Bioequivalence and Bioavailability Forum

Dear Detlew!

❝ ❝ These recommendations are inline with recent product-specific guidances of the FDA …

❝ with the exception that the FDA recommends (T = cut-off time)

❝     Cmax,                     AUC(0-T), AUC(T-tlast) and AUC(0-inf)

❝ whereas the EMA demands

❝     Cmax(0-T), Cmax(T-tlast), AUC(0-T), AUC(T-tlast)

❝ if I interpret the Q&A and the product specific guidances right.

Absolutely correct. Eagle eye! Tougher to pass.

❝ Can we expect an additional burden by the two Cmax values?

Yes. Not so much by the CV, but – at least for MPH formulations – the PE. Examples (PE, CI, CV%):
                      Cmax                   Cmax0-4                 Cmax0-t
Markowitz et al.1 67.6 62.2  73.3 15     53.3  48.9  58.9 17
Wang et al.2                             97    85   111   22.7   91   84    99   13.9
Fischer et al.3  103.0 96.5 110.0  8.9  103.8  96.4 111.7 10.0  102.7 95.9 109.9  9.2
Tuerck et al.4    86   81    91   12    106   100   113   12.4   82   77    88    14
Haessler et al.5  68.6 63.3  74.3 17.0   73.3  66.6 80.7  20.4   70.2 64.5  76.4  18.0
Schütz et al.6    76.6 66.7  87.8  9.2   79.1  69.6 90.0  18.3   74.9 63.8  88.0  23.0
In the 2^nd study two development formulations (slow, fast) of Ritalin LA were tested. In the 3^rd study the same formulation was tested (intact capsule vs. sprinkled). In these studies all metrics passed, slightly higher CVs for ‘partial C_max’ (hey – a new term!). In the 4^th study almost all metrics passed. In all studies where different formulations were compared^1,5,6 the global C_max failed as well; wouldn’t say that partial C_max is more discriminatory.

❝ What to do in cases where there are no distinct Cmax in both phases like the concentration-time curves of Methylphenidate ER products shown on slide 43 (bottom left) of the presentation you have linked?

These curves are typical for MPH MR formulations. You have to deal with profiles of similar shape but different lag-times and the zero-order input of the osmotic pump (OROS ‘Concerta’). Everybody went with a pragmatic approach and uses the maximum concentration (C≤4 and C>4) ignoring the actual shape (also Q&A: “… cut-off time point, which needs to be pre-specified and universally applied to all subjects …”). See this goody from a 60 mg MD study:

It might well be that a couple of subjects show a C_max,0-4 at 4 h despite there was a decrease from an earlier peak or there is no clearly defined peak in one of the two sections at all. BTW, would be nice to know how these guys deal with it.

❝ BTW: I can't see any return of clinical reasoning in the EMA Q&A.

❝ ❝ "The identification of this cut-off time point should aim to describe the plasma concentrations in the first phase ... ".

Hhm. I don’t get your point here. Can you elaborate?

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1. Markowitz JS, Straughn AB, Patrick KS, DeVane CL, Pestreich L, Lee J, Wang Y, Muniz R. Pharmacokinetics of Methlphenidate After Oral Administration of Two Modified-Release Formulations in Healthy Adults. Clin Pharmacokinet. 2003;42(4):393–401. doi:10.2165/00003088-200342040-00007.
   
2. Wang Y, Lee L, Somma R, Thompson G, Bakthiar R, Lee J, Rekhi GS, Lau H, Sedeck G, Hossain M. In Vitro Dissolution and In Vivo Oral Absorption of Methlphenidate from a Bimodal Release Formulation in Healthy Volunteers. Biopharm Drug Dispos. 2004;25:91–8. doi:10.1002/bdd.390.
   
3. Fischer R, Schütz H, Grossmann M, Leis HJ, Ammer R. Bioequivalence of a methylphenidate hydrochloride extended-release preparation: comparison of an intact capsule and an opened capsule sprinkled on applesauce. Int J Clin Pharmacol Ther. 2006;44(3):135–41. doi:10.5414/CPP44135.
   
4. Tuerck D, Wang Y, Maboudian M, Wang Y, Sedek G, Pommier GF, Appel-Dingemanse S. Similar bioavailability of dexmethylphenidate extended (bimodal) release, dexmethylphenidate immediate release and racemic methylphenidate extended (bimodal) release formulations in man. Int J Clin Pharmacol Ther. 2007;45(2):662–8.
   
5. Haessler F, Tracik F, Dietrich H, Stammer H, Klatt J. A pharmacokinetic study of two modified-release methylphenidate formulations under different food conditions in healthy volunteers. Int J Clin Pharmacol Ther. 2008;46(9):466–76.
   
6. Schütz H, Fischer R, Großmann M, Mazur D, Leis HJ, Ammer R. Lack of bioequivalence between two methylphenidate extended modified release formulations in healthy volunteers.
   Int J Clin Pharmacol Ther. 2009;47(12):761–9. doi:10.5414/CPP47761.