Bioequivalence and Bioavailability Forum

Shlonak Ayman,

❝ […] do the metabolite (Favipiravir RTP) need to be measured or only the Favipiravir, since no FDA or EMEA related guidance issued till date.

Parent is always preferred, even if a pro-drug (FDA Section V.A.1., EMA Section 4.1.5). You have to know which dose(s) will be administered (FDA Section VI.B.1., EMA Section the 4.1.6). Please consult the relevant guidelines (FDA, EMA IR, MR) with answers to these questions at hand:

• Is is a pro-drug?
  
• Are you able to measure the parent at the intended dose with sufficient accuracy & precision (LLOQ ≤5% C_max in any of the subjects)? Obtain information about the between-subject variability to get an idea what to expect in the worst case.
• For the FDA:
  • AUC_0–72 acceptable as an alternative to AUC_0–t & AUC_0–∞ (but not for HVD(P)s).
• For the EMA:
  • LLOQ sufficient to get a reliable estimate of AUC (AUC_0–t ≥80% AUC_0–∞) with the intended sampling schedule?
    If IR, AUC_0–72 (without extrapolation) is an alternative.
    If MR, AUC_0–t & AUC_0–∞ mandatory.
    
  • If at the highest strength difficult, is it possible (safety!) to administer a higher dose?
• If problems with the parent (pro-drug or not), provide hard data to justify measuring a metabolite (active or not; if ever possible the first in the chain). If in doubt, consider a scientific advice (at a “difficult” member state). Assess BE based on the metabolite and report the parent descriptively (no CI).

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P.S.: The EMEA (European Agency for the Evaluation of Medicinal Products) was renamed to EMA (European Medicines Agency) back in 2005.