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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 flux measurements as an in vitro tool for assessing the risk of bioavailability reduction due to drug-drug interactions (DDI) caused by acid reducing agents (ARAs). The device incorporates 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 pH 1.6 or pH 4.0 media then converting to FaSSIF after 30 min. GDC-0810 showed no significant difference in flux between the two conversion experiments. A supersaturation phase was observed 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 pH 4.0, resulting in a 95% decrease in flux compared to pH 1.6 experiment. The extent of flux reduction and the total accumulated API mass in the absorption chamber agreed well with the 89% reduction in mean Cmax and the 82% reduction in mean AUC from dog PK study between animals treated with pentagastrin and famotidine. Testing of the compound A optimized formulation tablets showed a 25% reduction in flux and in vitro absorbed amount by changing pH 1.6 to 4.0, correlating well with the AUC decrease in clinical studies. Good correlation between in vitro data and in vivo PK data demonstrated the applicability of the method for formulators to develop drug products mitigating DDI from ARAs.

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The authors would like to recognize contribution of Mr. Ram Lingamaneni of Pion Inc. (currently at Catalent) who helped collecting data presented in this paper. The authors would like to acknowledge Drs. Dawen Kou and Mark Ragains of Genentech for their input during the execution of the project, Dr. Gena Dalziel of Genentech for GDC-0941 discussions, and Dr. Lichuan Liu of Genentech for technical discussions on GDC-0810 during the manuscript preparation.

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Correspondence to Konstantin Tsinman.

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Guest Editor: Sandra Klein

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Li, J., Tsinman, K., Tsinman, O. et al. Using pH Gradient Dissolution with In-Situ Flux Measurement to Evaluate Bioavailability and DDI for Formulated Poorly Soluble Drug Products. AAPS PharmSciTech 19, 2898–2907 (2018).

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  • pH gradient dissolution
  • in-situ flux measurement
  • acid reducing agents (ARAs)
  • drug-drug interactions (DDIs)
  • dosage form