Bioequivalence and Bioavailability Forum

Dear all,

if you want see what’s going on behind the curtains of the new MR GL I can recommend two recent publications:

1. P Paixão, LF Gouveia, JAG Morais
   An alternative single dose parameter to avoid the need for steady-state studies on oral extended-release drug products
   Eur J Pharmaceut Biopharmaceut; e-pub ahead of print, 5 Nov 2011
   DOI: 10.1016/j.ejpb.2011.11.001
   
2. A García-Arieta, S Morales-Alcelay, M Herranz, JM de la Torre-Alvarado, A Blázquez-Pérez, M^aL Suárez-Gea, C Álvarez
   Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products
   Int J Pharmaceut; e-pub ahead of print, 12 Nov 2011
   DOI: 10.1016/j.ijpharm.2011.11.022

C_τ (the concentration measured in single dose at the intended dosage interval) was suggested (Barcelona, Feb 2011). If BE (eventually after scaling) was demonstrated for this metric no multiple dose study was deemed to be necessary. However, at the MR conference in Berlin (Nov 2011) this option seemed to be off the table. I was rather skeptical about its applicability for CR formulations where k_a<k_e (flip-flop PK). Accumulation IMHO is based on the residual AUC (SD: τ→∞) and not a single concentration. The simulations by Paixão et al. proved me wrong. Since another metric is added to the BE requirement in SD, sample sizes have to be increased. But this is more than outweighed by the dropped MD study. On the other hand I would say García-Arieta et al. give only anecdotal reports (six cases) which were not sufficiently powered to demonstrate BE for C_τ.