Establishing virtual bioequivalence and bio-related dissolution specifications for naproxen using physiologically based pharmacokinetic modeling and in vitro biorelevant dissolution testing.

Abstract

Objective: The aim of the present study was to assess the accuracy of the PBPK model in predicting the pharmacokinetic behavior of weakly acidic BCS class II drugs in humans through a multipronged approach of in vitro dissolution, in vivo studies, and in silico simulations.

Significance: We envision that accurate prediction of in vivo pharmacokinetic behavior of drugs is expected to be achieved if physiological pharmacokinetic models can be organically combined with the physicochemical and bio pharmacological properties of the drugs, as well as their in vitro dissolution behavior.

Methods: In the current study, using naproxen, a BCS class II drug, as a model drug, GastroPlus^® was applied to bridge the in vitro dissolution and in vivo pharmacokinetic behaviors to establish an alternative method for predicting pharmacokinetics in humans.

Results: The test products with different in vitro dissolution profiles were shown to be bioequivalent to the reference product. In addition, a Biphasic In vitro Dissolution Test method of bio-related dissolution methods was constructed to correctly predict the bioequivalence of naproxen tablets. Finally, extrapolation of the combined PBPK model to humans showed that drugs with different in vitro dissolution profiles are bioequivalent in humans.

Conclusions: These findings will help demonstrate the biowaiver of naproxen tablets, which has implications for scale-up or post-approval changes in naproxen tablets.