Bioequivalence and Bioavailability Forum

Hi Vishal,

❝ In calculation of terminal partial AUC (AUC cut off t-tlast) […] in such cases what is meaning of tlast?

❝ is this last time of blood collection or its last time of dosing interval?

By convention, \(t_\textrm{last}\) is the time point of the last measurable concentration. There is no relationship with the last sampling time point. Sometimes in a SD study (issues with the LLOQ), \(t_\textrm{last}\) can be earlier than late sampling time point(s). If you have relevant accumulation, it rarely happens after multiple doses.

❝ for example-In study blood collection is 72.00 hrs, However dosing interval of Drug is 24.00 hrs then early partial AUC will be AUC(0-12 hrs) & what would be the Terminal Partial AUC?

I guess you are are talking about SD studies (fasting and fed) and hope to get a waiver for the multiple dose study (‘no risk of accumulation’)? Sampling should be sufficiently long (in your case 72 h) to get a reliable estimate of \(\small{\lambda_\textrm{z}}\) (you need it for \(\small{AUC_{0-\infty}}\)). The late cut-off is the intended dosing interval \(\small{\tau}\) (in your case 24 h). If you have no justification for another cut off time, the GL suggests \(\small{\tau}/2\). Hence you need these PK metrics:

1. \(\small{AUC_{0-t_\textrm{last}}}\)
   
2. \(\small{AUC_{0-\infty}}\)
   
3. \(\small{AUC_{0-\tau}}\)
   
4. \(\small{_\textrm{partial}AUC_{0-\textrm{cut off}}}\)
   
5. \(\small{_\textrm{partial}AUC_{\textrm{cut off}-{\tau}}}\)

• The first two are required in all SD studies of MR products.
  
• If \(\small{100\times AUC_{0-\tau}/AUC_{0-\infty}\geq 90\%}\) and you pass BE for all PK metrics, the MD study can be waived and you’re done.
  
• If you fail at least one of the partial \(\small{AUC\textrm{s}}\) and pass both \(\small{AUC_{0-t_\textrm{last}}}\) and \(\small{AUC_{0-\infty}}\), the SD-part is done and you continue with the MD study. There you have to demonstrate BE only for \(\small{AUC_{0-\tau}}\).

Once you succeed in the MD study, failing \(\small{AUC\textrm{(s)}}\) in the SD study don’t matter (they were just an option to waive the MD study): You passed the required PK metrics both in the SD study \(\small{(AUC_{0-t_\textrm{last}}}\) and \(\small{AUC_{0-\infty}}\)) and in the MD study \(\small{(AUC_{0-\tau})}\).

Note that waiving the MD study works only for products with a fast \(\small{t_{1/2}}\). Any \(\small{t_{1/2}>\sim 3\,\textrm{h}}\) (esp. controlled release with flip-flop PK) practically never works.
If you have to deal with a multiphasic release product, you have to (additionally to \(\small{C_\textrm{max})}\) demonstrate BE of the maximum concentrations in each phase. For two phases you have to show BE for 7 (seven!) PK metrics. Good luck!

Of note, I suggest to perform the fed study first because all too often it is more difficult than fasting (products can have different food effects). I’ve seen many cases where fasting passed BE (sponsor happy) only to see the fed study terribly failing. Ended in a re-formulation and repeating both (this time in the ‘right’ order).