murthynaidu
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India,
2014-06-20 16:46
(3569 d 01:10 ago)

Posting: # 13103
Views: 5,525
 

 Regarding the Cτ,ss (Ctau at steady state) calculation [NCA / SHAM]

Dear All,
I have calculated Cτ,ss for a steady state study using the formula
Clast*exp(-Kel(τ-tlast)) for the concentration data on day6. The dosing interval for the study was 12 hrs and the sampling schedule on day6 is also having 12.00 hr and extended upto 36.00 hrs. I have refered the forum and the lectures given on these topics but i am not able to get conclusion on which data i have to perform BE for Cτ,ss
  1. For the data calculated using the formula
  2. For The data at 12.00 hr on day6
  3. For The average of all predose samples collected
  4. For the Pre dose sample data collected on Day 6
Regards,
MurthyNaidu


Edit: Category changed. [Helmut]
Helmut
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Vienna, Austria,
2014-06-20 17:20
(3569 d 00:36 ago)

@ murthynaidu
Posting: # 13104
Views: 4,696
 

 What’s stated in the protocol?

Hi Murthy,

❝ I have calculated Cτ,ss for a steady state study using the formula

❝ Clast*exp(-Kel(τ-tlast)) for the concentration data on day6.


That’s only necessary if you have deviations from the planned sampling time point.
Otherwise Ĉlast = Clast since
  • τ – tlast = 0
  • 0 = 1…

❝ The dosing interval for the study was 12 hrs and the sampling schedule on day6 is also having 12.00 hr and extended upto 36.00 hrs.


Hhm, generally one would not sample in steady state beyond the dosing interval. If the drug does not show diurnal variations in PK, the target metric for extent of BA would be AUC0–τ (and no need to sample a second profile on day 6). If the drug has time-dependent PK, the target metric would by AUC0–24 (i.e., cov­er­ing two pro­files). Generally after the first period one would directly switch to the res­pective other for­mu­la­tion. Since you sampled at 36 hours did you employ a full washout?

❝ I have refered the forum and the lectures given on these topics but i am not able to get conclusion on which data i have to perform BE for Cτ,ss.


Well, you should have stated the relevant PK metrics together with the method(s) of calculation already in the protocol, right? In analogy to AUC look at Ĉ12 or Ĉ24.

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murthynaidu
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India,
2014-06-20 17:48
(3569 d 00:08 ago)

@ Helmut
Posting: # 13107
Views: 4,605
 

 What’s stated in the protocol?

Dear Helmut

Thanks for your immediate reply.

A full wash out was considered and in protocol it was stated about Cτ,ss is the concentration at the end of dosing interval in steady state. As the EMEA new guideline for MR product is suggesting for the evaluation of Cτ,ss as one of the primary parameter.

I have read in the forum stating that the requirements as per the new or draft guidelines shall also be addressed to avoid further queries from regulatory at the time of submission. Since there are no time point deviations in sample collection i have to check BE for concentration at 12 hr or 24 hrs on day 6.

Regards,
Murthynaidu
Helmut
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Vienna, Austria,
2014-06-20 18:17
(3568 d 23:38 ago)

@ murthynaidu
Posting: # 13108
Views: 4,601
 

 Avoid ambiguities…

Hi Murthy,

❝ A full wash out was considered…


Consider avoiding such a design in the future. Start administering the respective other for­mu­la­tion immediately after the last sample harvested in the first period. That’s called a “switch-over” design and stated in EMA’s GL:

In steady-state studies, the washout period of the previous treatment can overlap with the build-up of the second treatment (direct switching), provided the build-up period is suf­fi­ci­ently long (at least 5 times the terminal half-life).

This not only “saves” one biosample per subject, it also shortens the duration of the study and there­fore reduces the chance of drop-outs.

❝ …and in protocol it was stated about Cτ,ss is the concentration at the end of dosing interval in steady state.


OK.

❝ […] the requirements as per the new or draft guidelines shall also be addressed to avoid further queries from regulatory at the time of submission.


Correct.

❝ Since there are no time point deviations in sample collection i have to check BE for concentration at 12 hr or 24 hrs on day 6.


If you have no diurnal variations / time dependent PK C12 – or C24 otherwise. Know the drug/for­mu­lation and avoid ambiguities in the next protocol. ;-)

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