Bioequivalence and Bioavailability Forum

Dear Stefano!

❝ My concerns regard the urinary parameters: amount of drug excreted (Ae), maximum excretion rate (R_max) and elimination half life (t_½).

❝ • Ae. In your post you suggest to use an additive model.

Yes. Personal views, as mostly.

❝ However, in the FDA guidance […] an analysis based on log-transformed data is requested

I know. FDA also wants subjects to consume a diet of 2500-3500 Calories per day for the 16 days of hospitalization. That's a tough slimming cure! I would expect volunteers to loose a lot of weight. Not suitable for a cross-over. That's about science in (some) guidelines.

❝ From your experience, both these approaches are acceptable?

Ae, R_max: OK, even the last guideline-oriented regulator has heard about the holy grail of log-transformation by now. More science-oriented ones would accept a non-transformed analysis. To be honest my last urine study dates more than 15 years back. And, yes I didn't get complaints about any of them.

My reasoning is: Plasma metrics are based on concentrations (ratios! The volume of distribution comes into play), but urine metrics are based on amounts (mass).

❝ • t_½. The same considerations as for plasma concentration half life apply for this parameter?

Which considerations do you mean? The concept of BE-testing relies on the assumption of time-invariant clearances. Unless we go for stable isotope simultaneous iv administration, we have no means to check this assumption. We simply ignore it. If we have an absorption faster (k_a > 5k_el) than elimination, the apparent elimination should be roughly the same for both formulations. But I've rarely seen anybody testing for equivalence of t_½. An excpetion are PK-interaction studies, where a comparison is mandatory (concept of constant clearances may not hold).

❝ As regards renal clearance (CLr, based also on blood AUC) I think that, if we assume log-normality for Ae, the same distribution can be hypothesized for this parameter.

Following your assumption, yes.

❝ But if we assume normality for Ae, how should CLr be analysed?

Tricky. Like D. Labes said: Next question, please.