Bioequivalence and Bioavailability Forum

Hi Osama,

❝ ❝ at the end an script to play with.

❝ ❝

❝ ❝ For any elimination half life of > 7 hours and an intended dosing interval of 24 hours it will be impossible to get the MD study waived. Red are formulations with flip-flop PK (k_a ≤ k_el).

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❝ Could you please kindly add more explanation.

About the script or about what I’m doing here?

OK, seriously: Acc. to the EMA’s GL the MD study can be waived if AUC_τ–∞ is ≤10% of AUC_0–∞. Of course, in the SD study you would sample longer than τ to get a reliable estimate of λ_z and show that AUC_0–t ≥ 80% AUC_0–∞. Furthermore, you would try to show equivalence of partial AUCs.
When you develop an extended release formulation you try to slow down absorption, i.e., decrease the k_a/k_el-ratio – which the script does. That’s all you can do cause k_el is drug-specific. In an ideal case (e.g., no absorption window) the AUC will not be affected, only C_max will be lower and delayed. So far, so good.
But it has a nasty side effect. The early part of the AUC (until τ) will decrease and the late part increase, making waiving the MD study not possible due to the ≤10% of AUC_0–∞ limit.*

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• Scheerans C, Heinig R, Mueck W. Proposal for defining the relevance of drug accumulation derived from single dose study data for modified release dosage forms. Biopharm Drug Dis. 2015; 36(2): 93–103. doi:10.1002/bdd.1923. Open access.