pjs
★    

India,
2015-05-20 12:25
(3235 d 09:42 ago)

Posting: # 14854
Views: 5,092
 

 Pharmacokinetics linearity [Regulatives / Guidelines]

Dear all,

What information may be needed to extrapolate linearity for the oral solution dosage form.
  1. Innovator has developed tablet and has established linearity in the dose range e.g. 10-200mg (oral) and 2-10 mg (IV).
  2. Generic oral solution has been available in the strength of 5mg/5ml and 25 mg/5ml.
If we develop oral solution which is Q1 same and Q2 similar (no excipient affecting GI motility/similar to generic). How can we prove linearity for 5mg/5ml strength and get biowaiver?

Drug is BCS class 3

Has been used in the general population for more than 10 years and the submission is for Europe.

Regards,
PJS
pjs
★    

India,
2015-05-28 14:26
(3227 d 07:41 ago)

@ pjs
Posting: # 14865
Views: 4,070
 

 Pharmacokinetics linearity

Dear all,

Further to this post.
  1. As mentioned pharmacokinetics is linear after IV administration of 2-10 mg. Hence can it be assumed that metabolism and elimination are linear in this range?? Hence if absorption is linear after oral administration in this dose range can linearity be suggested? Also what can be reasons for nonlinearity at lower dose? The drug is BCS class3 but if it would be BCS class1 than can no difference in absorption be assumed and linearity be suggested (not intended drug but just hypothetical case)?

  2. Another option is doing BE study at higher strength 25 mg and after successfully completing it, using the same subjects to dose 5 mg and extrapolating linearity in terms of Cmax and AUC.
    What about regulatory acceptance?

  3. If Cmax and AUC data are available for the dose 25 mg and 50mg and lndose vs lnAUC pass through 0 can linearity be assumed for 5 mg also?

Please suggest.

Regards,
PJS
nobody
nothing

2015-05-28 15:44
(3227 d 06:23 ago)

@ pjs
Posting: # 14866
Views: 4,027
 

 Pharmacokinetics linearity

❝ 3. If Cmax and AUC data are available for the dose 25 mg and 50mg and lndose vs lnAUC pass through 0 can linearity be assumed for 5 mg also?


OMG! General principles of linear regression: Never extrapolate beyond your data range actually measured.

What kind of science is that here? :-o

Kindest regards, nobody
ElMaestro
★★★

Denmark,
2015-05-28 16:14
(3227 d 05:53 ago)

@ nobody
Posting: # 14867
Views: 4,092
 

 Pharmacokinetics linearity

Hi both,

❝ ❝ 3. If Cmax and AUC data are available for the dose 25 mg and 50mg and lndose vs lnAUC pass through 0 can linearity be assumed for 5 mg also?


❝ OMG! General principles of linear regression: Never extrapolate beyond your data range actually measured.


I guess this means never extrapolate, only interpolate? Bioanalysts will yay this proposal :-)

I don't like the "lndose vs lnAUC" thing; it sounds a bit wrong. It must be AUC as function of dose -without logs- that gives a straight line through origo. Anyways, (0,0) is usually the most accurately known point on the entire curve.

Pass or fail!
ElMaestro
Dr_Dan
★★  

Germany,
2015-05-28 16:32
(3227 d 05:35 ago)

@ ElMaestro
Posting: # 14868
Views: 4,073
 

 Pharmacokinetics linearity

Dear PJS
Honestly, I do not understand your question. The originator demonstrated linearity after i.v. and oral administration (irrespectively of formulation type tablet or solution). I guess you develop an oral solution formulation whereas the originator is a solid oral formulation. In this case your formulation is no generic. In order to make reference to the originator´s dossier in a mixed application you need to show bioequivalence of your oral solution formulation against the solid oral formulation. Since the drug is a BCS class III substance it will become hard to achieve equivalence in terms of AUC and Cmax using the same strength. Good luck! I guess you will need a clinical study in order to demonstrate safety and efficacy.
I hope this helps.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
pjs
★    

India,
2015-05-28 16:58
(3227 d 05:09 ago)

@ Dr_Dan
Posting: # 14869
Views: 4,035
 

 Pharmacokinetics linearity

Dear all,

Thanks for your response.

I am talking about interpolating the linearity.

One case i can think of the nonlinearity at lower dose is drug is getting degraded in the GI tract due to some enzyme and only after above certain concentration the enzyme get saturated and linear pharmacokinetics can be availed. Or above certain concentration only can be bound to transporter (due to competition with other GI content to get bound with the transporter).

We will be doing one BE study at higher streangth (25mg/5ml sol vs 25 mg tab )and using that data to support the article 10(3) application But would like to apply for the biowaiver for lower strength. Yes, It would be difficult to prove BE as its BCS class 3 drug. However one company has filed generic application using the same strategy and had also availed biowaiver for lower strength. Just quriuous regarding the data that they may have submitted.

Please revert back in case of further clarification.

Regards,
PJS
nobody
nothing

2015-05-28 17:50
(3227 d 04:18 ago)

@ pjs
Posting: # 14871
Views: 4,001
 

 Pharmacokinetics linearity

❝ I am talking about interpolating the linearity.


If you have data for 25 and 50 mg and from this you conclude on 5 mg you extrapolate. Not interpolate. Get your terminology right.

That's not funny anymore.

@Maestro: Absolutely right, extrapolation is nonsense. Except for stock markets and so call "economic sciences" (aka "voodooooo" that makes the world go arround...)

:-D

Kindest regards, nobody
pjs
★    

India,
2015-05-28 18:11
(3227 d 03:56 ago)

@ nobody
Posting: # 14875
Views: 3,984
 

 Pharmacokinetics linearity

Dear nobody,

Apologies for the wrong terminology. What i mean to say was extrapolating the linearity on lower range. I also had doubts regarding this option as mentioned in my earlier post. But just wanted to know forum members view on that.

Apart from point 3 of earlier post would like to know view about the 1st and 2nd point of the forum members.

Has any body experinece in filling generic product in which similar extrapolation of the linearity has been done and accepted by the agency.

Thanks.

Regards,
PJS
Dr_Dan
★★  

Germany,
2015-05-29 11:03
(3226 d 11:04 ago)

@ pjs
Posting: # 14881
Views: 3,936
 

 Pharmacokinetics linearity

Dear PJS
I do not know if I get things right, but IMHO the whole discussion would only make sense if you claim bioequivalence of your BE formulation (25mg/5ml sol which will be tested vs 25 mg tab ) also to the lower tablet strength (i.e. 5mg/1ml sol vs 25 mg tab). But as far as I understood you want to waive the 5mg/5ml strength. This is a different formulation (not dose proportional composition) and consequently you will need another BE study.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
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