Bioequivalence and Bioavailability Forum

Dear Chiku!

❝ Does this mean only Fasting and Fed is required for MR or we should follow NfG 1999 where Fasting fed and Steady state is recommended.

The Q&A document quoted the 1999 MR NfG (Appendix I, 2-way cross-over studies: T_fasting/R_fasting and T_fed/R_fed). Inline with the IR GL (2010) a 4-way cross-over is now an acceptable alternative design (In cases where information is required in both the fed and fasted states, it is acceptable to conduct either two separate two-way cross-over studies or a four-way cross-over study.). Nothing has changed concerning the recommendation (fed + fasting). A clarification was made concerning a “suspected non-linear food effect”:

For both single-unit formulations and multiple-unit formulations, the highest strength should in general be studied. In case a non-linearity in the food effect is suspected, the food interaction study should be performed with the highest and the lowest strength.

Steady state is still recommended. On a case-to-case basis this requirement was waived in the past (some delayed / multiphasic / pulsatile release formulation with essentially no accumulation). Might ‘make it’ to the MR GL draft, but I’m not too optimistic.

• Pro (simulations):
  Paixão P, Gouveia LF, Morais JGA. An alternative single dose parameter to avoid the need for steady-state studies on oral extended-release drug products
  Eur J Pharm Biopharm. 2012;80(2):410–7. doi:10.1016/j.ejpb.2011.11.001
  
• Con (case study)
  García-Arieta A, Morales-Alcelay S, Herranz M, de la Torre-Alvarado JM, Blázquez-Pérez A, Luisa Suárez-Gea M, Álvarez C. Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products. Int J Pharm. 2012;423(2):321–5. doi:10.1016/j.ijpharm.2011.11.022

❝ Any idea when will MR guideline BE studies be published?

According to conversations with members of the PK group I had in Budapest two weeks ago end of QIII/2012.