14 replies to this topic

[Angus McLean]

Partial exposure metrics (0- x hr) are provided by Phoenix WinNonlin in terms of AUC. I wonder there is a way of obtaining the corresponding partial Cmax to each partial AUC exposure metric requested of the program. I know that you can read them off manually, but to automate it just like the AUC data would be most useful.

 

Angus

[Helmut Schütz]

Hi Angua,

 

well, that’s a controversial PK metric. I don’t know of a single (!) publication exploring its usefulness (at least in BE). However, it is mandatory for multiphasic release products according to EMA’s Q&A-document.

What I do: Fire up the data wizard and include/exclude time-points according to the truncation I have used for pAUCs. Then I run two NCAs – asking only for Cmax. To avoid confusion, I rename the respective results to Cmax1 and Cmax2 and later merge them with the global NCA-results.

[Angus McLean]

Many thanks...................................................BE concept can be useful in showing lack of BE.

 

Spinne am Morgen bringt Gluck und Geben!

 

Angus

[Simon Davis]

the other option is add a sort variable to your NCA (and dataset) that distinguishes the phases you are looking at, then you can do it in a single NCA object.

 

  Simon

[Angus McLean]

Thanks Simon. I think I know what you mean i.e. if (0-15) minutes, and (15-30) minutes are time interval of interest then they would be assigned a sort variable e.g. A and B. Simply go through all subjects in the data set and assign to each subject in all of the treatments. Now I wonder how to denote the time different time segments. A and B would clash with the treatment assignments, 1 and 2 would clash with the period assignments. Could I use 0-15 and 15-30 as the sort variable. not A and B.

 

I am already using partial exposure metrics AUC(0-15), AUC(15-30). Are you suggesting not using the partial exposure metrics provided by the program, but doing both AUC and Cmax partial exposure metrics according to the sort variable say 0-15 assigned.

 

 

Angus

[Simon Davis]

Yes - if you separated it out for each phase of the profile you want to assess then you probably wouldn't need to request partial AUCs but could just report the AUCt. The downsides I can see would be that you wouldn't be able to report meaningful clearance, volume etc from this NCA object, and that you might have issues extrapolating AUC if your actual times aren't quite covering the phase you are interested in.

 

 As for what to label them, you could use anything you want, doesn't have to be just a letter or a number, e.g. "pAUC1", "pAUC2"

 

 Simon

[Nathan Teuscher]

Another alternative is to run 2 NCA objects. The first object is the one you have already constructed with partial AUCs. The second NCA object will include a sort key based on the intervals where you would like to generate additional "Cmax" values. The sort key is simply another column with values that correspond to specific intervals (e.g. "0-2", "2-5", etc.). In this second NCA object, you can ask for only the Cmax output to minimize confusion with multiple values for other PK parameters.

 

Nathan

[Angus McLean]

Simon: Thanks I will try this and see how it goes. (I used to use Kinetica for NCA.)

 

The downside you mention relates to apparent clearance and apparent volume. I say apparent since both parameters are convoluted with F (fraction absorbed) so what you get is usually Cl/F, V/F. More common in the preclinical world.

 

 It is not a downside for me, since my interest is purely exposure in terms of Cmax0-t and AUC0-t at a number of time interval windows I will stipulated. Essentially I am after partial exposure metrics at these windows, in terms of not only AUC (intrinsic to the program), but additionally in terms of Cmax.

 

For example I an individual has intense pain then the time scale of relief of that pain is important. 10 minutes can feel like 10 hours.

 

I will let you know how it goes,

 

Angus

[Angus McLean]

Nat: thanks..................................................I do follow the strategy.

 

Angus

[Angus McLean]

NAT: I think you are suggesting that for the second NCA object then you insert a column into the input file you already have after it has been imported to phoenix. Then you use that column as a sort column....yes?

 

I am working with actual times not nominal times so here is an example below of one subject's times. The times vary a bit of course as you are aware. I am setting partial AUC metrics to 4-15, 4-30 and 4-60 and finally 60-180. Now regarding Cmax In terms of your suggestion. You can see below we have a time point at 12 and one at 16 minutes so how handle having a Cmax metric between 4-15. Would 4-15 be entered from 4 up to 16 minutes and for 4-30 enter 4-30 from the 4 minute point out to 36 minutes e.t.c.

 

4

9

12

16

21

36

52

69

99

130

191

Angus

[Nathan Teuscher]

Angus,

 

Overlapping intervals is much more difficult to capture ... I had assumed separate but consecutive intervals ... but it can be done. Since you have overlapping intervals, I think I would use a Data Wizard Filter to create the desired subset of data by including times within the desired intervals (4-15 min, 4-30 min, 4-60 min, and 60-180 min). Each interval would require a separate data wizard. Then each dataset would need an NCA object.

 

From a scientific point of view, I'm not sure why you are interested in these overlapping intervals and what one might learn from defining the interval-specific Cmax values.

 

Nathan

[Angus McLean]

Thanks Nat: from a scientific point of view partial AUC0-t metrics are used to describe exposure windows for PK profiles. The question arises if anything is to be gained by presenting the corresponding window Cmax 0-t? After all exposure is usually characterized by the two metrics..

 

When comparing profiles between a test and reference bolus formulations e.g a sublingual tablet one wonders if one can differentiate or characterize the early exposure better by examining the early exposure metrics for both AUC and Cmax. e.g 0-15 minutes. In my specific case one seeks a pule of drug rapidly (for efficacy).

 

What do you think?

 

Angus

[Nathan Teuscher]

Thanks Angus, I have used partial AUCs before, but generally we use non-overlapping windows (e.g. 0-15 min, 15-60 min, 1-2 hr, etc.) to characterize the different phases of the absorption profile. With overlapping windows (such as you described, the results get a bit muddy and comparisons can be confusing. In essence, each subsequent interval dilutes any response from the previous interval.

 

You are correct that total exposure is evaluated using 2 metrics (AUC and Cmax). These two metrics were chosen as the most accurate combination that describes an entire concentration time profile. The assumption is that if the AUCs match and the Cmax values match, than the overall "shape" of the PK profile should be similar (even identical). Now we all know cases where AUC and Cmax fall within prescribed equivalence ranges, yet the PK profiles are markedly different, however, the theory still exists that we can boil down an entire profile to 2 values.

 

Partial AUCs are an attempt to further characterize different portions of the concentration-time profile. Specifically, they are used to evaluate the absorption phase to identify differences in the rate of absorption which may affect efficacy for certain classes of drugs (e.g. methylphenidate HCl). AUC is used because it represents the average concentration over a defined period of time. Cmax is not used because it is a metric that is meaningless outside of the full PK profile. Interval-specific maximums do not provide information about the eventual maximum concentration, nor the timing of such a maximum. A ranked statistical test of Tmax would provide an equal amount of information as trying to interpret interval-specific maximum concentrations.

 

If the sponsor is trying to show more rapid efficacy (using absorption as a surrogate for efficacy), then I would compare Tmax values or pAUCs. If there are distinct peaks (e.g. multiphasic release compared to multiple doses) then perhaps multiple Cmax and Tmax values could be useful ... but that doesn't seem to apply for your situation. I think I'm with Helmut on this one, partial area Cmax's don't appear to be logical or useful.

[Angus McLean]

NAT: Thank you for your thoughts. Regards the last paragraph I have Tmax and pAUC to support our position for more rapid onset....no problem.

somewhat

   I just wondered if the argument could be embellished by including corresponding partial C max values.

 

I am not sure that it will; I just thought I would look at it to see what comes out.

 

You may be correct.......................nothing to be gained and of course we have the shape of the profile to compare.

 

 

Angus

[Angus McLean]

For got to add..........................I used the Mann-Whitney test (nonarametric) to evaluate difference in Tmax and it did discriminate between the two set of T max values.

 

 

Angus