Bioequivalence and Bioavailability Forum

Dear Forum Members

This is regarding the analyte to be measured for proving bioequivalence for Ezetimibe Tablets for EU submission.

In case of Ezetimibe, after rapid absorption the parent drug is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Ezetimibe and ezetimibe glucuronide constitutes approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. But the parent drug is quantifiable and the complete pharmacokinetics of the unchanged drug can be established.

As per the CHMP Guidance on the investigation of bioequivalence in the section 4.1.5 it is mentioned as; In principle, evaluation of bioequivalence should be based upon measured concentrations of the parent compound. The reason for this is that Cmax of a parent compound is usually more sensitive to detect differences between formulations in absorption rate than Cmax of a metabolite. In the same discussion it is also mentioned as also for inactive pro-drugs, demonstration of bioequivalence for parent compound is recommended. The active metabolite does not need to be measured.

Do we need to provide bioequivalecne for metabolite as well for Ezetimibe or we can simply move ahead with BE of parent?
Our regulatory/analytical team is inclined towards proving the BE for metabolite as well for some unkown reasons quoting USFDA guidance.

Does any one has any experienceing of submitting Ezetimibe to EMEA?

Regards
Siri