Bioequivalence and Bioavailability Forum

Dear all,

in recently published revisions of product-specific guidances (see this post) partial \(\small{AUC}\) is given as an alternative to \(\small{t_\text{max}}\). As far as I understand, the cut-off time has to be somehow (‼) related to \(\small{t_\text{max}}\) of the comparator and pre-specified in the protocol. So far, so good.
However, questions arise.

• In SmPCs sometimes the arithmetic mean is given and only rarely the median or the range. The latter is most problematic. In either case, the value depends on the sampling schedule of the original study/studies.
  
  
• We are interested in detecting potential differences in the absorption of IR products. We know – for decades – that \(\small{C_\text{max}}\) is a poor surrogate¹ of \(\small{k_\text{a}}\) and \(\small{C_\text{max}/AUC}\) would be a better metric.^2–5 For these particular products the EMA is not happy with \(\small{AUC}\) and \(\small{C_\text{max}}\) alone (why?) and requires something else additionally. The following table shows how much of a drug will already be absorbed at certain cut-off times:$$\small{\begin{matrix}
  t_\text{cut} & \text{abs}\phantom{0}(\%)\\\hline
  \hfil t_\text{max} & \approx84.29\\
  2\times t_\text{max} & \approx97.53\\
  3\times t_\text{max} & \approx99.61\\
  4\times t_\text{max} & \approx99.94
  \end{matrix}}$$

Which cut-off times will be appropriate? \(\small{t_\text{max}}\) or later? Any partial \(\small{AUC}\) with a relatively early cut-off will be highly variable⁵ and reference-scaling is not acceptable – though it is for MR products.^6,7 Health Canada and the FDA treat partial \(\small{AUC}\) only as supplementary information, i.e., assess only the point estimate.

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1. Tóthfalusi L, Endrényi L. Estimation of C_max and T_max in Populations After Single and Multiple Drug Ad­mi­ni­stra­tion. J Pharma­co­kin Phar­ma­­codyn. 2003; 30(5): 363–85. doi:10.1023/b:jopa.0000008159.97748.09.
   
2. Endrényi L, Fritsch S, Yan W. C_max/AUC is a clearer measure than C_max for absorption rates in investigations of bio­equi­va­lence. Int J Clin Pharmacol Ther Toxicol. 1991; 29(10): 394–9. PMID 1748540.
3. Schall R, Luus HG. Comparison of absorption rates in bioequivalence studies of immediate release drug formulations. Int J Clin Phar­ma­col Ther To­xi­col. 1992; 30(5): 153–9. PMID 1592542.
   
4. 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. PMID 8500920.
   
5. Lacey LF, Keene ON, Duquesnoy C, Bye A. Evaluation of Different Indirect Measures of Rate of Drug Absorption in Comparative Phar­ma­co­kinetic Studies. J Pharm Sci. 1994; 83(2): 212–5. doi:10.1002/jps.2600830219.
   
6. EMA/CHMP/EWP. Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms. London. 20 November 2014. Online.
   
7. Only for multiphasic release products early partial \(\small{AUC}\) represents the first absorption phase. For control release products it represents part of distribution / elimination.