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jag009 ★★★ NJ, 2012-10-15 18:23 (5004 d 14:26 ago) Posting: # 9417 Views: 5,201 |
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Hi everyone, Just some monday morning thoughts (US EST time)... Does anyone have experience with studies whereby the test and reference products were bioequivalent but Tmax values were very different, i.e. T=6 hrs, R=12 hrs, p<0.05? Lets say both sample size (>24) and Sampling time (hourly) were sufficient. Any roadblocks from regulatory agency (US, Europe, etc.) Thanks John |
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Helmut ★★★   Vienna, Austria, 2012-10-15 18:41 (5004 d 14:08 ago) @ jag009 Posting: # 9418 Views: 4,714 |
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Good morning! ❝ […] studies whereby the test and reference products were bioequivalent but Tmax values were very different, i.e. T=6 hrs, R=12 hrs, p<0.05? Lets say both sample size (>24) and Sampling time (hourly) were sufficient. If both AUC and Cmax were equivalent, you are speaking of a DR formulation, right? ❝ Any roadblocks from regulatory agency (US, Europe, etc.) Personal experience only in the “etc.” category. See this goody (especially Case Study 2). — 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, 2012-10-15 21:38 (5004 d 11:11 ago) @ Helmut Posting: # 9419 Views: 4,642 |
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Good afternoon Helmut  I meant modified release excluding DR (Delayed Release). Just a hypothetical question that's all. I have experience with DR and we had to show that Tlag was not significantly different as part of the BE criteria. We used Wilcoxon sign rank test. What about modified release? As far as I know from a US regulatory point of view this is not considered an issue since BE is AUCs and Cmax only. John |
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Helmut ★★★ Vienna, Austria, 2012-10-15 21:59 (5004 d 10:50 ago) @ jag009 Posting: # 9420 Views: 4,680 |
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Good evening John!  ❝ I meant modified release excluding DR (Delayed Release). Just a hypothetical question that's all. I have experience with DR and we had to show that Tlag was not significantly different as part of the BE criteria. We used Wilcoxon sign rank test. Yep. Luv nonparametrics. What do you mean by “we had to show that Tlag was not significantly different …”? In the US? Surprise. ❝ What about modified release? As far as I know from a US regulatory point of view this is not considered an issue since BE is AUCs and Cmax only. AFAIK yes. Maybe it’s better to talk about controlled release (CR); IMHO MR includes both CR and DR (my simple mind would say: CR = everything which ≠ IR). With CR we might cross the border of flip-flop PK (ka ≤ ke). AUC∞ might be problematic, since we are extrapolating absorption – which does not continue forever. Nobody knows what happens after the last sampling time point with a CR formulation. From a PK point of view I can’t imagine a situation where AUCt, AUC∞, and Cmax are equivalent and tmax is not (i.e, a large difference like in your OP). — 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, 2012-10-16 00:54 (5004 d 07:55 ago) @ Helmut Posting: # 9421 Views: 4,602 |
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Dear Helmut and John, ❝ From a PK point of view I can’t imagine a situation where AUCt, AUC∞, and Cmax are equivalent and tmax is not (i.e, a large difference like in your OP). Even with prolonged release formulations giving a pseudo-plateau, slightly decreasing for T (tmax 6 hours), slightly increasing for R (tmax 12 hours) ? There you could get similar Cmax and AUC, with a different tmax, couldn't you ? To come back to John's initial question: ❝ Any roadblocks from regulatory agency (US, Europe, etc.) If you have a situation like above, it should be possible to argue. Regards Ohlbe — Regards Ohlbe |
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Helmut ★★★ Vienna, Austria, 2012-10-16 16:06 (5003 d 16:43 ago) @ Ohlbe Posting: # 9424 Views: 4,695 |
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Dear Ohlbe! ❝ Even with prolonged release formulations giving a pseudo-plateau, slightly decreasing for T (tmax 6 hours), slightly increasing for R (tmax 12 hours) ? There you could get similar Cmax and AUC, with a different tmax, couldn't you ? Oh, you are absolutely right. tmax in such a case is not meaningful. For flat profiles t75% (or even HVD) is a better choice.* BTW, t75% is a mandatory metric in Russia. ❝ To come back to John's initial question: ❝ ❝ Any roadblocks from regulatory agency (US, Europe, etc.) ❝ ❝ If you have a situation like above, it should be possible to argue. Right; at least FDA and EMA don’t ask for tmax.
— 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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jag009 ★★★ NJ, 2012-10-16 23:22 (5003 d 09:27 ago) @ Helmut Posting: # 9426 Views: 4,577 |
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Hi Helmut, ❝ Yep. Luv nonparametrics. What do you mean by “we had to show that Tlag was not significantly different …”? In the US? Surprise. A long long time ago (2000s) in my previous life we were developing a generic of a DR product which is designed to be given in the evening to have morning effect. The drug has a specific Tlag which FDA required us to meet in addition to BE criteria. John |
Ing. Helmut Schütz