On the usefulness of four in vitro methodologies in screening for product related differences in tacrolimus exposure after oral administration of amorphous solid dispersions with modified release characteristics in the fasted state

Objective: To investigate the usefulness of four in vitro methodologies in screening for product related differences in tacrolimus exposure after oral administration of amorphous solid dispersions with modified release characteristics in the fasted state. Methods: Initially, Advagraf® (5 mg tacrolimus/capsule), Envarsus® (4 mg tacrolimus/tablet) and a modified release Test Tablet (5 mg tacrolimus/tablet) were subjected to in vitro biorelevant performance testing simulating fasted state conditions using a small-scale two-stage biphasic system, a small-scale two-stage dissolution – permeation (D-P) system, the compendial apparatus IV (open loop mode) and the biorelevant gastrointestinal transfer (BioGIT) system. Early and total exposure, after single dose administrations of the three products to twelve healthy adults in the fasted state on a crossover basis, were then evaluated. Subsequently, the usefulness of in vitro data in qualitatively predicting product related differences in early exposure and in total exposure were assessed. Results: Product related differences in tacrolimus early exposure were successfully predicted by data collected with compendial apparatus IV. The two-stage biphasic system was useful for predicting differences in early exposure between the non-disintegrating Envarsus® and the disintegrating products (Advagraf® or Test Tablet). BioGIT data were useful only for discussing clinical data early after administration of the two disintegrating products. Prediction of product related differences in total exposure was successful only when the compendial apparatus IV was used for comparing the two disintegrating products. Conclusions: Biorelevant in vitro performance testing with compendial apparatus IV was useful for qualitatively predicting differences in tacrolimus early and total exposure after administration of disintegrating products with modified release characteristics in the fasted state.