Bioequivalence and Bioavailability Forum

Dear Dr. Pravin!

❝ As per EU BA/BE Guidline, the exclusive use of the compartmental based estimates are not recommended,...

Not only as per EU, but also WHO (1.9MB PDF) and many country's national guidelines (for details please consult the Guidelines page).

Citing WHO (Annex 7, 6.6.4):

'Area under the plasma/serum/blood concentration–time curve from time zero to time t (AUC0–t), where t is the last sampling time point with a measurable concentration of the API in the individual formulation tested. The method of calculating AUC-values should be specified. In general AUC should be calculated using the linear/log trapezoidal integration method. The exclusive use of compartmental-based parameters is not recommended.'

❝ i want to know the meaning of this sentence.

A useful reference for the topic is Sauter et al. (1992)^*)

In PK we generally distinguish between model based analysis (e.g. 'classical' PK, physiologically based PK [PBPK], population PK [PopPK],...) and noncompartmental analysis (NCA), which is the preferred method for BE.
Since BE serves as a tool in decision-making (is based on confirmatory statistics), metrics (C_max/t_max, AUC,...) must be calculated unambiguously.

NCA takes C_max/t_max simply from the observed profile; AUC is calculated by the trapezoidal rule (TR).
Although variants of the trapezoidal rule exists (using raw data: 'linear' TR, using log-transformed data 'log' TR, and mixtures of both: linear TR up to t_max - log TR after t_max, or linear TR for all increasing sections of the profile - log TR for all decreasing sections), if the method is stated in the protocol (and followed in the evalution...) results can be reproduced exactly (and reviewed by regulators) even by means of a pocket calculator!

On the contrary results from model-based PK are almost impossible to reproduce from raw-data unless all of the following is given:
Software (version, operating system), model-definition (micro- or macroconstants, clearance-based, explicit solutions or differential equations), fitting algorithm (Gauss-Newton and its variants, Simplex,...), initial estimates (starting conditions for iterations), constraints (side conditions, tuning parameters), convergence criteria, maximum number of iterations, weighting scheme,...

*) Sauter R, Steinijans VW, Diletti E, Böhm E and H-U Schulz
   Presentation of results from bioequivalence studies
   Int J Clin Pharm Ther Toxicol 30/Suppl.1, S7-30 (1992)

P.S.: Instructions.htm#Plt!