Bioequivalence and Bioavailability Forum

Hi ElMaestro & Prashant,

❝ If you can prove to regulators that PK is linear or proportional or whatever the term is (Hötzi, in which direction do the terminological winds blow these days?) then that is perhaps a very good start…

EMA uses only the term “dose proportionality” in relation to linear PK. Pharmacokineticists will tell you that’s a power model E(Y|D) = α·D ^β, where α >0 and β ≠ 0. No departure from dose linearity if the 95% (!) confidence interval (L, U) of β is 0.75 < L < 1 < U < 1.25. For EMA it’s just dose-nor­ma­lized AUC within ±25%.

❝ …but I could be a little afraid that it is not necessarily enough.

Exactly.

❝ Would like to hear other people's opinion about the regulatory principle.

One of my cases: Only IR on the market. One product 5/10/20 mg, another one 10/20/40 mg. Maximum approved daily dose 60 mg.

• 20 mg new MR vs. 2 × 10 mg IR, hybrid pathway (two clinical studies; individualized doses up to 60 mg). ⇒ Approval of 20 mg.
  
• Dose proportionality of new MR 10/20/40 mg; BE of dose-adjusted PK-metrics compared to 20 mg strength, 95% (Bonferroni!) CIs. ⇒ Approval of 10 & 40 mg.
  The BfArM told us that nowadays they would want to see 4 × 10 mg & 1 × 40 mg vs. 2 × 20 mg…
  
• Dose proportionality biowaiver for 5 mg strength.
  
• Line extension for new 50/60 mg MR. BE 60 mg vs. 2 × 30 mg. Two clinical studies.
  
• Dose proportionality biowaiver for 50 mg strength. ⇒ Approval of 50 & 60 mg.

❝ If I were you I would definitely take a scientific advice even if it means some cost and time consumption.

As we did…