## No rule is the rule - lambda(z) of MD BE [NCA / SHAM]

Dear Helmut,

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

I see.

» » So, it looks like that no lambdaz, no NCA...
»
» Why? According to my knowledge no guideline specific for MD-studies calls for λz.

Sorry about this. I was thinking something else. You're right.

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

In Taiwan, we have to provide three Cmins before starting sampling for Css(n) at the steady-state (SS) for one dosing interval to prove that we do have Cmax(ss) and AUCtau(ss). For example, if the tau is fixed at 24 hr, then we start dosing volunteers for 5 consecutive days. And on the 3rd, 4th and 5th day, we need get each blood sample before next dose as Cmin. So we will have 3 Cmins and a serial C(n)ss within one tau at SS on the 6th day as the attached plot. Unfortunately, sometimes these three Cmins data before SS can be quite noisy. It can be difficult to tell the SS has been reached. In this situation, we can provide half-life (T1/2) at the same time to prove that the SS has been reached during the time period that we collect blood samples for one tau. For instance, If estimated T1/2 is 18 hr, then we do collect blood samples at SS since it has been 120 hr which is more than 5*T1/2 (90 hr). That's why we have to play with elimination from SS within tau.

» [..] washed out - I would expect any estimate within the MD-profile to be biased towards faster elimination.

Nice example. I did that once. I used nonlinear regression to fit conc-time data obtained from a MD BE study. Of course, I tried 1-, 2- and 3-compartment PK models and then used AIC to pick the final model. From fitting results of the final model, I got T1/2 indirectly with further calculation. That helped me to explain "Hey! I really did sampling at SS." The approach was accepted with that case.

» Do Chinese guidelines call for λz, accumulation index, ?

No. Not even FDA, EMEA or Japan for MD BE study, as far as I remember. So no rule is the rule.

» » » Vss is a strange metric.
» » Indeed. We calculate Vss just because WinNonlin does so.
»
» That’s not a good reason.

I know. Just because people or regulators have been getting used to WinNonlin.

» WinNonlin carries some really outdated legacy from previous versions. I talked to Simon last week, and it seems at Pharsight is reluctant in removing anything in order to keep backwards-compatibility. BTW, who needs a 80% confidence interval or – even worse – Westlake's confidence intervals? Does anybody understand how WinNonlin calculates the ridiculous a posteriori power?

, only can be heard exclusively at this Forum.

» [...] added data analysis for MD BE/BA since this release.
»
» Great!

We will still use ARS, TTT, or AIC or the combination methods as we do with SD BE study to estimate lambdaz without including Cmax(ss) in bear. Options are up to user.

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

explained as above. Many thanks.

All the best,
-- Yung-jin Lee
bear v2.8.8:- created by Hsin-ya Lee & Yung-jin Lee
Kaohsiung, Taiwan http://pkpd.kmu.edu.tw/bear