NCA without lambda(z) [NCA / SHAM]

posted by Helmut Homepage – Vienna, Austria, 2009-07-16 14:06 (4252 d 08:08 ago) – Posting: # 3959
Views: 12,127

Dear Hsin-ya & Yung-jin,

» For what purpose to take blood sample after tau? Is it worth to do so?

I only said that I have seen people doing so. IMHO, it does not make any sense.

» » In steady state within τ you may get a value similar to SD, but with noisy data – and if more than one compartment is needed to describe [...]

» So, it looks like that no lambdaz, no NCA... :-(

Why? According to my knowledge no guideline specific for MD-studies calls for λz.

» » I would not try to play around with elimination from steady state within τ.

An example for different λz-estimates obtained from SD and MD for a two-compartment model (similar to this post, but τ=24h, 4 doses): Running WinNonlin’s PK model 11 (extravascular, first order absorption, 2 compartments, no lag-time, micro-constants parametrization, w=1/y2) we get
V1_F  76.41   L
K01    2.422  /hr  (t½ 0.2862 hr)
K10    0.1410 /hr  (t½ 4.916  hr)
K12    1.383  /hr  (t½ 0.5014 hr)
K21    0.9421 /hr  (t½ 0.7357 hr)

NCA-estimation of λz from the last three points (12/14/24hr) gives 0.1233/hr (t½ 5.624hr). If we use the predicted concentrations we would get 0.1030/hr (t½ 6.732hr). Running a simulation of the dosage regimen and estimating λz from data in the last interval (84/86/96hr) we get 0.1397/hr (t½ 4.963) – which is faster than the SD-estimate. Metaphorically speaking in log-scale in any given dosage interval we place another ‘triangle’ on top of the remaining profile – it’s clear that the descending slope gets steeper. If one is really interested in λz and has no SD-phase in the study, sampling should continue until concentrations from previous doses are washed out – I would expect any estimate within the MD-profile to be biased towards faster elimination.

» It is inevitable for us in Taiwan or in China to conduct a multiple-dose BE/BA study when the target product is modified release dosage form.

OK, same in the EU.

» The formula is only for when conducting both a SD and a MD BE/BA studies simultaneously. If we just have a MD BE study, we still need a lambdaz.

Do Chinese guidelines call for λz, accumulation index, :blahblah:?

» » Vss is a strange metric.
» Indeed. We calculate Vss just because WinNonlin does so.

That’s not a good reason. :cool:
WinNonlin carries some really outdated legacy from previous versions. I talked to Simon last week, and it seems that Pharsight is reluctant in removing anything in order to keep backwards-compatibility. BTW, who needs an 80% confidence interval or – even worse – Westlake’s confidence intervals? Does anybody understand how WinNonlin calculates the ridiculous a posteriori power?

» Since we're about to release next version (v2.3.3) of bear, we added data analysis for MD BE/BA since this release.

Great!

» I used to estimate lambdaz of MD study with the same method that we did in SD study. However, I was not very comfortable to do so for a long time.

Given my comments from above I’m not convinced whether it is really needed and makes sense at all.

Dif-tor heh smusma 🖖
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Complete thread:

Activity
 Admin contact
21,371 posts in 4,463 threads, 1,496 registered users;
online 2 (0 registered, 2 guests [including 2 identified bots]).
Forum time: Sunday 21:15 CET (Europe/Vienna)

When people learn no tools of judgment
and merely follow their hopes,
the seeds of political manipulation are sown.    Stephen Jay Gould

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5