Bioequivalence and Bioavailability Forum

Dear Andrew!

❝ […] I wonder whether you have any specific tips for BE studies with narrow therapeutic index drugs. I've just been playing with NQuery Advisor which tells me that, as we all know very well, for an intra-subject CV of 23.5% I need a minimum of 24 subjects where acceptance limits are 80% to 125%. If, however, I narrow the limits to 90% to 111.1%, I find that for the same CV I'll need 230 subjects. I had not expected this!

My dear, science is a cruel mistress. (Paul Shenar as Dr. Laurence)

Power curves are unforgiving - especially when you change the T/R-ratio or the acceptance range.

❝ I accept that most NTI drugs probably have fairly low intra-subject CVs, but I'm trying to design a study for Levothyroxine where the problem of endogenous levels coupled with the fact that the 600mcg dose does not increase blood levels all that much over baseline means that, in my limited experience anyway, the CVs for AUC can be quite high. [Well over 23.5%.]

Levothyroxine is not considered an NTID in Canada. No product specific GL in the US, but Liothyronine is also not considered an NTID.
In Europe NTIDs are assessed on a case-by-case basis. Little is published yet (tacrolimus: AUC 90%-111%, C_max 80%-125%; ciclosporine: AUC and C_max 90%-111%).
Would be interesting to know how Denmark will defend their requirements (updated on 8 Feb 2010) in the light of European harmonization (all immunosuppressives AUC and C_max 90%-111% vs. EMA-Q&A tacrolimus AUC 90%-111%, C_max 80%-125%).