Bioequivalence and Bioavailability Forum

Hi Mahmoud,

we have to wait for Yung-jin passing by when it comes to bear.

I have some questions / remarks.

❝ […] new requirements issued by the Bioequivalence committee at the central administration of pharmaceutical affairs (CAPA) at the ministry of health and population in egypt.

Are these requirements available on the net? The latest version I know is of January 2010, which states:

For t_max descriptive statistics should be given. If t_max is to be subjected to a statistical analysis this should be based on non-parametric methods and should be applied to untransformed data.
For parameters describing the elimination phase (t_1/2) only descriptive statistics should be given.

❝ […] ANOVA for K (1st order elimination rate constant), t1/2 and tmax for test and reference products;

• Identical clearance after T and R is one of the assumptions in bioequivalence. Think about the basic equation of PK: AUC = F × D / CL.
  For two treatments we have a set of two equations with six unknown variables (F_T, F_R, D_T, D_R, CL_T, CL_R) and two constants (AUC_T, AUC_R). Only if we assume [sic] that D_T = D_R and CL_T = CL_R we can eliminate these variables from the equations and end up with a comparison of Fs based on the ratio of observed AUCs. To ask for a comparison of clearances (expressed as k or t_½) is strange. Furthermore, CL is a property of the drug not the formulation. In BE we are not interested in that.
  BTW, asking for a comparison of both k and t_½ demonstrates a lack of understanding of statistics. They differ only by a factor of ln(2). Any comparison will give identical variance, CI, etc.
  
• ANOVA for t_max doesn’t make sense. Contradicts the next point.

❝ […] also can it perform Kruskal Wallis analysis for tmax…

Kruskal Wallis makes only sense for more than two treatments and will give only a global comparison. IMHO, not very helpful since post-hoc tests for pairwise comparisons with a Bonferroni-adjustment are needed.