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velupharm ☆ 2007-03-30 18:58 (7026 d 02:47 ago) Posting: # 606 Views: 12,112 |
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Dear all we are developing clopidogrel formulation. As far as the European regulatory point of view, can we prove BE only with its inactive metabolite, as clopidogrel itself becomes BLQ after 2hrs post dose (As Per SmPC)? |
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Ohlbe ★★★ France, 2007-03-30 19:44 (7026 d 02:02 ago) @ velupharm Posting: # 607 Views: 10,701 |
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Dear Velupharm, The situations where metabolites can be used instead of the parent compound are listed in the EU Note for guidance on bioequivalence and commented upon in the Q&A document issued by EMEA last year (see here). In a presentation at the DIA Euromeeting on Wednesday this week Martin Olling from the Dutch Medicines Evaluation Board really insisted on the use of the parent compound whenever possible. Exclusive use of a metabolite, especially a non-active metabolite, could lead to real problems and should be appropriately justified. I am not sure reference to the LOQ mentioned in the SmPC, deriving from a bioanalytical method developped 10 years ago or more, would be considered as a sufficient justification  .Regards Ohlbe |
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Imran ☆ Mumbai, 2007-04-11 12:54 (7014 d 08:51 ago) @ velupharm Posting: # 663 Views: 10,602 |
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Hi, After administration of Clopidogrel you can not detect the plasma concentration after 2 hours because clopidogrel is a prodrug and completely converted into inactive carboxilic acid metabolite. Therefore, primary pharmacokinetic parametes (Cmax, AUC0-t and AUC0-inf) only should be considered for inactive carboxilic acid metabolite of clopidogrel. Regards, Sankar NJ |
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drks ☆ 2007-05-29 09:53 (6966 d 11:52 ago) @ velupharm Posting: # 751 Views: 11,230 |
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Dear All, ❝ As far as the european regulatory point of view, can we prove BE only with its inactive metabolite, as clopidogrel itself becomes BLQ after 2hrs post dose (As Per SmPC)? Considering the difficulties with clopidogrel BE estimation,
Helmut, please share your comments on this. best regards kshitij |
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Helmut ★★★   Vienna, Austria, 2007-05-29 13:47 (6966 d 07:58 ago) @ drks Posting: # 753 Views: 10,496 |
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Dear Kshitij! ❝ Helmut, please share your comments... I'm a little bit short of time, therefore only a few very brief comments. ❝ Considering the difficulties with clopidogrel BE estimation, ❝ 1. is it possible that the BE assessment be done on the basis of PD end points? ❝ 2. Can platelet aggregation be utilised for estimating the bioequivalence of the clopidogrel? ❝ 3. and most important, has there been any submission (and approval) of clopidogrel formulation to any regulatory agency?
❝ I am aware that there are good methods for the estimation of clopidogrel ❝ now. The ones I have seen, demonstrate high variability of PK parameters of clopidogrel…  — 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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drks ☆ 2007-05-30 12:13 (6965 d 09:33 ago) @ Helmut Posting: # 759 Views: 10,481 |
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Dear Helmut, Thanks for your prompt response! ❝ I'm a little bit short of time, therefore only a few very brief comments. No problem. Any useful response is highly appreciated. Your comments have always been a great support to us in this Forum. Thanks again! ❝ 3. I know of at least one. Please excuse me for my half question. i meant any submission (and approval) of clopidogrel formulation based upon a study using PD end points. So, is the submission, which you are referring to, based on PD endpoints? ❝ The ones I have seen, demonstrate high variability of PK parameters of clopidogrel… I agree. |
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Helmut ★★★ Vienna, Austria, 2007-05-30 14:47 (6965 d 06:58 ago) @ drks Posting: # 760 Views: 10,526 |
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Dear Kshitij! ❝ i meant any submission (and approval) of clopidogrel formulation based upon a study using PD end points. So, is the submission, which you are referring to, based on PD endpoints? No…  — 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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lukamar ☆ Poland, 2009-01-13 12:56 (6371 d 07:49 ago) @ Helmut Posting: # 3023 Views: 9,784 |
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Hi all, I'd like to come back to BE issues related to clopidogrel. According to appendix IV to draft of new BE guideline, if parent compound is not active (like clopidogrel) you must answer next question about PK linearity of parent compound and active metabolite. Since active metabolite of clopidogrel is not detectable in plasma (according to SmPC), there is no answer for this question (or is it?). And of course this excludes possibility of demonstrating BE for active metabolite even if you pass this step on decision tree. The question is what now? Submit the study based only on BE of parent drug? Submit the study based on BE of parent and inactive metabolite? Or perform clinical study based on PD endpoints? Thanks is advenace for your suggestions. Best regards, Łukasz |
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lukamar ☆ Poland, 2009-01-19 11:33 (6365 d 09:12 ago) @ lukamar Posting: # 3059 Views: 9,757 |
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Hi again Please let me ask again - any ideas how to deal with clopidogrel? I know that internet forum is not best place for sharing such a valuable knowledge, but any kind of info will be highly appreciate. Is "sorry - we can not measure active metabolite" the only rationale for performing BE study on Clopidogrel PK only? I know that in theory formulation does not affect human metabolism, but if so, where idea of measuring metabolites comes from at first place? I hope that I expressed my doubts clearly enough  Best regards Łukasz Edit: Full quote removed. Please see this post! Helmut |
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Ohlbe ★★★ France, 2009-01-22 00:42 (6362 d 20:03 ago) @ lukamar Posting: # 3100 Views: 9,742 |
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Dear all, ❝ Is "sorry - we can not measure active metabolite" the only rationale for performing BE study on Clopidogrel PK only? Just to make the discussion a bit more complex: a method for the determination of the active metabolite of clopidogrel in plasma was published recently: Quantitative determination of clopidogrel active metabolite in human plasma Makoto Takahashia, Henrianna Pang, Kiyoshi Kawabata, Nagy A. Farid and Atsushi Kurihara Journal of Pharmaceutical and Biomedical Analysis, Volume 48, Issue 4, 1 December 2008, Pages 1219-1224 The LLOQ in this paper is too high to follow a full PK profile with a single dose of 75 or even 150 mg (it was applied to a single dose of 600 mg), but the method may be further refined to improve the LLOQ (the described LLOQ is 0.5 ng/ml, which is 20 or 50 times higher than what is currently achieved for unchanged clopidogrel), or used at least to study the Cmax, as suggested in the new draft EMEA guideline. Regards Ohlbe |
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Helmut ★★★ Vienna, Austria, 2009-07-31 16:24 (6172 d 05:21 ago) @ Ohlbe Posting: # 4000 Views: 9,365 |
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Dear Ohlbe and all, yesterday EMEA’s EWP-PK group declared their current position on the topic:
— 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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ElMaestro ★★★ Denmark, 2009-07-31 21:10 (6172 d 00:35 ago) @ Helmut Posting: # 4002 Views: 9,293 |
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Dear HS, ❝ • PK data for the inactive metabolite, clopidogrel carboxylic acid, should be regarded as supportive only. Having observed the development of the EU BE-requirements over some years I have the clear impression that the regulators are going in the direction of preferring to think of BE as a quality issue rather than a clinical issue (there pro's and con's for both, I guess) and along with that the regulators seem to adhere more and more rigorously to the formalised requirements, so that they do not need to take decision on basis of judgement (anyone remember the cookbook thread?). If your results are not in accordance with the guidance, if your CI is 0.01 points outside the acceptance limits etc, well, then you do not have an equivalent formulation and your dossier faces rejection with very little opportunity to e.g. discuss clinical relevance and such. Because of this it is difficult for me to understand what supportive data are or when they become handy or make a difference. In fact I could be afraid we are getting to a point where supportive data could not be used by an applicant to claim BE but could be used by regulators as basis for rejections. Anyone else been thinking thoughts like this, or am I alone in the universe? EM. |
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Helmut ★★★ Vienna, Austria, 2009-07-31 21:39 (6172 d 00:06 ago) @ ElMaestro Posting: # 4003 Views: 9,265 |
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Dear ElMaestro, your first paragraph is a perfect aggregation.  ❝ Because of this it is difficult for me to understand what supportive data are or when they become handy or make a difference. In fact I could be afraid we are getting to a point where supportive data could not be used by an applicant to claim BE but could be used by regulators as basis for rejections. Last January in Bonn I asked Jan Welink what ‘supportive’ actually means. He said: ‘Only means ±SD, plasma profiles, etc. – no calculation of a point estimate and confidence interval.’ The other six members of the PK-group on the panel agreed. No disagreement from the Austrian member (he was in the audience). The member from Hungary was absent; no idea about the French one (anonymous). So what it is it for? Back to eye-ball pharmacokinetics (‘Well, that's a nice curve – but look at the strange secondary peak at 12 hours…’)! ❝ Anyone else been thinking thoughts like this, … Looking for a passionate heretic - gimme a call! ❝ … or am I alone in the universe? Don’t know – have you ever considered joining SETI? — 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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Ohlbe ★★★ France, 2009-07-31 21:48 (6171 d 23:57 ago) @ Helmut Posting: # 4004 Views: 9,218 |
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Dear ElMaestro and Helmut, ❝ Last January in Bonn I asked [...] what ‘supportive’ actually means. To make it short: you can do it if you have money to waste  ❝ ❝ In fact I could be afraid we are getting to a point where supportive data could not be used by an applicant to claim BE but could be used by regulators as basis for rejections. Agreed. Regards Ohlbe |
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lukamar ☆ Poland, 2009-01-13 13:35 (6371 d 07:11 ago) @ Helmut Posting: # 3024 Views: 9,692 |
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Hi Helmut, ❝ 3. I know of at least one. In EU? From what I know it's still not possible due to patent situation... Or you were just talking about originator application? (Just to be sure that I understood you blinking face correctly... ) |
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Helmut ★★★ Vienna, Austria, 2009-01-14 15:33 (6370 d 05:13 ago) @ lukamar Posting: # 3029 Views: 9,714 |
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Dear Łukasz! ❝ ❝ 3. I know of at least one. ❝ ❝ In EU? From what I know it's still not possible due to patent situation... I didn’ say that the study was performed in the EU… I can’t give any more details, or the sponsor probably will arrange a meeting of some guys from the Russian Mafia and myself. — 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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Ohlbe ★★★ France, 2009-01-17 18:57 (6367 d 01:48 ago) @ lukamar Posting: # 3056 Views: 9,665 |
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Dear Lukamar, ❝ In EU? From what I know it's still not possible due to patent situation... You can make the application, independently of the patent situation. What you won't be able to do is put the drug on the market... Actually a generic clopidogrel was put on the market in Germany some months ago. Sanofi-Aventis referred the case to court. Regards Ohlbe |
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drdds ● 2007-06-04 11:08 (6960 d 10:37 ago) @ drks Posting: # 773 Views: 10,415 |
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Dear Kshitij, Clopidogrel is rapidly absorbed after oral administration, with peak plasma levels of the main circulating metabolite occurring approximately 1 hour after dosing. The pharmacokinetics of the main circulating metabolite are linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150 mg of clopidogrel. Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites. Cmax (µg/ml) 6.66±1.70 Tmax (hours) 2.31±0.91 t½ (hours) 6.94±2.76 so i believe the PD is not the solution. DDS. |
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ElMaestro ★★★ Denmark, 2009-01-14 18:22 (6370 d 02:24 ago) @ drks Posting: # 3030 Views: 9,767 |
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Dear kshitij, ❝ 2. Can platelet aggregation be utilised for estimating the bioequivalence of the clopidogrel? It might be possible, in which case you would probably have to give reasonable proof that your method gives better chance of detecting a clin. meaningful difference than if you evaluate the PK of parent compound, metabolites etc. How on earth you can do this I cannot tell. But in case you try I would be the first to gamble on a referral at my local bookmaker. Best regards EM. |
Ing. Helmut Schütz