Bioequivalence and Bioavailability Forum

Hi Shuanghe,

THX for your explanations!

❝ ❝ Multiple strengths of drugs with nonlinear PK (grater than proportional increase in AUC)?

❝ ❝ EMA: highest strength.

❝ ❝ FDA: highest therapeutic dose.

❝

❝ I think that FDA also recommend highest strength, same as EMA. See line 316–319 in the draft guidance. Where did it mention highest therapeutic dose?

See lines 325–326 of the draft (and also the 2003 guidance). Applicable if linear PK is documented. I was referring to Davit et al.* (all authors of the FDA). Excerpt:

[…] generally the highest dose strength be used for in vivo BE studies, unless reasons of safety justify using a lower strength. In the case of drug substances that are characterized by nonlinear PK over the clinical dosing range, Canada, the EMA, USA, and WHO specify which dose strength should be used in these cases, depending on the type of nonlinearity and the underlying mechanism.

Dose strength used in the in vivo studies

• Similarities
  All recommend that generally in vivo studies should be performed on the highest strength, unless reasons of safety justify use of a lower strength
  
  
• Differences
  Some jurisdictions specify which strength should be used for drugs with nonlinear PK over the clinical dosing range, as follows
  EMA: the strength to be used depends upon the type of nonlinearity and the underlying causes
  If the nonlinearity is characterized by greater than proportional increases in AUC with increasing dose, conduct the BE studies on at least the highest strength
  USA: the strength to be used depends upon the type of nonlinearity
  If the nonlinearity is characterized by greater than proportional increases in AUC with increasing dose, conduct the BE studies on at least the highest therapeutic dose (38)

Highest dose vs. highest strength was a major issue at the 1^st GBHI conference in Amsterdam 2015. No consensus reached…

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• Davit B, Braddy AC, Conner DP, Yu LX. International Guidelines for Bioequivalence of Systemically Available Orally Administered Generic Drug Products: A Survey of Similarities and Differences. AAPS J. 2013; 15(4): 974–90. doi:10.1208/s12248-013-9499-x.
  
  38. FDA. Draft Guidance on Phenytoin Sodium. 2008.