Bioequivalence and Bioavailability Forum

Dear Jag009!

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❝ Assuming a drug is highly protein bound (>99%), non-saturable metabolism, and linear clearance, and shows non-linear PK (AUC increases less than proportional) at high doses due to saturated protein binding. If one creates a salt form of this drug such that the rate of absorption is increased (faster Tmax) but bioequivalent to the non-salt form in terms of Cmax and AUC, would the salt form drug show nonlinear PK at a lower dose than the non-salt form?

As per EMA guideline: For drugs with a less than proportional increase in AUC with increasing dose over the therapeutic dose range, bioequivalence should in most cases be established both at the highest strength and at the lowest strength (or a strength in the linear range), i.e. in this situation two bioequivalence studies are needed. If the non-linearity is not caused by limited solubility but is due to e.g. saturation of uptake transporters and provided that conditions a) to d) above are fulfilled and the test and reference products do not contain any excipients that may affect gastrointestinal motility or transport proteins, it is sufficient to demonstrate bioequivalence at the lowest strength (or a strength in the linear range).
Regards,
Divyen Shah