

My question here is,

In a BE study of FDC (or drug with two isomers), If any subject had pre-dose > 5 percent of the Cmax for one drug (or one isomer), What should be followed
  1. Drop the subject from the statistical analysis of both the drug (or both the isomer) or
  2. Drop only for the statistical analysis of a drug (or a isomer) for which the pre-dose observed was > 5 percent of the Cmax and include for other drug (or isomer).
Regards
NK
Helmut
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Vienna, Austria,
2024-08-05 10:36
(90 d 14:20 ago)

@ NK
Posting: # 24129
Views: 1,306
 

 FDC or isomers: C0 > 5 % of Cmax

Hi NK,

The ICH’s M13A will soon supersed the FDA’s guidance. However, a similar procedure is stated in its Section 2.2.3.3 Carry over.

❝ In a BE study of FDC (or drug with two isomers), If any subject had pre-dose > 5 percent of the Cmax for one drug (or one isomer), What should be followed

❝  1.Drop the subject from the statistical analysis of both the drug (or both the isomer) or

❝  2. Drop only for the statistical analysis of a drug (or a isomer) for which the pre-dose observed was > 5 percent of the Cmax and include for other drug (or isomer).


The idea of assessing the predose concentrations in higher period(s) is to check whether the washout was sufficiently long. The treatment comparison in the presence of unequal carryover would – unavoidably – be biased and there is no statistical method to adjust for it. For details see this article.
In a FDC half lives of components are generally different. In a drug with two isomers the half lives are likely different as well. Therefore, #2 because the washout was long enough for the respective other drug / isomer.

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Achievwin
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US,
2024-08-05 21:08
(90 d 03:48 ago)

@ Helmut
Posting: # 24134
Views: 1,302
 

 FDC or isomers: C0 > 5 % of Cmax

❝ The ICH’s M13A will soon supersed the FDA’s guidance. However, a similar procedure is stated in its Section 2.2.3.3 Carry over.


❝ The idea of assessing the predose concentrations in higher period(s) is to check whether the washout was sufficiently long. The treatment comparison in the presence of equal/unequal carryover would – unavoidably – be biased and there is no statistical method to adjust for it.


Oh my equal/unequal carryover – never ending story
Helmut
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Vienna, Austria,
2024-08-06 00:39
(90 d 00:17 ago)

@ Achievwin
Posting: # 24139
Views: 1,249
 

 Carryover. A Never Ending Story.

Hi Achievwin,

❝ Oh my equal/unequal carryover – never ending story


THX for quoting my title! :-D

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Ohlbe
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France,
2024-08-08 20:09
(87 d 04:47 ago)

@ Helmut
Posting: # 24143
Views: 1,153
 

 Inducers/inhibitors

Dear Helmut,

❝ In a FDC half lives of components are generally different. In a drug with two isomers the half lives are likely different as well. Therefore, #2 because the washout was long enough for the respective other drug / isomer.


Yes, but... what if the drug which is still detected induces or inhibits the metabolism of the drug which is no longer detected ?

Regards
Ohlbe
Helmut
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Vienna, Austria,
2024-08-09 10:26
(86 d 14:30 ago)

@ Ohlbe
Posting: # 24144
Views: 1,136
 

 Inducers/inhibitors

Dear Ohlbe!

❝ … what if the drug which is still detected induces or inhibits the metabolism of the drug which is no longer detected ?


That’s a very good point!
One of the prerequisites of a crossover design is that subjects in later period(s) are in the same physiological state than in the drug-naïve first. This is not necessarily always the case – even after a ‘suitable’ washout. Examples:
  • A multiple dose study of the auto-inducer car­bama­ze­pine is more sensitive to detect differences between formations than a single dose study (esp. of the rate of BA).1,2
  • In crossover studies of biosimilars unequal carryover was regularly observed in the past, unavoidable biasing the treatment effect. There­fore, studies should be performed in a parallel design.3,4
Assessing pre-dose concentrations in a crossover design is only one piece of the cake. As usual: Know the PK of the drug and your formulation. If no data of DDIs of the components of the FDC are available, a small pilot study would help.


  1. Tóthfalusi L, Endrényi L. Approvable generic carbamazepine formulations may not be bioequivalent in target patient populations. Int J Clin Pharmacol Ther. 2013; 51(6): 525–8. doi:10.5414/cp201845.
  2. Schütz H. Steady-state studies. Presentation at: Network of Scientific Excellence. Campinas, BR. 11–13 February, 2020. Online.
  3. EMA, CHMP. Guideline on the Clinical Investigation of the Pharmacokinetics of Therapeutic Proteins. London. 24 January 2007. Online.
  4. Schütz H. Unequal carry-over – “solved” in BE but still an Issue in Assessing Biosimilarity? Satellite Short Course at the 2nd Annual Biosimilars Forum. Budapest. 5 October 2017. Online.

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qualityassurance
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2024-08-05 14:48
(90 d 10:07 ago)

@ NK
Posting: # 24131
Views: 1,276
 

 Predose concentration more than 5 % of Cmax

Hello NK,

I completely agree with Helmut. Go with No. 2.

Regards,
QA
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