joyjac
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Philippines,
2006-10-06 02:26

Posting: # 282
Views: 11,929
 

 Similarity Factor (f2) [Dissolution / BCS / IVIVC]

There are instances when a better dissolution profile (on 12 units) is obtained for the test drug/generic than the reference-innovator drug, particularly, for BCS class II drugs (high permeability, low solubility) and BCS Class IV drugs (low permeability, low solubility). In some cases, the test drug achieved faster dissolution than the reference-innovator drug. Calculation of f2 value would also indicate that the 2 are not similar. Would you think it is alright to proceed with the BE testing even if the dissolution profile testing does not show similarity between the test and reference drug, f2 being lower than 50? Would there be a possibility that the test drug will show suprabioavailability? Potency assay showed uniformity among the tablets or capsules for both test and reference drug and within 90-110%. BTW, the drug in question is nifedipine, both test and reference are prepared as soft gel capsules.

Your thoughts on the above will be highly appreciated.
Helmut
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Vienna, Austria,
2006-10-06 16:05

@ joyjac
Posting: # 291
Views: 10,715
 

 Similarity Factor (f2)

Dear Joy!

» […] In some cases,
» the test drug achieved faster dissolution than the reference-innovator drug. Calculation of f2 value would also indicate that the 2 are not similar. Would you think it is alright to proceed with the BE testing even if the dissolution profile testing does not show similarity between the test and reference drug, f2 being lower than 50?

IMHO yes - because your dissolution test may be over-discriminating, but start with a pilot study in order to get some first impressions. ;-)

Have a look at a presentation (623kB PDF) by Lawrence X. Yu (FDA, Office of Generic Drugs), held at the 'AAPS Workshop on Dissolution Testing for the 21st Century' (01 May - 03 May 2006, Arlington, VA, USA).
Note: the conference's website will not be 'up' forever, but is still active today (2006-10-06). A summary of presentations is available at Dissolution Technologies (61kB PDF).
Also see the first example in an article (1.02MB PDF) by S Spagnoli and M Di Maso.

» Would there be a possibility that the test drug will show suprabioavailability?

Again yes (see above). :-(

» […] BTW, the drug in question is nifedipine, both test and reference are prepared as soft gel capsules.

Oh, that's a BCS Class II model compound!

Just to cite from the International Biopharmaceutical Classification System Data Base Newsletter (July 2003, 20kB PDF):

Nifedipine
Dr Johannes Krämer and his co-workers of the company PHAST, Homburg (Saar) Germany, volunteered to write a review on a very interesting active substance: nifedipine.
From this review, the first draft is already written.
Jayachandar G, Amidon GL, Junginger HE, Krämer J, Midha KK, Shah VP, Stavchansky S, Stippler E, and DM Barends
Biowaiver considerations for nifedipine based on Biopharmaceutics Classification System (BCS) Literature Data

But according to the FIP biowaiver progress table (24kB Excel97) with 11 Sep 2006 the monograph is not finished yet.

I think regulators will be weary granting a biowaiver for IR nifedipin (Class II…), because not only the extent of BA, but also the rate is of concern (cardiac AEs).

Cheers,
Helmut Schütz
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