Bioequivalence and Bioavailability Forum

Dear all,

as a first augury of the new MR guideline (draft expected QIV 2012), the Q&A document was updated (Section 12). Excerpt:

Biphasic modified release formulations are characterised by two phases of drug release: a first phase determined by the immediate release dose fraction to provide a therapeutic drug level shortly after administration, and a second extended release phase to provide the dose fraction required to maintain an effective therapeutic level for a prolonged period. The clinical rationale behind their development is that a rapid onset of action is required in addition to subsequent prolonged release characteristics.

For the pharmacokinetic evaluation, these two phases should be separated through a cut-off time point, which needs to be pre-specified and universally applied to all subjects and for both test product and reference product. The identification of this cut-off time point should aim to describe the plasma concentrations in the first phase driven by the immediate release dose fraction whilst avoiding bias through an increasing contribution of the extended release phase.

Equivalence needs to be shown for both extent and rate of absorption (reflecting AUC and C_max for conventional bioequivalence criteria), separately for both phases:

• For the first phase, the assessment of equivalence should be based on the truncated AUC from t=0 until the cut-off time describing the immediate release dose fraction, and on C_max during the first phase.
  
• For the second phase, the assessment of equivalence should be based on the AUC from the cut-off time until the end of observation period, and on C_max during the second phase.

These considerations are in principle valid for studies in fed state and in fasting state. If no significantly different pharmacokinetic profile between fasting and fed state is expected then the cut-off time point should be identical.

These recommendations are inline with recent product-specific guidances of the FDA (methylphenidate ER capsules: fasting 3 h, fed 4 h, zolpidem ER tablet: fasting 1.5 h, fed no cut-off).