Bioequivalence and Bioavailability Forum

Hi Maulik,

❝ The drug product is a prolonged release formulation with biphasic release pattern (IR+MR). The initial maximum concentration achieves at about 1 to 2 hours (due to release of IR Part) and Peak plasma concentration achieves at about 6 to 8 hours.

❝

❝ […] For single dose study of multiphasic modified release drug product following parameters has to show bioequivalence.

❝ AUC_0-t, AUC_0-∞, _partialAUCs and C_max in all phases.

❝ I have kept AUC_0-t, AUC_0-∞, _partialAUC_0-2, _partialAUC_2-t.

Correct.

❝ (1) Please help to understand the meaning of "C_max in all phases".

❝ Shall I consider it as C_max(0-2) & C_max(2-t)?

Yes. Pre-specified cut-off time 2 hours. Hence, 1^st phase ≤2 hours and 2^nd phase >2 hours. You have to demonstrate BE for both.

❝ (2) As per the guideline, C_max(x+1) and _partialAUC_(x+1) also need to be evaluated. In this case shall I consider it as C_max(2+1) = C_max0-3 & _partialAUC₍₂₊₁₎ = _partialAUC_(0-3)?

No. The “x” in the table of Section 6.8.2.1 is an index denoting the phase – not a time point. In your case: C_max(1) = C_max(0–2), C_max(2) = C_max(2–t), _partialAUC₍₁₎ = _partialAUC_0–2, _partialAUC₍₂₎ = _partialAUC_2–t – exactly as you correctly guessed in the beginning of your post.

For most biphasic products the first phase is critical in terms of variability. Consider reference-scaling (both C_max and partial AUC).