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srinivasu ☆ 2010-06-12 13:53 (5849 d 17:45 ago) Posting: # 5506 Views: 10,337 |
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Dear all, Is there any calculations or methods for estimating BE based on vitro dissolution studies in multi pH, except f1, f2. thanks, Srinivasu |
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Helmut ★★★   Vienna, Austria, 2010-06-12 14:32 (5849 d 17:05 ago) @ srinivasu Posting: # 5507 Views: 9,008 |
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Dear Srinivasu! ❝ Is there any calculations or methods for estimating BE based on vitro dissolution studies in multi pH, except f1, f2. It’s only possible to predict BE if you have established an in vivo-in vitro-correlation (IVIVC). Such a correlation may (!!) exist only if the release from the formulation is the rate-limiting step of the in vivo absorption processes. Therefore IR formulations are no candidates at all! For details see FDA's GL. Anyhow, that’s only useful for your own formulations – with an established IVIVC you may set dissolution limits based on side-batches, or may perform a major change in manufacturing without a BE study. Of course IVIVC wouldn’t make sense in the comparison of a generic to an innovator. If you only want to get an alternative to f1 & f2 (IR formulations), you can try to model the release and compare parameters (A, B) of the fits by means of statistical tests. Candidate functions:
— Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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srinivasu ☆ 2010-06-12 14:53 (5849 d 16:44 ago) @ Helmut Posting: # 5508 Views: 9,129 |
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❝ ❝ Is there any calculations or methods for estimating BE based on vitro dissolution studies in multi pH, except f1, f2. ❝ ❝ It’s only possible to predict BE if you have established an in vivo-in vitro-correlation (IVIVC). Such a correlation may (!!) exist only if the release from the formulation is the rate-limiting step of the in vivo absorption processes. Therefore IR formulations are no candidates at all! Dear Helmut, Thank you very much for your immediate reply. This question related to MR product and find the below vitro release results in multi pH. Let me know the chances of bioequivalence. Multi Ph dissolution study for Gliclazide Mr-30 vs Reference product Media TIME (hr) Cumulative release Test ptd Cumulative release Reference with regards, Srinivasu Edit: Table coded; tabs are collapsed to a single blank! Please use the preview before submitting your post in the future. [Helmut] |
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Helmut ★★★ Vienna, Austria, 2010-06-12 18:04 (5849 d 13:33 ago) @ srinivasu Posting: # 5509 Views: 9,077 |
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Dear Srinivasu, have you read my original reply (given below)? ❝ ❝ It’s only possible to predict BE if you have established an in vivo-in vitro-correlation (IVIVC). ❝ Let me know the chances of bioequivalence. No idea; I don’t have a crystall ball and I’m not a friend of reading tea leaves. It’s like you want to know something about the dark side of the moon and are equipped with a telescope only. But you need a space probe: Perform a (pilot) BE study. Concerning your first question on other methods to compare dissolution profiles: You have an asymetric sigmoidal function. Based on your data you may fit e.g. a 4-parameter logistic function Y=(-dissinf/(1+(x/inflect)^slope)^asym)+dissinf, but what will you gain? You have only 5 degrees of freedom. Parameters (95% CI) are:
parameter test referenceThough the reference shows a ‘better’ fit, CIs of many parameters include zero and therefore are noninformative (aka nonsense). ![[image]](img/uploaded/image49.png) Does this image show us anything new (what we haven’t seen by f1=19.2% & f2=43.4)? Obviously not. If you want to start serious formulation development, you should start (!) with a small three-way cross-over study (test, reference, i.v. or an oral solution). Afterwards (!) try to develop a dissolution method which allows to establish an IVIVC (preferably Level A by deconvolution). Only then, you may peek at The Dark Side of the Moon… — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Dr_Dan ★★ Germany, 2010-06-14 11:30 (5847 d 20:07 ago) @ Helmut Posting: # 5510 Views: 8,987 |
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Dear Helmut, dear all I totally understand Srinivasu. From the point of view of a generic company it is very frustrating to see that comparable dissolution does not mean bioequivalence between test and reference. In case of a high soluble drug with a good bioavailability there should be no problem but in other cases we can not predict the outcome. Therefore we try to find some in vitro test which would make the in vivo testing more predictable. I would like if all participants in this forum could share their experience and I am looking forward to your replies. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Helmut ★★★ Vienna, Austria, 2010-06-15 14:43 (5846 d 16:55 ago) @ Dr_Dan Posting: # 5514 Views: 9,013 |
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Dear Dan, Srinivasu & all! ❝ I totally understand Srinivasu. From the point of view of a generic company it is very frustrating to see that comparable dissolution does not mean bioequivalence between test and reference. I do understand this desire too. Sorry if I was too harsh in my reaction, but the question scratched the basics. ❝ In case of a high soluble drug with a good bioavailability there should be no problem but in other cases we can not predict the outcome. Even then it might be problematic. Imagine we perform not only dissolution testing, but opt for a model of the upper GIT (like TNO’s TIM-1). It’s telling that TNO talks about ‘bioaccessability’ – not bioavailability. If the drug is subjected to presystemic metabolism or affected by active transport any in vitro model will fail. ❝ Therefore we try to find some in vitro test which would make the in vivo testing more predictable. You are not alone – everybody does.  Now for some heresy: How do you assess the predictability of you in vitro test without in vivo data? Is f2>50 in three pHs enough? Would you go for physiological media (FASSIF/FESSIF)? — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Dr_Dan ★★ Germany, 2010-06-15 18:02 (5846 d 13:36 ago) @ Helmut Posting: # 5519 Views: 8,897 |
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Hi Helmut Honestly I have no experience with physiological media (FASSIF/FESSIF). Can you imagine any situation where this is reasonable? Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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ElMaestro ★★★ Denmark, 2010-06-17 02:03 (5845 d 05:35 ago) @ Helmut Posting: # 5532 Views: 8,918 |
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Dear HS, ❝ Would you go for physiological media (FASSIF/FESSIF)? In which category does 40% ethanol belong? Oh, and Dr_Dan: I got really confused by your post. We are just discussing approval principles for generics here; how did the word "reasonable" find its way into this thread? Best regards EM. |
Ing. Helmut Schütz