Bioequivalence and Bioavailability Forum

Hi Mittyri,

❝ Do I understand it right, that at least 3 points should be planned after the ending of absorption? What kind of parameters should I take into account for sampling time calculation?

Talking about when absorption ends makes little sense I think. You satisfy regulators by being able to characterise well the first 80% of the entire concentration/time-curve. For that purpose you should have 3 points or more in the elimination phase.

❝ For example: according to the literature data the absorption ends up in 20h, so should we add at least 3 timepoints after 20h to be able to calculate the terminal rate constant?

No that's not really it. Absorption, distribution, metabolism and elimination and distribution all happen simultaneously. As above your goal is to have 3+ points in the terminal elimination phase. And note with some APIs you may have apparent bi- or trimodel elimination so you should focus on the last of the elimiation phases. Plenty points well beyond Tmax is a good idea.

❝ I'm unable to make head nor tail of different types of halflives

❝ We have halflife of API (derived from IV profile in originator's studies), halflife of prolonged release formulation (from other BEQ studies), apparent halflife (from originator's PK studies).

❝ Which type of halflife should be used for washout calculation?

Yeah its a mess of sorts. If you work on a CR formulation then the half-life you see is not the half-life you can compare to what you get from an IV study and that may in turn be different from IR formulation half-lives. Compare to the formulation that resembles your own.
Be aware of genetic variation. Use common sense. Give a little more info, please, then we'll have a look

I think first thing is to understand what your are involved in. For an extended release formulation the late absorption from the formulation interferes with the determination of the elimination half life. It makes it longer. You could obtain this apparent half-life from a prior modified release formulation and use 6 half lives past the Tmax as your last sampling time.

For example if your Tmax from the MR formulation is 10 hours and your half life is 6 hours from the MR formulation then your last sampling time would be (10+6*6)= 46 hours.

Hope this helps, but more information is needed to do better,

Angus

Hi Mittyri,

I agree with what ElMaestro and Angus wrote. Essentially it is very simple: Assuming that you sample long enough – what you “see” in the terminal’ phase is always driven (but not identical to) the slowest pro­cess. For IR it is likely elimination (sometimes also redistribution from a deep compartment) and for CR it may be absorption.
Think about a simple one-compartment model, po administration. In a mathematical sense the two rate constants are not identifiable. You only assume that k_a > k_el. You can only be sure once you have ad­mi­nistered the drug iv. Have a look at this presentation, slide 19. I simulated a true elimination of eight hours (iv, yellow line). Hey, it’s easy to create new formulations on the desk! I started with an IR (ab­sorption t_½ one hour) and slowed it down gradually. Once we have k_a = k_el we enter flip-flop PK. Not so evident in the linear plot but the lin/log-plot is interesting. As long as k_a > k_el we get an un­biased estimate of the elimination (the lines are only shifted to the right; same slope). In the flip-flop any beyond absorption drives the process.
Another nice observation: If we chance the absorption and keep elimination constant, the curves inter­sect the iv-curve at their respective t_max/C_max. Of course, AUC_∞ is identical.
Now see the next slide. Until we reach flip-flop PK, AUC_∞ is practically unbiased. Some bias creeps in afterwards. Truncated AUC will not work any more – that’s why the MR-GL tells us for CR forms AUC₇₂ is not acceptable as the only metric for extent of BA (like for IR and DR).
But – slide 22: If you have k_a ≪ k_el, the (still ongoing) absorption might be interrupted if the for­mu­la­tion leaves the GIT. Shit happens sometimes with matrix forms and osmotic pumps…

❝ Which type of halflife should be used for washout calculation?

The predominant (i.e., relevant) one. I don’t know your formulation.