Bioequivalence and Bioavailability Forum

Hi Nastia,

another part. I love your attitudes of questioning the foundations of what we are doing. Proves that you are a true scientist.

Reach for the stars,
even if you have to stand on a cactus.   Susan Longacre

I know that, been there. But you do it barefooted. Kudos!

❝ C_apical was invented in order to explore the shape of the peak more precisely. As far as I understood it was first mentioned in an article in 1988⁵ […] If C_apical is so promising parameter, why can't I find any trials with it in results (excepting [6] and a paper on controlled release gastroretentive dosage forms tested on dogs). Or my search methods are too poor? I would be grateful if anyone will give an example of it's calculation.

That’s the first reference I’m aware of as well. Never tried it.

❝ The concentration at the end of the intended dosing interval (C_τ) should serve as an analogue of C_min with lack of multiple dose studies.

Yes, but that’s a sad, sad story. I did my best at the GBHI in Amsterdam (2018) as well as Nuno Silva and Jack Cook in Bethesda (2019). Voices crying in the wilderness.

❝ The lag time matters when we deal with delayed-release formulations. Note that Phoenix defines it as time of observation prior to the first observation with a measurable (non-zero) concentration but not the time to the first observation with a measurable concentration. There could also be other ways⁷ to define it.

Correct. Lag-time means before a concentrations is measurable, hence, it cannot be the first measured one. It’s somewhere before the first measured one. As we discussed in the linked thread, I think that Detlew’s approach is pragmatic. Ref.7 would smell too much of modeling for regulators, I guess.

❝ T_50%between (half-value duration)…

AFAIK, the HVD (Half Value Duration) appeared for the first time already in 1974¹ as \(\small{\Delta_{1/2}}\) – part of the “Retardquotient” which compares “the degree of retardation” with IR as \(\small{R_\Delta=\frac{\Delta_{1/2,MR}}{\Delta_{1/2,IR}}}\). Suggested was
\(\small{\begin{array}{ll}
R_\Delta\leqslant 1 & \text{no retardation} \\
R_\Delta\sim 1.5 & \text{weak retardation} \\
R_\Delta\sim 2 & \text{medium retardation} \\
R_\Delta\geqslant 3 & \text{strong retardation} \\
\end{array}}\)

I found it in my bible² (stop searching; in German and out of print for ages) and some later stuff.^3,4 The Two Lászlós renamed it to HaVD to avoid confusion with highly variable drugs.
Enduring the discussions about PK metrics at the GBHI-workshops was like a flash-back after a bad LSD-trip. Stirring up murky waters which cleared more than thirty years ago.

❝ "Therapeutic response" ('Where it exists, consideration must be given to the "therapeutic window."')⁸. But aren't there limitations that could not afford to make a statement of any correlation between plasma concentrations and effect?

You are a keen thinker! Though Jerome was head of the FDA’s CDER at that time, he felt into the trap of confusing PK with PD.

Pharmacokinetics may be simply defined as
what the body does to the drug,
as opposed to pharmacodynamics, which may be defined as
what the drug does to the body.   Leslie Z. Benet

PD is connected via a more or less complicated link model to PK. Ask a modeler for horror stories. One is sure: The time point of E_max is later than t_max and differences between formulations might be dampened in PD (though the variability of PD measurements can be awful). Ask ten physicians and eleven will tell you that safety is directly related to C_max. Not that easy. Of course the same holds for C_min (or C_τ if you prefer) which is not directly related to efficacy. Hence the bracketing approach of comparing MR with IR (see this post) is – from a purely scientific perspective – built on sand. Unfortunately for  many  most drugs we have no clue about PK/PD. We have PK data from Phase I and PD data from Phase II. Quite often we have in Phase II only sparse sampling and the PK/PD models are not that good (pun!).

Another⁵ about \(\small{AUC\frac{above\, C_{av}}{below\, C_{av}}}\) (sorry, in German except the abstract):

It goes back to a proposal of the late Harold Boxenbaum⁶ of the days when “the flatter, the better” was a common slogan. I liked Harold because he didn’t give a shit about dress codes (always showed up in jeans, leather jacketed, wearing cowboy boots and a Stetson) and had a sharp tongue.

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1. Meier J, Nüesch E, Schmidt R. Pharmacokinetic criteria for the evaluation of retard formulations. Eur J Clin Pharmacol. 1974;7:429-32.
   
2. Meier J. Bioverfügbarkeit und Absorption. In: Meier J, Rettig H, Hess H, editors. Biopharmazie. Theorie und Praxis der Pharmakokinetik. Stuttgart, New York: Georg Thieme; 1981. p. 247–76. ISBN 3-13-603106-6.
   
3. Steinijans VW. Pharmacokinetic Characteristics of Controlled Release Products and Their Biostatistical Analysis. In: Gundert-Remy U, Möller H, editors. Oral Controlled Release Products – Therapeutic and Biopharmaceutic Assessment. Stuttgart: Wissenschaftliche Verlagsanstalt; 1988. p. 99–115.
   
4. Steinijans VW, Hauschke D. Modified-Release Dosage Forms: Acceptance Criteria and Statistics for Bioequivalence. Drug Inf J. 1993;27:903–9. doi:10.1177/009286159302700332.
   
5. Blume H, Siewert M, Steinijans V, Stricker H. Bioäquivalenz von per os applizierten Retard-Arzneimitteln. Konzeption der Studien und Entscheidung über Austauschbarkeit. Pharm Ind. 1989;51(9):1025–33.
   
6. Boxenbaum H. Pharmacokinetic Determinants in the Design and Evaluation of Sustained-Release Dosage Forms. Pharm Res. 1984;1(2):82–8. doi:10.1023/A:1016355431740.