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jag009 ★★★ NJ, 2016-02-02 21:16 (2998 d 06:08 ago) Posting: # 15919 Views: 6,041 |
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Hi all, New guidances were posted for Methylphenidate ER last week from FDA: Metadate CD, Aptensio XR Those guys really confuse me now  Why AUC7-t and AUC8-t instead of AUC7-12 and AUC8-12 for Metadate CD?John |
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Helmut ★★★   Vienna, Austria, 2016-02-03 15:10 (2997 d 12:13 ago) @ jag009 Posting: # 15923 Views: 5,132 |
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Hi John, ❝ Those guys really confuse me now Duno. Citizen petition (aka straw men of the innovator)? Do you remember this one? The FDA received five comments. Most interesting the one by the two Lászlós about the S×F interaction and the one by Mallinckrodt about the clincial relevance of the new cut-off times. — 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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jag009 ★★★ NJ, 2016-02-03 23:53 (2997 d 03:31 ago) @ Helmut Posting: # 15927 Views: 5,198 |
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Hi Helmut, What I don't get it why 7-t for metadate CD whereas every other product is 7-12.. Okay citizen's petition... Look at PK profile of Aptensio XR, which has peaks at 2 hr and 8 hr Aptensio XR ![[image]](http://www.aptensioxr.com/hcp/img/about/plasma-concentration-sm.png) Ritalin LA. ![[image]](http://medlibrary.org/lib/images-rx/ritalin-la-1/ritalin-la-04.jpg) Shouldn't Aptenio have 7-t as well for partial AUC since blood level is significantly high at the back due to the late release of the 2nd component? John P.S. I highly doubt that you will see subxform interaction test for the other ADHD dual release products other than Concerta... |
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mittyri ★★ Russia, 2016-02-05 00:35 (2996 d 02:49 ago) @ jag009 Posting: # 15929 Views: 5,128 |
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Hi John, I don't have an answer to your question, but I've found an abstract from FDA that can lift the veil a little bit. Please look through this hodgepodge: Abstracts Accepted for American Conference on Pharmacometrics 2015 And you cand find this one: Assessment of Partial AUC Requirement for Bioequivalence Evaluation of Methylphenidate Hydrochloride Extended-Release Oral Suspension by Nan Zheng and Lanyan (Lucy) Fang from FDA. What's inside the box: We evaluated the sensitivity of PK (Cmax, AUC0-t, AUC0-3, AUC3-7, AUC7-12 and AUC3-24) and PD (Effmax, AUEC0-t, AUEC0-3, AUEC3-7, AUEC7-12 and AUEC3-24) endpoints in response to formulation changes. With the formulationspecific model parameters varied for the test formulation, we calculated the test-to-reference ratios of these PK and PD parameters in a typical study subject, and calculated the chances of passing when bioequivalence testing was based on Cmax, AUC0-t, AUC0-3, AUC3-7, AUC7-12 and AUC3-24, in simulated single-dose, 2-sequence, 2-treatment bioequivalence studies. <...> Dose level, fraction of total dose, lag time and absorption rate for the first order absorption, lag time and duration for the zero order absorption, were identified as the formulation-specific model parameters. PK endpoints are in general more sensitive than PD endpoints to changes in formulation-specific model parameters. For example, values of all PK endpoints increase proportionally with dose while PD endpoints exhibit less than dose proportional increase. AUC0-3 and AUC7-12 are more sensitive than AUC0-t to changes in most of formulation-specific model parameters. Conclusions: Because rapid onset and sustained exposure up to 12 h are important to achieve desirable therapeutic outcome for Quillivant XR and because partial AUCs are more sensitive to formulation specific parameter changes than the conventional metrics of Cmax and AUC, we recommend using partial AUCs in bioequivalence evaluation of generic MPH extended-release oral suspension. — Kind regards, Mittyri |
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jag009 ★★★ NJ, 2016-02-06 00:00 (2995 d 03:23 ago) @ mittyri Posting: # 15937 Views: 5,044 |
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Thanks Mittyri, Yes I see the merits of having partial AUC up to 12 hours for the products of interest in our discussion. What I fail to understand is why only Metadate CD has AUC7-t and AUC8-t while all other methylphenidate bi-release ER products (Concerta, Ritalin LA, Aptensio, Focalin XR) use partial AUCs up to 12 hours. Have a look at the profiles of various Methylphenidate products (ok we are looking at mean plots). All profiles show more or less similar blood levels at >=12 hours and after. ![[image]](http://www.medscape.com/content/2003/00/46/27/462703/art-pharm462703.fig6.gif) Oh well, like Helmut wrote "citizen's petition" John |
Ing. Helmut Schütz