6 replies to this topic

[drughunter]

Hello,

 

I'm having a disagreement with a DMPK colleague on the proper way to use Phoenix WinNonLin and I'm hoping others on the forum can provide some clarity. The disagreement is regarding the appropriate way to perform nca analysis for *single-dose* iv PK data (with plasma conc data from 0-24 h) using WinNonLin.

 

My colleague is adamant that the tau parameter should be set to 24h (since that is the last time-point measured) and that CLss is the appropriate clearance parameter to report and use from the output.

 

I suggest that for single-dose analysis, the tau parameter should be left blank and the appropriate clearance parameter to report/use is CL_obs. My understanding is that setting tau and using the CLss output parameter is only appropriate if your input data is from a multiple-dosing scenario.

 

Am I right or wrong here? 

 

Assuming I am correct, what are the potential ramifications of my colleague consistently calculating and reporting only steady-state CLss (and Vss, etc.) values for all single-dose PK experiments?

 

Thank you.

[cradhakr]

Hi,

 

I have attached our help document explaining how Tau is used (Certara Phoenix Assistance) and the parameter estimated when using Tau( Certara Phoenix Assistance).

I hope this could help you and your collogues on the understanding on this issue. If you need further assistance please contact us at support@certara.com.

[Simon Davis]

Drughunter - firstly you are correct; for single-dose analysis, the tau parameter should ABSOLUTELY be left blank - otherwise it willbe treated as SS.

 

Note that for IV route some parameters with an SS suffix can be calculated from single dose which may be where your colleagues. confusion comes from.

 

Vss(_obs, _pred): For non-steady-state data: An estimate of the volume of distribution at steady-state based on the last observed (obs) or last predicted (pred) concentration.

= (MRTINF)(C)

 

 Simon.

 

PS you can see the original Gibaldi reference Gibaldi M, D Perrier D. Pharmacokinetics. New York: Marcel Dekker; 2nd ed. 1982,  here;
https://forum.bebac....#p16644<br><br>
 

Edited by Simon Davis, 05 August 2021 - 11:18 AM.

[Simon Davis]

two other snippets from the same reference that maybe useful to you and your colleague.

Attached Thumbnails

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[drughunter]

Thank you for the confirmation all. Your answers are consistent with my understanding. I believe that the misunderstanding(s) of my colleague are much broader in the DMPK community than most would like to admit. I base this on the responses of other DMPK professionals to this same question. Not a single other DMPK professional thought there was any issue with setting tau and reporting CLss instead of CL_obs for single-dose data. This is based on a survey of 5 ADME/DMPK professionals with over 65 combined years of experience in industry. 

 

The common responses included:

• CLss should always be used instead of CL_obs since it "matches" Vss. Since all drugs will eventually reach steady state when dosed in therapeutic situations, you obviously want the parameters to both be "ss". I mean just look at the "ss" suffix -- it makes sense that they should match. If you want to use "CL_obs," you would need to match it with "V_obs," and that isn't a parameter that is used in PK analysis.
• If you leave tau blank, WNL won't calculate the accumulation factor, which is a very important parameter to know, so you need to set tau even when using single-dose data.

 

Based on this experience I think a feature request for new versions of WNL would be to integrate a more "hand-holding" user interface that helps the user pick whether tau should be set. Right now, correctly setting (or not setting) tau depends on the user having read the manual -- and I think it is clear that few users have read the manual. Also are there ways to improve the output to help guide users to report the correct parameters? Perhaps add a note to the outputs that instruct users not to use "CLss" when analyzing single-dose data.

Edited by drughunter, 07 August 2021 - 06:30 PM.

[drughunter]

Hello again. Even after being presented with the information from this thread, the information in the manual, and the information in the literature, the senior DMPK colleague I work with is still convinced that setting tau and reporting CLss is the correct way to analyze single-dose i.v. data. He now additionally claims that CLss is the clearance parameter that the FDA requires for single-dose PK analysis -- and therefore discussions of other analysis methods are irrelevant.

 

I find this very confusing. Can anyone imagine any circumstance where it would make sense to set tau and report CLss when analyzing single-dose iv PK data? Anyone ever heard of the FDA requesting CLss for single-dose i.v. data? I'm looking for any foothold to understand what is going on.

Edited by drughunter, 03 September 2021 - 01:56 AM.

[Simon Davis]

I would struggle too and would suggest your colleague provides the references for his/her case?

Maybe they are getting confused between a CL value derived from modelling vs those of NCA ?   Simon