ryraman2661 ☆ India, 2023-12-23 09:41 (453 d 19:21 ago) Posting: # 23802 Views: 3,399 |
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Dear All, Kindly clarify following point. For AUC(0 to inf) for determination of Kel (elimination rate constant), shall we include Tmax point also for lambda _z lower. Is there any specific guidance is there to fix lambda z lower or not to take Tmax point If Tmax point is included for 20 % subjects, will there be any query from regulators. Both Cmax and AUC(0 to t) are passed. Subject experts in this forum can kindly give their opinion / advise. Thanks for your support |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2023-12-23 12:46 (453 d 16:16 ago) @ ryraman2661 Posting: # 23803 Views: 2,700 |
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Hi Raman, ❝ For AUC(0 to inf) for determination of Kel (elimination rate constant), shall we include Tmax point also for lambda _z lower. ❝ Is there any specific guidance is there to fix lambda z lower or not to take Tmax point Let’s consider a one-compartment model with an absorption half life of 1 h, an elimination half life of 4 h, and last sampling at 24 h. The true \(\small{t_\text{max}=2.67\phantom{0}\text{h}}\). Now we estimate \(\small{\lambda_\text{z}}\) increasing with time. $$\small{\begin{matrix} t_\text{start} & \text{abs}\phantom{0}(\%) & \widehat{\lambda}_\text{z} & \widehat{t}_\text{el} & \text{bias}\phantom{0}(\%)\cr\hline \hfil t_\text{max} & \sim84.29 & 0.1630 & 4.253 & +6.31\\ 2\times t_\text{max} & \sim97.53 & 0.1715 & 4.041 & +1.02\cr 3\times t_\text{max} & \sim99.61 & 0.1727 & 4.013 & +0.32\cr 4\times t_\text{max} & \sim99.94 & 0.1731 & 4.004 & +0.11 \end{matrix}}$$It’s clear that if we would start at \(\small{t_\text{max}}\), the estimate would be biased because absorption is still ongoing. On the other hand, at \(\small{\geq2\times t_\text{max}}\), absorption is practically complete and the bias negligible. That’s the idea of the TTT-method1 (search the forum for details and examples). If you have a tight sampling schedule (in order to ‘catch’ Cmax), even starting with the one after tmax might still be too early. Say, you sampled every 20 minutes and the automatic algo (in WinNonlin’s lingo ‘Best Fit’) suggests to start at 3 h. Then 12.5% are not absorbed yet and the estimate is ‘contaminated’ (bias +5.45%). Hence, visual inspection of fits is mandatory and manual selection of time points necessary. In simulations of two-compartment models visual inspection outperformed automatic methods.2 ❝ If Tmax point is included for 20 % subjects, will there be any query from regulators. ❝ Both Cmax and AUC(0 to t) are passed. <terminology> T is the SI abbreviation of the absolute temperature and t the one for time. Hence, we should use tmax instead of Tmax. </terminology>
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ryraman2661 ☆ India, 2023-12-26 09:40 (450 d 19:22 ago) @ Helmut Posting: # 23810 Views: 2,630 |
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Dear Helmut, Thanks for your reply on tmax. In one study, we have drawn samples up to 96.00 hrs post dose. we have stated only Cmax and AUC(0 to t) as primary parameters for bioequivalence in our protocol. We have, mentioned AUC(0 to inf) as secondary parameter. Sponsor wants AUC also to be tested for BE criteria. Our statistician says, if we include tmax points for some subjects, it is passing. Shall we submit the AUC(0 to inf) data, (including tmax)? |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2023-12-26 16:30 (450 d 12:32 ago) @ ryraman2661 Posting: # 23812 Views: 2,609 |
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Hi Raman, ❝ Thanks for your reply on tmax. ❝ In one study, we have drawn samples up to 96.00 hrs post dose. we have stated only Cmax and AUC(0 to t) as primary parameters for bioequivalence in our protocol. We have, mentioned AUC(0 to inf) as secondary parameter. Was this an IR formulation? If yes, AUC0–∞ is only required as a primary metric for the FDA. Not required according to the ICH M13A draft and it will be removed by the FDA once ICH M13A will be finalized. ❝ Sponsor wants AUC also to be tested for BE criteria. ❝ Our statistician says, if we include tmax points for some subjects, it is passing. Shall we submit the AUC(0 to inf) data, (including tmax)? Furthermore, it’s cherry picking to try something to make any PK metric pass. ![]() — 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 |
ryraman2661 ☆ India, 2023-12-28 13:19 (448 d 15:43 ago) @ Helmut Posting: # 23815 Views: 2,526 |
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Dear Helmut, Thanks for your reply |