Babe_Ruth
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USA,
2018-06-19 16:13

Posting: # 18924
Views: 1,291
 

 Exclusion of PK parameters where less than 3 quantifiable concentrations [NCA / SHAM]

I read in a PK report: "Where less than 3 quantifiable concentrations, AUC is not reported." Is this because of imprecision and inaccuracy with calculations due to lack of data points?

Should this rule be extended to all PK parameters (such as Tmax/Cmax)? What's the harm or benefit for excluding Tmax/Cmax?

The way I see it, if you only have two sequential concentrations above quantifiable limit, then you can generate a Tmax, but you can't be sure of the accuracy of Tmax, especially if Cmax is barely above quantitation limit of the assay used.


Edit: Category changed; see also this post #1[Helmut]
Helmut
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Vienna, Austria,
2018-06-19 23:12

@ Babe_Ruth
Posting: # 18925
Views: 1,086
 

 Reliable estimates?

Hi Babe_Ruth,

» I read in a PK report: "Where less than 3 quantifiable concentrations, AUC is not reported."

Bad English?

» The way I see it, if you only have two sequential concentrations above quantifiable limit, then you can generate a Tmax, but you can't be sure of the accuracy of Tmax, especially if Cmax is barely above quantitation limit of the assay used.

I know that some people report “Cmax” based on two concentrations and “AUC” on three. IMHO, that’s crap. I don’t belong to the club of guideline-addicts but
  • EMA (2010)
    A sufficient number of samples to adequately describe the plasma concentration-time profile should be collected. The sampling schedule should include frequent sampling around predicted tmax to provide a reliable estimate of peak exposure. In particular, the sampling schedule should be planned to avoid Cmax being the first point of a concentration time curve. The sampling schedule should also cover the plasma concentration time curve long enough to provide a reliable estimate of the extent of exposure which is achieved if AUC(0–t) covers at least 80% of AUC(0–∞). At least three to four samples are needed during the terminal log-linear phase in order to reliably estimate the terminal rate constant (which is needed for a reliable estimate of AUC(0–∞)).
  • FDA (ANDA draft 2013)
    We recommend drawing blood samples at appropriate times to describe the absorption, distribution, and elimination phases of the drug. For most drugs, we recommend collecting 12 to 18 samples, including a predose sample, per subject, per dose. This sampling should continue for at least three or more terminal elimination half-lives of the drug. The exact timing for sample collection depends on the nature of the drug and the rate of input from the administered dosage form. The sample collection can be spaced in such a way that the maximum concentration of drug in the blood (Cmax) and terminal elimination rate constant (Kel) can be estimated accurately. At least three to four samples should be obtained during the terminal log-linear phase to obtain an accurate estimate of λz from linear regression.
I leave it you counting words like sufficient, reliable, appropriate, accurate

Cheers,
Helmut Schütz
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