Bioequivalence and Bioavailability Forum

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 lambda_z, no NCA...

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

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

An example for different λ_z-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 λ_z 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 λ_z 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 λ_z 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 lambda_z.

Do Chinese guidelines call for λ_z, accumulation index, ?

❝ ❝ V_ss is a strange metric.

❝ Indeed. We calculate V_ss just because WinNonlin does so.

That’s not a good reason.
WinNonlin carries some really outdated legacy from previous versions.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 lambda_z 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.