## Rattleback [NCA / SHAM]

Dear Helmut!

» Not only that (it’s a side-effect). What are we interested in? Extent of absoption (cleary AUC) and rate of absorption (k

So what are the main requirements for the ideal PK metric? Not to change and have low variability? Returning to C

» Seriously, László (The Younger) asked me the same question years ago, which I could not answer. Martin helped us out. It doesn’t matter: The sum/difference of two normal distributions will be normal, the same here: It will be log-normal.

Much easily I should have read something about it somewhere on the forum. Can you please also clarify the distribution of T

» The jury is out.

That's correct but too much individual approach - we couldn't know beforehand all the thin nuances of the PD of the specific drug, sometimes it is even impossible to find in literature any PK data for some drugs while planning new study... So I think the overall approach should be more general.

» OK, some people calculated \(\small{VRT = S_2/S_0-(S_1/S_0)^2}\), the “Variance of Residence Times” or “Gravity Duration” (stop searching; out of fashion for decades). The coordinates \(\small{\{MRT\:|\:VRT\}}\) define the “Center of Gravity” of the curve.

Why not? The static moments of the plain curve 'Concentration-time' (C(t)) are:

First is connected with MRT (muliplyed by total square of the curve), and the second should reflect some ideal Concentration-unit parameter (the height of the gravity center). Why not to use it like some alternative to C

» Only nice to print a profile, cut it a out, push a pin through it, and make a weird whizz wheel for kids.

Oh, if we'll proceed further in the power of moments we should be able to calculate moment of inertia - then one can take that curve to the orbital station in order to research Dzhanibekov effect.

» There is a big problem with it. To get a reliable estimate of AUC one has to cover 95% (!) of AUC

Could you please explain this more detaily? What do you mean in getting a reliable estimate of AUC?

» Not only that (it’s a side-effect). What are we interested in? Extent of absoption (cleary AUC) and rate of absorption (k

_{a}and possibly t_{lag}). k_{a}is not easily accessible in NCA. C_{max}is a*composite*surrogate (because influenced by AUC). Easy to show: Define any PK model and vary ƒ whilst keeping k_{a}and t_{lag}constant. C_{max}will change… C_{max}/AUC is an attempt to deal with that.So what are the main requirements for the ideal PK metric? Not to change and have low variability? Returning to C

_{max}/AUC - do we need more strict conditions to prove BE on its base keeping in mind its much lower variability (narrow CI for example) - cause it's always within the limits? (In old (e.g. below 2013) russian protocols I even saw the opposite situation when the confidence limits for C_{max}/AUC (as well as C_{max}) were choosen to be "75,00-133,00%")» Seriously, László (The Younger) asked me the same question years ago, which I could not answer. Martin helped us out. It doesn’t matter: The sum/difference of two normal distributions will be normal, the same here: It will be log-normal.

Much easily I should have read something about it somewhere on the forum. Can you please also clarify the distribution of T

_{1/2}: it is always presented as Mean±SD, is it correct? (Mean=Arithmetic Mean). It seemed to me I've read somewhere on the forum that for study planning we should use not the mean T_{1/2}but the confidence level for it, but I couldn't find this thread now. Is it correct to use standard approach to calculate CI for untransformed T_{1/2}as normally distributed data or should we use other approaches like nonparametric median confidence intervals or bootstrap?» The jury is out.

*E.g.*, for biphasic methylphenidate the cut-off time (FDA: 3 h fasting, 4 h fed) is based on PD indeed (at that time ~90% of patients show the maximum effect). Makes sense.That's correct but too much individual approach - we couldn't know beforehand all the thin nuances of the PD of the specific drug, sometimes it is even impossible to find in literature any PK data for some drugs while planning new study... So I think the overall approach should be more general.

» OK, some people calculated \(\small{VRT = S_2/S_0-(S_1/S_0)^2}\), the “Variance of Residence Times” or “Gravity Duration” (stop searching; out of fashion for decades). The coordinates \(\small{\{MRT\:|\:VRT\}}\) define the “Center of Gravity” of the curve.

Why not? The static moments of the plain curve 'Concentration-time' (C(t)) are:

\(M_t=\int t\cdot C(t)dt\);

\(M_C=1/2\cdot\int C(t)^2dt\)

First is connected with MRT (muliplyed by total square of the curve), and the second should reflect some ideal Concentration-unit parameter (the height of the gravity center). Why not to use it like some alternative to C

_{max}?» Only nice to print a profile, cut it a out, push a pin through it, and make a weird whizz wheel for kids.

Oh, if we'll proceed further in the power of moments we should be able to calculate moment of inertia - then one can take that curve to the orbital station in order to research Dzhanibekov effect.

» There is a big problem with it. To get a reliable estimate of AUC one has to cover 95% (!) of AUC

_{0–∞}(note that I’m not taking about BE but hard-core PK). For AUMC is should be 99%. I’m quoting Les Benet. Don’t blame me.Could you please explain this more detaily? What do you mean in getting a reliable estimate of AUC?

—

"Being in minority, even a minority of one, did not make you mad"

"Being in minority, even a minority of one, did not make you mad"

### Complete thread:

- Fantastic PK parameters and where to find them Astea 2020-06-12 14:22 [NCA / SHAM]
- Fantastic post 👍🏽 Helmut 2020-06-12 16:23
- RattlebackAstea 2020-06-13 10:17
- Chatter Helmut 2020-06-13 12:28
- Reinventing the Hula-Hoop Astea 2020-06-16 01:33
- Hula-Hoop references Helmut 2020-06-16 13:07
- Prof. Keller vs. Yamaoka mittyri 2020-06-17 14:28
- SHAM(e) math Astea 2020-06-23 14:41
- SHAM(e) math Helmut 2020-06-23 15:55
- OT: Möbius strip Astea 2020-06-23 21:41
- OT: Möbius strip Helmut 2020-06-24 11:29

- OT: Möbius strip Astea 2020-06-23 21:41

- SHAM(e) math Helmut 2020-06-23 15:55

- SHAM(e) math Astea 2020-06-23 14:41

- Prof. Keller vs. Yamaoka mittyri 2020-06-17 14:28

- Hula-Hoop references Helmut 2020-06-16 13:07

- Reinventing the Hula-Hoop Astea 2020-06-16 01:33

- Chatter Helmut 2020-06-13 12:28

- RattlebackAstea 2020-06-13 10:17
- More stuff Helmut 2020-06-13 15:28
- MRT and Gravity duration mittyri 2020-06-14 22:24
- Fantastic PK parameters and where to find them ElMaestro 2020-06-16 09:46
- Cauchy distribution mittyri 2020-06-16 10:54
- Cauchy distribution Helmut 2020-06-16 13:14
- Cauchy distribution ElMaestro 2020-06-20 10:33
- noncentral normal ratio mittyri 2020-06-20 23:04

- Cauchy distribution mittyri 2020-06-16 10:54

- Fantastic post 👍🏽 Helmut 2020-06-12 16:23