Bioequivalence and Bioavailability Forum

Dear Imran!

❝ Does any guideline suggest to use normalised Cmax for PK and Statistical calculation.

Not a suggestion, but an option.
The European Note for Guidance states in Section 3.3:

‘From the primary results, the bioavailability characteristics desired are estimated, namely AUC_t, […] or any other justifiable characteristics […]’

In the recent past some EU-regulators wanted us to include C_max/AUC for MR-products (not as a primary rate parameter, but descriptively).

Some statisticians are concerned about which method should be applied comparing C_max/AUC, since (by convention, PK-reasoning and bioanalytical grounds) both parameters are assumed to follow a lognormal distribution (evaluation by a parametric multiplicative model, e.g., ANOVA). Now what’s the statistical distribution of the ratio of two lognormal distributions?
Most people are pragmatic (simply ignoring the problem), others opt for a nonparametric method.
Unfortunately to my knowledge nobody ever has published on this topic…

❝ I have compared 90% CI data of Cmax and normalised Cmax, and both the results are different.

Different metrics give different results.
In most cases intra-subject variability of C_max/AUC is lower than C_max’s – resulting in a tighter confidence interval.

References:

1. Endrényi L, Yan W. Variation of C_max and C_max/AUC in investigations of bioequivalence. Int J Clin Pharm Ther Toxicol. 1993; 31(4): 184–9.
   
2. Schall R, Luus HG, Steinijans VW. Choice of characteristics and their bioequivalence ranges for the comparison of absorption rates of immediate-release drug formulations. Int J Clin Pharm Ther. 1994; 32(7): 323–8.