Bioequivalence and Bioavailability Forum

Dear All,

Phenytoin is an anticonvulsant drug indicated for the management of generalised tonic-clonic seizures and complex partial seizures. Phenytoin has a narrow therapeutic window with non linear PK and is highly protein-bound of which free (unbound) phenytoin is the component producing the pharmacological effect.

As per the current EU guidance, Section 4.1.9 - Narrow therapeutic index drugs; In specific cases of products with a narrow therapeutic index, the acceptance interval for AUC should be tightened to 90.00-111.11 %. Where Cmax is of particular importance for safety, efficacy or drug level monitoring the 90.00 - 111.11 % acceptance interval should also be applied for this parameter. It is not possible to define a set of criteria to categorise drugs as narrow therapeutic index drugs and it must be decided case by case if an active substance is an NTID based on clinical considerations.

In case of Phenytoin, Cmax is around 4 - 9 hours while the time required to reach its therapeutic range i.e. 20 mg / mL is around 15 hours (time taken to have clinical effect). Hence Cmax is not significant in relation to efficacy.

The mean plasma half-life of Phenytoin is 22 hours (range 7 to 42 hours) following oral administration; variability is due to the saturation kinetics. As Phenytoin has longer half-life, Cmin trough levels can be used as a surrogate for AUC in clinical practice. Given the long terminal half-life, Phenytoin accumulates during repeated dosing and due to this accumulation, a potential difference between formulations in Cmax after single dosing can be expected to be less at steady state, if AUC is the same for the two formulations.

Based on this feel that Cmax is of not particular importance in case of Phenytoin. Therefore, normal acceptance limits 80.00 – 125.00 % for Cmax while tighter acceptance limits 90.00 – 111.11 % for AUC can be used in single dose bioequivalence studies for Phenytoin.

Please suggest the way forward on my opinion.