ryraman2661
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India,
2023-12-23 09:41
(71 d 17:55 ago)

Posting: # 23802
Views: 800
 

 Selection of points for Elimination rate constant [NCA / SHAM]

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
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Vienna, Austria,
2023-12-23 12:46
(71 d 14:50 ago)

@ ryraman2661
Posting: # 23803
Views: 675
 

 Don’t include tmax

Hi Raman,

❝ For AUC(0 to inf) for determination of Kel (elimination rate constant), shall we include Tmax point also for lambda _z lower.

In general, no. See this article (scroll down to the section ‘Past and Present’ for some references).

❝ Is there any specific guidance is there to fix lambda z lower or not to take Tmax point

No. However, the earliest time point of the estimation of λz is the one after tmax in the automatic algorithms of standard PK software (Phoe­nix WinNonlin, PKanalix).
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.

No idea.

❝ Both Cmax and AUC(0 to t) are passed.

Fine.

<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>


  1. Scheerans C, Derendorf H, Kloft C. Proposal for a Standardised Identification of the Mono-Exponential Ter­mi­nal Phase for Orally Administered Drugs. Biopharm Drug Dispos. 2008; 29(3): 145–57. doi:10.1002/bdd.596.
  2. Noe DA. Performance characteristics of the adjusted r2 algorithm for determining the start of the terminal disposition phase and comparison with a simple r2 algorithm and a visual inspection method. Pharmaceut Stat. 2019; 1–13. doi:10.1002/pst.1979.

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ryraman2661
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India,
2023-12-26 09:40
(68 d 17:56 ago)

@ Helmut
Posting: # 23810
Views: 597
 

 Don’t include tmax

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
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Vienna, Austria,
2023-12-26 16:30
(68 d 11:07 ago)

@ ryraman2661
Posting: # 23812
Views: 578
 

 Fishy

Hi Raman,

❝ Thanks for your reply on tmax.

Welcome.

❝ 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.

Fine, so far.
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.

Why didn’t the sponsor want that earlier, i.e., to be mentioned in the SAP as primary?

❝ 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)?

Teach your statistician basic PK and the principles of NCA.
Furthermore, it’s cherry picking to try something to make any PK metric pass. :cherry picking:

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ryraman2661
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India,
2023-12-28 13:19
(66 d 14:18 ago)

@ Helmut
Posting: # 23815
Views: 488
 

 Fishy

Dear Helmut,

Thanks for your reply
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