Bioequivalence and Bioavailability Forum

Hi Chintamani,

please follow the Policy of the Forum!

❝ Please justify why we take lower limit of quantification (LLQC) 4 to 5 Half life of Cmax and Upper limit of quantification (ULOQ) two times of Cmax.

How can I justify what you do? Which C_max are you taking into account? The mean? Probably a bad idea.

If a drug shows a low between-subject CV ULOQ = 2× mean C_max will be too high – you would have to deal with an unnecessary wide calibration range. It’s better to use a narrower range and validate dilution – expecting only a few samples to be out – instead. On the other hand if a drug shows high between-subject CV (e.g., polymorphism) an ULQQ of 2× mean C_max will be too low by far.

The LLOQ should fulfill two requirements:

1. ≤5% of the (individual!) C_max values in order to rule out carry-over and
   
2. low enough that AUC_t ≥ 80% of AUC_∞.

The latter is not applicable if AUC₇₂ is employed. In a steady state study in a switch-over design with substantial accumulation LLOQ ≤5% C_max is debatable.

Not only the PK of the drug, but also the biopharmaceutical properties of the formulation (IR vs. MR) and the design (SD vs. MD) drive the calibration range.