Bioequivalence and Bioavailability Forum

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 lambda_z, no NCA...

❝

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

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 C_mins before starting sampling for C_ss(n) at the steady-state (SS) for one dosing interval to prove that we do have C_max(ss) and AUC_tau(ss). For example, if the tau is fixed at 24 hr, then we start dosing volunteers for 5 consecutive days. And on the 3^rd, 4^th and 5^th day, we need get each blood sample before next dose as C_min. So we will have 3 C_mins and a serial C_(n)ss within one tau at SS on the 6^th day as the attached plot. Unfortunately, sometimes these three C_mins 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 (T_1/2) 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 T_1/2 is 18 hr, then we do collect blood samples at SS since it has been 120 hr which is more than 5*T_1/2 (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 T_1/2 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 λ_z, accumulation index, ?

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

❝ ❝ ❝ V_ss is a strange metric.

❝ ❝ Indeed. We calculate V_ss 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❝ WinNonlin carries some really outdated legacy from previous versions.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 lambda_z without including C_max(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.