Bioequivalence and Bioavailability Forum

Hi Mahesh,

❝ My concern regarding Phenytoin NTID for EMA submission what would be the BE criteria for the same?

❝

❝ Cmax and AUC - 90 % CI 90.00 to 111.11% (what’s the mean of AUC only, is AUC0-t or AUC0-t and AUC0-inf)

The EMA does not require AUC_0-∞. AUC_0-t and C_max (for IR) are the main PK metrics of interest. There is no product-specific guidance for phenytoin published. In Canada phenytoin is classified as a NTID. Denmark requires the 90% CI both for AUC and C_max to be within 90.00–111.11% for anti­epileptics (apart from levetiracetam and benzodiazepines).

❝ Or

❝ Cmax: 80.00 to 125.00 % and AUC: 90 % CI 90.00 to 111.11%

Duno. If in doubt go for a scientific advice.

❝ How we assure that both AUC and Cmax are important for safety and efficacy for Phenytoin or Narrow therapeutic drugs?

Don’t know what you mean by that. Due to the nonlinear PK of phenytoin reaching toxic levels in steady state is the main safety issue. Accumulation is lead by AUC – not the C_max.