Bioequivalence and Bioavailability Forum

Dear Srinetram & Suresh!

❝ The lower Cmax of simvastatin, the inactive prodrug, is not expected to have any clinical significance particularly when the AUC0-t and AUC0-inf; of simvastatin is bioequivalent to that of the reference tablet. Besides the active metabolite beta hydroxyacid of Simvastatin is complying the 90% confidence for Cmax, AUC(0-t), AUC(0-inf).

Right. EMA's EMEA/618604/2008 Rev. 1 (Questions & Answers: Positions on specific questions addressed to the EWP therapeutic subgroup on Pharmacokinetics, 23 July 2009) stated:

4. Interpretation of bioequivalence data in relation to both parent and metabolite PK data
Q: The EWP PK group was asked to comment on the interpretation of Cmax data in cases where both parent and metabolite PK data have been provided, where a single parameter (C_max of parent in this case) does not comply with acceptance criteria and of those exceptional situations in which parent C_max data might not prevail.
A: […] For some products bioequivalence may need to be demonstrated both for parent and metabolite AUC and C_max. This may be applicable e.g. for some statins for which it has been described that the outcome obtained with the parent does not predict the outcome of the metabolite and this discrepancy does not seem to be related to a high variability. This discrepancy seems to be related to the complex pharmacokinetic of these drugs with active transport in the absorption, hepatic uptake and hepatic elimination. Therefore, for some of the statins both parent and metabolite should presently be measured and evaluated separately. In this situation parent C_max does not prevail over metabolite C_max. Hence, with the current guideline, the need for demonstration of bioequivalence both for parent and metabolite AUC and C_max must be decided on a case by case basis.

The current version of the Q&A document (22 July 2010) states:

Note: The following positions have been deleted: Interpretation of bioequivalence data in relation to both parent and metabolite PK data / July 2010 / Covered by the revised Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1)

The current guideline states in Section 4.1.5:

Parent compound or metabolites
Inactive pro-drugs
Also for inactive prodrugs, demonstration of bioequivalence for parent compound is recommended. The active metabolite does not need to be measured. However, some pro-drugs may have low plasma concentrations and be quickly eliminated resulting in difficulties in demonstrating bioequivalence for parent compound. In this situation it is acceptable to demonstrate bioequivalence for the main active metabolite without measurement of parent compound. In the context of this guideline, a parent compound can be considered to be an inactive pro-drug if it has no or very low contribution to clinical efficacy.

(my emphasis)

Reviewing the literature and in connection with the July 2009 Q&A document, simvastation is classified as a prodrug and BE should be assessed based on beta-hydroxyacid simvastatin.
Note that this represents the current point of view of EMA.

❝ And for support you can get a lot of data from mhra website.

Maybe. Note that previous studies were done before the current BE-GL came into force.

FDA's product specific guideline (Final May 2008) states:

Analytes to measure: Simvastatin and its beta-hydroxyacid metabolite in plasma.
Please submit the metabolite data as supportive evidence of comparable therapeutic outcome.
For the beta-hydroxy metabolite of simvastatin, the following data should be submitted:
individual and mean concentrations, individual and mean pharmacokinetic parameters, and geometric means and ratios of means for AUC and C_max
Bioequivalence based on (90% CI): Simvastatin

You did not mention your target country. On which compound(s) did you want to claim BE according to your protocol? Though you may want to adapt your evaluation to current developments, (some) regulators are allergic to any changes simply because you don't like the results. For the future, I would suggest to amend your protocol before the evaluation - otherwise it might look like cherry-picking.