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pjs ★ India, 2015-05-20 12:25 (3595 d 16:20 ago) Posting: # 14854 Views: 5,702 |
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Dear all, What information may be needed to extrapolate linearity for the oral solution dosage form.
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 |
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pjs ★ India, 2015-05-28 14:26 (3587 d 14:19 ago) @ pjs Posting: # 14865 Views: 4,567 |
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Dear all, Further to this post.
Please suggest. Regards, PJS |
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nobody nothing 2015-05-28 15:44 (3587 d 13:01 ago) @ pjs Posting: # 14866 Views: 4,513 |
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❝ 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 |
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ElMaestro ★★★ Denmark, 2015-05-28 16:14 (3587 d 12:31 ago) @ nobody Posting: # 14867 Views: 4,580 |
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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 |
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Dr_Dan ★★ Germany, 2015-05-28 16:32 (3587 d 12:14 ago) @ ElMaestro Posting: # 14868 Views: 4,556 |
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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 |
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pjs ★ India, 2015-05-28 16:58 (3587 d 11:48 ago) @ Dr_Dan Posting: # 14869 Views: 4,517 |
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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 |
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nobody nothing 2015-05-28 17:50 (3587 d 10:56 ago) @ pjs Posting: # 14871 Views: 4,492 |
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❝ 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...)  — Kindest regards, nobody |
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pjs ★ India, 2015-05-28 18:11 (3587 d 10:35 ago) @ nobody Posting: # 14875 Views: 4,464 |
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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 |
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Dr_Dan ★★ Germany, 2015-05-29 11:03 (3586 d 17:42 ago) @ pjs Posting: # 14881 Views: 4,427 |
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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 |
Ing. Helmut Schütz