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Cedric ☆ Singapore, 2014-04-29 15:50 (4436 d 18:42 ago) Posting: # 12900 Views: 8,555 |
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What is the basis behind the requirement that the LLOQ of the calibration range has to be less than 5% of Cmax? Is the BE result still valid if the LLOQ is > 5% of Cmax? Edit: Please follow the Forum’s Policy. [Helmut] |
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Helmut ★★★   Vienna, Austria, 2014-04-29 16:19 (4436 d 18:13 ago) @ Cedric Posting: # 12901 Views: 7,605 |
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Hi Cedric, ❝ What is the basis behind the requirement that the LLOQ of the calibration range has to be less than 5% of Cmax? The cut-off for excluding subjects (“substantial” carry-over from earlier periods in cross-over studies due to a too short wash-out phase) in many guidelines on BE is 5% of Cmax. ❝ Is the BE result still valid if the LLOQ is > 5% of Cmax? ≤5% of Cmax is the target mentioned in guidelines on bioanalytical method validation. Now the question is: Where to get the value of Cmax from? I would suggest to be conservative (i.e., not work with an average reported in the literature) but take between-subject variability into account. Many GLs on BE require ≥80% of AUC∞ and/or ≥3t½ to be covered by measured data. There is no simple relationship between the suggested LLOQ and these metrics, but should be seen as a reasonably good starting point. Some drugs are metabolized by enzymes showing genetic polymorphism. Even if you have taken that into account (extensive metabolizers result in a high LLOQ/Cmax-ratio) sometimes you face ultra-fast metabolizers… However, in a cross-over study the test/reference-ratio would still be valid. — 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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Cedric ☆ Singapore, 2014-04-30 16:24 (4435 d 18:08 ago) @ Helmut Posting: # 12902 Views: 7,436 |
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❝ The cut-off for excluding subjects (“substantial” carry-over from earlier periods in cross-over studies due to a too short wash-out phase) in many guidelines on BE is 5% of Cmax. Thanks for the clear explanation. A quick clarification.. the rules for excluding subjects with substantial carry-over should be the pre-dose level is greater than 5 % Cmax. what is the relationship between the predose < 5 % Cmax and LLOQ < 5 % Cmax. 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! [Helmut] |
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Shuanghe ★★ Spain, 2014-04-30 17:35 (4435 d 16:57 ago) @ Cedric Posting: # 12903 Views: 7,396 |
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Hi Cedric, ❝ ... A quick clarification.. the rules for excluding subjects with substantial carry-over should be the pre-dose level is greater than 5 % Cmax. what is the relationship between the predose < 5 % Cmax and LLOQ < 5 % Cmax. In order to be able to exclude those subject who has predose > 5% Cmax firstly you need to have method to detect that concentration (hence the LLOQ of 5% of Cmax). To give an example, if the LLOQ of your method is 10% of the Cmax, what if a subject with predose of 8% of the Cmax? He/she should be excluded but you are unable to detect such subject because the predose concentration is below your LLOQ. — All the best, Shuanghe |
Ing. Helmut Schütz