Bioequivalence and Bioavailability Forum

Dear Detlew!

❝ From all what you have explained to me I have the impression that two so-called 'Cmax' values are not so very sound. I have the impression that the authors of the Q&A have had some ideal time courses with distinct bi-phases in their mind.

First of all let me thank you again for your eagle eye. When I (rather too quickly) read the Q&A I was happy with the change because I think it’s a scientific valid approach. The term “biphasic MR formulations” is correct but does not imply that the profiles will exhibit some kind of “trough” between two distinct peaks. In other words: “biphasic” is related to pharmaceutical technology which may or may not translate into PK.

In presentations of the PK-working party about the MR guideline two different types of “multiphasic MR products” were distinguished:

• Biphasic release (loading dose + maintenance dose)
  
• Pulsatile release (delivers a burst of drug release at one or more predetermined time intervals)

Whilst the former consist of an IR part and a controlled release part the latter consists of one or more delayed relase part(s). Personally I don’t understand the difference between a “single-pulse system” and a conventional delayed release formulation, but I’m no specialist in pharmaceutical technology.
An interesting slide about metrics:^[1]

Multiphasic modified release products
(e.g. biphasic- or pulsatile-release)

• Partial AUC at different times after dosing
  e.g. AUC truncated at the population median of tmax values for reference formulation
  
• Similarity factor for comparison of shape of concentration vs. time profiles
  
• Clinical equivalence studies
  
• Special relevance of tmax (pulsatile peak 4h vs 6h)

Now let’s see:

• Truncation at population median: Though used by the FDA for many years (as a measure of early exposure) maybe EMA didn’t like it (data-driven?). OK, fixed cut-off instead.
  
• Similarity factor f₂: Not a statistic.^[2] Relevance? Not a single publication. Led to serious grumbling sounds in the audience at the EUFEPS workshop (Barcelona, February 2011).
  Difference factor f₁^[3] proposed a while ago; BE if f₁ ≤ 20.^[4] α, β? Throw away your sample size tables!
  
• Sure. Be prepared to setup nonparametric CIs of rating-scales according to Duchateau…
  
• Ha! Here we are. t_max for pulsatiles may be interesting. But: Even for simple DR formulations it’s a nightmare (different lag-times due to variable gastric emptying). Although I haven’t seen a two-pulse formulation myself I can imagine that it’s possible to have two distinguished peaks at e.g 3 and 5 hours in one case and at 7 and 10 hours in another. Fixed cut-off impossible (what if set to 6 h?). BTW, t_max leads to an anaphylactic shock of assessors. Maybe this is where the C_max,I and C_max,II come from?

For a comparison of some exotic metrics (together with two examples) see here (slides 24–32).

❝ The FDA approach seems here more straight I think, taking the partial AUC as measure of 'early exposure' (as they have suggested already since times) and the one Cmax as measure of 'peak exposure'.

Right, that’s clinical relevant thinking. Partial AUCs for efficacy and (global!) C_max for safety.

❝ It suffers at least not from the inconsistencies in defining some 'C_max,I' or 'C_max,II' where no maximum is seen.

Exactly. See zolpidem and all osmotic pump systems.

❝ I think the discriminatory value of the partial AUC is well enough seen from the examples in the presentation.

❝ Thus the additional metrics only raise the burden.

Right again. I’m afraid we will have to wait until the draft is published and flood the PK group with comments. In the meantime we have to work according to the Q&A. If your formulation does not contain MPH or zolpidem – where a consensus about the cut-off seems to exist – invest a good deal of time in search not only the literature about PK but also about PD.

---

1. Neuhauser J, Baumgärtel C. (AGES PharmMed, LCM)
   Understanding the proposed guideline for modified release. Presentation at “Innovations in Modified Release“, Berlin, 8 November 2011.
   
2. Liu J-p, Ma M-C, Chow S-C. Statistical Evaluation of Similarity Factor f₂ as a Criterion for Assessment of Similarity Between Dissolution Profiles. Drug Information Journal. 1997;31:1255–71.
   
3. Moore JW, Flanner HH. Mathematical Comparison of curves with an emphasis on in vitro dissolution profiles. Pharm Tech. 1996;20(6):64–74.
   
4. Bayoud HA, Awad AM. Performance of Several Bioequivalence Metrics for Assessing the Rate and Extent of Absorption. J Bioequiv Availab. 2011;3(7):174–7.
   doi:10.4172/jbb.1000080.