Bioequivalence and Bioavailability Forum

Dear Dan,

Thanks for your input!

❝ As far as I understood your drug administered as an IR formulation shows low intra-subject variability whereas the inter-subject variability in bioavailability is high. In other words patients will have consistently either high or low bioavailability. You aim to increase the low bioavailability with a MR formulation.

Correct!

❝ Do you really know the reason for differences in bioavailability? Is it metabolism or just BMI? (my question in this context: the percentage you present is it absolute or relative bioavailability?). If you identify a patient population which tends to have low bioavailability then you do not have to aim for BE as you already suggested and consequently you do not need to perform a formal sample size estimation. You just have to show that bioavailability of the drug in this patient population is increased by the MR formulation in comparison with the IR formulation. However, this will also mean that you have to proof efficacy and safety of the MR formulation.

Besides characteristics like BMI, it also has to do with absorption/metabolism. The compound is actively absorbed via a saturable mechanism. With the pilot PK we will try to identify the patient population that shows low BA and, moreover, to see whether our MR formulation may show signs that the concept would work.

It may be most informative to include patients who have been switched to injections (probably low-responders -> low BA), but this is regarded as unethical as we would then withdraw them from a therapy that works for them.

To get some information from this pilot PK on the feasibility of our formulation, I think we will still go for a 2x2 crossover, probably with 16 patients. Please let me know if you think an other design or sample size would be more informative.

Many thanks for your help!