Bioequivalence and Bioavailability Forum

Dear DLabes!

❝ IMHO it must be a feature. For what ever.

Of course it’s a feature, bugs don’t exist for software vendors…

❝ But I'm a little bit confused about the correct? entry. According to the definition (underlined by me)

❝ ❝ … Tlag is the time prior to the first measur­able (non-zero) concentration …

❝ I would guess 1.0<Tlag<1.5 .

Yes, sure! Now a couple of points.
WinNonlin comes up with 1.5, which is nice – and the value pragmatically most people would also give in NCA, but contrary to the definition given in the manual (last value prior […], which is 1).
OK, I cheated; my data are artificial ones using a one-compartment model with a lag-time of 1 hour:

\(C(t)=25.5\cdot(\textrm{e}^{-0.08\cdot(t-1)}-\textrm{e}^{-1.2\cdot(t-1)})\)

Kinetica v4.1.1 gives no definition of t_lag in the manual at all, but comes up with 1.

Little is published about NCA of t_lag, except in Cawello (2003), where an interval (like “between 1.0 and 1.5”) is suggested.* In the Glossary (p. 151) of the same reference another definition is given:

Lag-time: refers to the time period between administration of a drug and the occurrence of the first measurable concentration of the active component in the blood stream.
(my emphases)

Unfortunately the interval definition is scientifically valid but unsuitable for common statistical comparisons (yes, I know, fuzzy logic would help…). T_lag may sound exotic, but it can be an important parameter (e.g., for gastric resistant formulations or drugs with presystemic metabolism).

Long ago I played around with linear back extrapolation and solving for C=0, but unsuccessfully. In our example we would end up with lag-times of 0.53 (linear, 2 points) or 0.89 (quadratic, 3 points), which are contradictory to <LLOQs ‘reported’ at 0.75 and/or 1.
I also worked a little bit on splines, but this went well with some subjects and terrible with others… All back-extrapolation methods I tried were very sensitive to ‘noise’. Such a behavior is in agreement with compartmental methods, where fitting of the absorption process is often quite demanding.

So my question to the all of the forum’s members:
  What method are you using?
  [X] time point of first concentration > LLOQ
  [ ] time point prior to first concentration > LLOQ
  [ ] mean of these two time points
  [ ] a verbatim statement (like: between x and y hours)
  [ ] some kind of back-extrapolation (which one?)
  [ ] I’m using software (which one?) giving me a correct answer (which one?)

---

• Weimann H-J. Drug concentrations and directly derived parameters. In: Cawello W, editor. Parameters for Compartment-free Pharmacokinetics. Aachen: Shaker Verlag; 2003. p. 29-30.

Dear Helmut, d_labes,

I'm also a little confused about the results that Helmut quoted above. Running that same data in 5.2.1 I get the result of 1 for Tlag in the third group which agrees with the definition in the help file. I don't recall this function being changed for some versions in WNL so is there a typo in your table, or can you send me the workspace for further investigation?

❝ ... Tlag is the time prior to the first measur­able (non-zero) concentration ...

I would agree that probably Tlag lies somewhere between 1.0 and <1.5 but with NCA being model-independent I guess Pharsight decided to go for the prior one but obviously this will be heavily dependent on the sampling schedule so compartmental modelling is probably going to be more useful if you need to define this more 'precisely'.

I concur it would be useful for WNL to 'intrinsically' recognise BLQs but Helmut correctly states that the appropriate process is currently to recode non-numeric values first using (Tools > Status Codes).