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prashantmohite ☆ India, 2014-09-11 17:20 (3507 d 00:36 ago) Posting: # 13483 Views: 4,482 |
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Dear All, Can i go for widened BE limits (80 – 125 5) in case of Cmax for Phenytoin molecule for EU submission. Thanks in advance. Regards, Prashant |
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Ohlbe ★★★ France, 2014-09-11 19:57 (3506 d 22:00 ago) @ prashantmohite Posting: # 13484 Views: 4,094 |
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Dear Prashant, The only way to widen the acceptance limits in the EU is to have a replicate design study, find a CV of more than 30 % and go for scaling. But you will additionally have to discuss the clinical relevance. For phenytoin, IMHO, no chance. — Regards Ohlbe |
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ElMaestro ★★★ Denmark, 2014-09-11 21:00 (3506 d 20:57 ago) @ Ohlbe Posting: # 13485 Views: 4,048 |
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Dear Ohlbe, Dear Prashant, I read the question the other way around: Phenytoin is an entiepileptic which may or may not be an NTID – the jury is still out on that one. So it is either 90–111 (~high sample size) or 80–125 (~low sample size); when I read it I had the impression that it was a matter of finding out if there is a decent way to get away with the latter. My own opinion: Get a scientific advice in the RMS you aim for. If they approve 80–125 they are expected to defend their position if the whole thing ends up at CMD(h) or CHMP. — Pass or fail! ElMaestro |
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Ohlbe ★★★ France, 2014-09-11 21:25 (3506 d 20:31 ago) @ ElMaestro Posting: # 13486 Views: 4,073 |
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Dear ElMaestro, Dear Prashant, Maybe I misunderstood Prashant's message - but his message mentioned widened acceptance limits and (80 - 125 5). Prashant, was this a typo ? Or if I reformulate: are you trying to get acceptance limits wider than 80-125 (as I understood your question) ? Or are you trying to defend the use of the usual acceptance limits instead of narrowed limits (as understood by ElMaestro) ? — Regards Ohlbe |
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prashantmohite ☆ India, 2014-09-12 08:21 (3506 d 09:36 ago) @ Ohlbe Posting: # 13490 Views: 4,160 |
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Dear All, Phenytoin is an anticonvulsant drug indicated for the management of generalised tonic-clonic seizures and complex partial seizures. Phenytoin has a narrow therapeutic window with non linear PK and is highly protein-bound of which free (unbound) phenytoin is the component producing the pharmacological effect. As per the current EU guidance, Section 4.1.9 - Narrow therapeutic index drugs; In specific cases of products with a narrow therapeutic index, the acceptance interval for AUC should be tightened to 90.00-111.11 %. Where Cmax is of particular importance for safety, efficacy or drug level monitoring the 90.00 - 111.11 % acceptance interval should also be applied for this parameter. It is not possible to define a set of criteria to categorise drugs as narrow therapeutic index drugs and it must be decided case by case if an active substance is an NTID based on clinical considerations. In case of Phenytoin, Cmax is around 4 - 9 hours while the time required to reach its therapeutic range i.e. 20 mg / mL is around 15 hours (time taken to have clinical effect). Hence Cmax is not significant in relation to efficacy. The mean plasma half-life of Phenytoin is 22 hours (range 7 to 42 hours) following oral administration; variability is due to the saturation kinetics. As Phenytoin has longer half-life, Cmin trough levels can be used as a surrogate for AUC in clinical practice. Given the long terminal half-life, Phenytoin accumulates during repeated dosing and due to this accumulation, a potential difference between formulations in Cmax after single dosing can be expected to be less at steady state, if AUC is the same for the two formulations. Based on this feel that Cmax is of not particular importance in case of Phenytoin. Therefore, normal acceptance limits 80.00 – 125.00 % for Cmax while tighter acceptance limits 90.00 – 111.11 % for AUC can be used in single dose bioequivalence studies for Phenytoin. Please suggest the way forward on my opinion. |
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nobody nothing 2014-09-12 12:30 (3506 d 05:26 ago) @ prashantmohite Posting: # 13496 Views: 3,993 |
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❝ .... ❝ ❝ Based on this feel that Cmax is of not particular importance in case of Phenytoin. Hmmm, how about any safety concerns related to Cmax? — Kindest regards, nobody |
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kvgreddy06 ☆ India, 2014-09-13 09:18 (3505 d 08:39 ago) @ nobody Posting: # 13501 Views: 3,987 |
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Dear Prashant, As per USFDA, phenytoin is a narrow therapeutic index (NTI) drug, the Division of Bioequivalence currently recommends statistical analysis of bioequivalence study data using the reference-scaled average bioequivalence approach for NTI drugs as outlined in Warfarin guidance. As my opinion is Cmax and AUC should be in limits 90.00 – 111.11 %, Thanks, kvgr |
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Helmut ★★★   Vienna, Austria, 2014-09-14 17:24 (3504 d 00:32 ago) @ kvgreddy06 Posting: # 13506 Views: 4,018 |
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Hi kvgr, ❝ As per USFDA, phenytoin is a narrow therapeutic index (NTI) drug, the Division of Bioequivalence currently recommends statistical analysis of bioequivalence study data using the reference-scaled average bioequivalence approach for NTI drugs as outlined in Warfarin guidance. Do you have any references supporting your claim? FDA’s product specific guidances of 2008 (chewable tablets, oral suspension) state nothing about narrowing the acceptance range. ❝ As my opinion is Cmax and AUC should be in limits 90.00 – 111.11 %, FDA’s reference-scaling for NTIDs does no preset limits of the acceptance range – contrary to EMA (which was Prashant’s in original question). — 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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kvgreddy06 ☆ India, 2014-09-26 16:17 (3492 d 01:40 ago) @ Helmut Posting: # 13594 Views: 3,680 |
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Hi Helmut, ❝ Do you have any references supporting your claim? FDA’s product specific guidances of 2008… Recently we got a query from FDA. FDA itself suggested “phenytoin is a narrow therapeutic index (NTI) drug, the Division of Bioequivalence currently recommends statistical analysis of bioequivalence study data using the reference-scaled average bioequivalence approach for NTI drugs as outlined in Warfarin guidance” The OGD of phenytoin ER capsule is not available in current website, it was available in 2008. Regards. kvgr |
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Helmut ★★★ Vienna, Austria, 2014-09-14 17:42 (3504 d 00:14 ago) @ nobody Posting: # 13508 Views: 3,980 |
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Hi nobody, ❝ ❝ Based on this feel that Cmax is of not particular importance in case of Phenytoin. ❝ ❝ Hmmm, how about any safety concerns related to Cmax? I don’t think so. Steady state profiles of phenytoin are pretty “flat”. IMHO, AUC is the killer. Most neurologists are concerned about switching antiepileptic formulations. Below one of my early sins*. All of these formulations were approved and marketed in Austria in the early 1980s. ![[image]](img/uploaded/image268.png)
— 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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nobody nothing 2014-09-14 20:31 (3503 d 21:26 ago) @ Helmut Posting: # 13509 Views: 3,908 |
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...maybe some additional inspiration for the OP https://ejournals.library.ualberta.ca/index.php/JPPS/article/download/11759/13883 http://www.mhra.gov.uk/home/groups/comms-ic/documents/websiteresources/con341226.pdf http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm089482.pdf ...maybe avoid Denmark as RMS  — Kindest regards, nobody |
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Helmut ★★★ Vienna, Austria, 2014-09-14 17:39 (3504 d 00:17 ago) @ prashantmohite Posting: # 13507 Views: 3,942 |
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Hi Prashant, personally I support your reasoning. There were actually cases with bioinequivalent / suprabioavailable formulations which lead to the development of the BE-concept in the late 1970s. Phenytoin was one of them (warfarin and digoxin the others). The main issue with phenytoin is the non-linear PK which might lead to intoxications in steady state. This effect is (mainly) related to the AUC. Like ElMaestro I would also recommend a scientific advice. — 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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prashantmohite ☆ India, 2014-09-15 09:31 (3503 d 08:26 ago) @ Helmut Posting: # 13510 Views: 3,816 |
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Dear All, Thanks for your suggestions. Regards, Prashant |
Ing. Helmut Schütz