Physicochemical interactions between oral drug products: An integrated in vitro and PBPK modeling approach

While pharmacodynamic and pharmacokinetic drug-drug interactions are well established, physicochemical interactions between co-administered oral drug products and their impact on drug absorption remain poorly understood. This study combined biorelevant in vitro testing and physiologically based pharmacokinetic (PBPK) modeling to investigate such interactions between three commercially available drug products SPORANOX (itraconazole), ACTOS (pioglitazone) and GEVILON (gemfibrozil). The in vitro experiments revealed contradictory effects. The apparent solubility of itraconazole was improved in the presence of gemfibrozil, and certain cellulose-based polymers present in ACTOS and GEVILON inhibited precipitation of itraconazole after release from the amorphous solid dispersion. However, in release experiments, Tween 80 present in the GEVILON formulation led to lower itraconazole concentrations due to destabilization of supersaturation. PBPK modeling suggested that this effect could be one of the main reasons for the decreased bioavailability of itraconazole in the presence of the other drug products, as observed in prior clinical studies. This work highlights the potential relevance of physicochemical interactions between different drug products for the efficacy and safety of oral pharmacotherapy. The staged approach presented herein enables early detection of such interactions so that formulation strategies can be applied to mitigate them.