Bioequivalence and Bioavailability Forum

Dear Ramesh,

the usual question: for which country?

If you want to go to the US, ask the FDA’s review staff whether reference-scaling is acceptable. In conventional 2×2 cross-over studies we found sulfasalazine and 5-ASA to be highly variable (CV_intra 40–50 %; both for AUC and C_max). Other metabolites were nicer (sulfapyridine ≈13 %, N-acetyl-sulfapyridine ≈8 %, N-acetyl-5-ASA ≈23 %) – but the FDA is not asking for them. If you are thinking to opt for urine, forget it: sulfasalazine 60-70 %, sulfapyridine 15-25 %, N-acetyl-sulfapyridine 23-30 %, hydroxy-sulfapyridine 25-30 %, hydroxy-N-acetyl-sulfapyridine 20-25 %).

For the EMA you have to go with the parent. Convincing them that sulfasalazine is a pro-drug (I would say so) would not help because 5-ASA is highly variable as well. Scaling is acceptable for C_max only…