Using pH Gradient Dissolution with In-Situ Flux Measurement to Evaluate Bioavailability and DDI for Formulated Poorly Soluble Drug Products

This study described a pH-gradient dissolution method combined with fluxmeasurements as an in vitro tool for assessing the risk of bioavailability reduction due todrug-drug interactions (DDI) caused by acid reducing agents (ARAs). The deviceincorporates absorption chambers into USP II dissolution vessels, with fiber optic UV-probes monitoring concentration in situ. Dosage forms of Genentech BCS class II drugs,GDC-0810, GDC-0941, and compound A, were tested by starting the dissolution in either pH1.6 or pH 4.0 media then converting to FaSSIF after 30 min. GDC-0810 showed no significantdifference in flux between the two conversion experiments. A supersaturation phase wasobserved for GDC-0941 in the pH 1.6 experiments after media conversion to FaSSIF;however, it did not appear to occur in the pH 4.0 experiment due to low drug solubility at pH4.0, resulting in a 95% decrease in flux compared to pH 1.6 experiment. The extent of fluxreduction and the total accumulated API mass in the absorption chamber agreed well withthe 89% reduction in mean Cmax and the 82% reduction in mean AUC from dog PK studybetween animals treated with pentagastrin and famotidine. Testing of the compound Aoptimized formulation tablets showed a 25% reduction in flux and in vitro absorbed amountby changing pH 1.6 to 4.0, correlating well with the AUC decrease in clinical studies. Goodcorrelation between in vitro data and in vivo PK data demonstrated the applicability of themethod for formulators to develop drug products mitigating DDI from ARAs.