ratnakar1811 Regular India, 2013-03-05 08:30 Posting: # 10151 Views: 6,001 |
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Dear All, As per EMA guideline AUC(0-t) should cover at least 80% of AUC(0-∞) but in one of my study I have got this percentage more than 20% and the % in the study is around 31%. Is there any way by which I can justify this issue? Anybody has any such experience with the European regulators’? Your views are highly appreciated. Best Regards, Ratnakar |
d_labes Hero Berlin, Germany, 2013-03-05 11:12 @ ratnakar1811 Posting: # 10153 Views: 5,631 |
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Dear ratnakar, the 80% coverage of AUC(0-tlast) in relation to AUC(0-inf) is specified further in the EMA guidance under the heading "Reasons for exclusion": "As stated in section 4.1.4, AUC(0-t) should cover at least 80% of AUC(0-∞). Subjects should not be excluded from the statistical analysis if AUC(0-t) covers less than 80% of AUC(0-∞), but if the percentage is less than 80% in more than 20% of the observations then the validity of the study may need to be discussed." I interpret the 20% of observations as 20% of AUC values i.e. 2xsubjects in a classical 2x2x2 crossover. Don't ask me how the validity of the study may be discussed. Duno. — Regards, Detlew |
ratnakar1811 Regular India, 2013-03-06 08:50 @ d_labes Posting: # 10157 Views: 5,464 |
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Dear d_labes/forum members, Yes, in more than 20% of observations AUCinf has been extrapolated for more than 20% and i have received a query from EMA to discuss the validity of the study. I am just thinking what all points should be considered for the justification and further is there any way by which it can be justified? Best Regards, Ratnakar |
ElMaestro Hero Denmark, 2013-03-06 11:10 @ ratnakar1811 Posting: # 10158 Views: 5,608 |
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Hello Ratnakar, » Yes, in more than 20% of observations AUCinf has been extrapolated for more than 20% and i have received a query from EMA to discuss the validity of the study. From EMA? I guess you mean from one or more of the national agencies? » I am just thinking what all points should be considered for the justification and further is there any way by which it can be justified? Try and tell why this happened in the first place. If it was not intended then I guess your study could be argued to be slightly badly planned for which there are no obvious and acceptable excuses. On the other hand if you deliberately shortened sampling time for some reason (PI opinion, ethics, ADME-tox properties) then please give a little further info and let's see. — if (3) 4 Best regards, ElMaestro "(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018. |
Helmut Hero ![]() ![]() Vienna, Austria, 2013-03-06 14:35 @ ElMaestro Posting: # 10162 Views: 5,444 |
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Hi ElMaestro! » […] if you deliberately shortened sampling time for some reason (PI opinion, ethics, ADME-tox properties) then please give a little further info and let's see. No sure what you mean by ↑ that. Shortening the sampling wouldn’t help. — Cheers, Helmut Schütz ![]() The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes |
ElMaestro Hero Denmark, 2013-03-06 16:40 @ Helmut Posting: # 10164 Views: 5,435 |
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Hi HS, » No sure what you mean by ↑ that. Shortening the sampling wouldn’t help. Sorry, this was a dumb formulation, you are absolutely right. If the tox properties are unfavourable then one might need to dose so low that the drug is adme'd away by the time one for some reason or other would like to measure. Erm... Heh... even this sounds dumb now. Does bebac offer language courses? PS: I don't mean to indicate this would be an excuse in itself, rather it could be a cause. — if (3) 4 Best regards, ElMaestro "(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018. |
Helmut Hero ![]() ![]() Vienna, Austria, 2013-03-06 17:19 @ ElMaestro Posting: # 10165 Views: 5,404 |
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Servus! » Does bebac offer language courses? Depends. I’m far from being competent in standard German although I could offer counseling in its Austrian variant. The only language I really master is Viennese. Are you interested? Free lodging included. Visiting my favorite Heurigen mandatory. — Cheers, Helmut Schütz ![]() The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes |
ElMaestro Hero Denmark, 2013-03-07 17:19 @ Helmut Posting: # 10171 Views: 5,332 |
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Hi H., » Depends. I’m far from being competent in standard German although I could offer counseling in its Austrian variant. The only language I really master is Viennese. Are you interested? Free lodging included. Visiting my favorite Heurigen mandatory. Austrian German is a funny kind of Mickey Mouse language. I like the sound of it. Let's go and visit that place of yours next time I am in the area. Oh and haven't you heard? I converted to the Vegetophysticiologists. We only drink cabbage juice and eat mung beans. — if (3) 4 Best regards, ElMaestro "(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018. |
Helmut Hero ![]() ![]() Vienna, Austria, 2013-03-07 17:26 @ ElMaestro Posting: # 10172 Views: 5,377 |
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Hi ElMaestro! » Austrian German is a funny kind of Mickey Mouse language. I like the sound of it. Yep. For me it’s always amazing that native speakers of English love the Austrian’s accent whereas they hate the Kraut’s. Both sound awful to me. » […] I converted to the Vegetophysticiologists. We only drink cabbage juice and eat mung beans. Go to Gujarat. Next step Breatharianism. — Cheers, Helmut Schütz ![]() The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes |
Helmut Hero ![]() ![]() Vienna, Austria, 2013-03-06 14:30 @ ratnakar1811 Posting: # 10161 Views: 5,435 |
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Dear Ratnakar, EMA’s opinion [sic] that AUCt is a reliable estimate of extent of absorption only if AUCt ≥ 80% of AUC∞ is scientifically questionable – if (!) IR formulations are concerned (absorption practically completed at 2–4× tmax). Therefore, we need more information.
— Cheers, Helmut Schütz ![]() The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes |
cakhatri Regular India, 2013-03-10 08:59 @ Helmut Posting: # 10179 Views: 5,236 |
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Dear All, This is interesting topic as I too have had similar situation where in the ratio of AUC0-t / AUC0-inf was less than 80% in several cases. Can anyone clear my doubt on this, does this apply to the untransformed or Ln transformed data The ratios were fine with the Ln transformed data. Regards Chirag |
Helmut Hero ![]() ![]() Vienna, Austria, 2013-03-11 01:17 @ cakhatri Posting: # 10181 Views: 5,254 |
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Dear Chirag, » […] does this apply to the untransformed or Ln transformed data » » The ratios were fine with the Ln transformed data. Raw data! You need the ln-transformed data only in the BE-statistics. You would have to calculate the difference of logs and backtransform to get % covered. Example: AUCt 375, AUC∞ 500, covered: 100×375/500=75%. — Cheers, Helmut Schütz ![]() The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes |
Helmut Hero ![]() ![]() Vienna, Austria, 2013-03-11 03:17 @ Helmut Posting: # 10182 Views: 5,355 |
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Dear all, replying myself to clarify things. Starter: Scheerans et al. (2008).1 tmax in a monoexponential model is the root of the first derivative of the concentration-time curve and given by ln(ka/kel)/(ka-kel) The inflection point tinpt where the sign of the curvature changes (or the tangent moves from above to below the curve) is the root of the second derivative and given by2·ln(ka/kel)/(ka-kel) If you want to play around yourself I suggest to convert the Bateman-function to a sum of exponentials, i.e.,ƒ(x) = A(ℯ–kel·x – ℯ–ka·x). The derivatives areƒ’(x) = A(–kel·ℯ–kel·x + ka·ℯ–ka·x) and % abs = 100(1 – ℯ–ka·x) AUC in the interval [0, a] is given as the definite integral of ƒ(x) byA((ℯ–ka·x – 1)/ka – (ℯ–kel·x – 1)/kel) Example: A 400, ka 1.3863 (t½a 0.5), kel 0.6931 (t½el 1). Although Scheerans et al. recommended their procedure for ka ≥ 3kel in order to avoid problems with flip-flop PK (which is unlikely for IR formulations) I used a ratio of 2 in order to get nice numbers.
IMHO the cut-off of 80% is scientifically not justified for monoexponential models (including ones with a lag-time: homework). Would only make sense if we would use AUCs corrected by kel,3 which seems not to be acceptable by EMA (at least). It’s strange to judge the validity of a study based on elimination rather than essentially complete absorption. Unfortunately it is not that easy for multicompartimental models – or even worse – profiles with multiple peaks, though absorption will follow the same time course. MR (CR in particular) is another pot of tea. We might be in flip-flop limbo and personally I would not use AUCt as the main metric at all. I’m curious what the draft MR GL will tell us… I would suggest AUC∞ with an extrapolated area of well below 20%. @Ratnakar: If you want help it would be a good idea to answer all of the questions in my previous post (see the Forum’s policy).
— Cheers, Helmut Schütz ![]() The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes |
Brus Junior Spain, 2018-11-20 13:01 (edited by mittyri on 2018-11-20 14:25) @ ratnakar1811 Posting: # 19644 Views: 825 |
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Dear Ratnakar, How did you justify the clarification? How can it be justified that the extrapolated AUC is greater than 20%? Best Regards, Brus Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Mittyri] |