Abstract 382: Concomitant administration of acid reducing agents can impact the pharmacokinetics of the balanced pan-PI3K and mTOR inhibitor PQR309

Abstract

Abstract Introduction Acid reducing agents (ARAs) - such as proton pump inhibitors, H2-antagonists or antacids - are commonly prescribed medications to reduce stomach acidity in cancer patients. Increased gastric pH can significantly impair the dissolution of agents that exhibit pH-dependent solubility, thus possibly reducing their absorption and influence their pharmacokinetics (PK). PQR309 is a novel oral balanced dual pan-PI3K and mTOR inhibitor currently in clinical development for treatment of solid tumors and hematological malignancies. PQR309 is a weak base and exhibits pH-dependent solubility. Therefore, the assessment of the potential for drug-drug interactions with ARAs is essential to avoid treatment failure in cancer patients. Methods GastroPlusTM v.9.0 (Simulations Plus, Inc.) was used to build a physiologically-based absorption and pharmacokinetic (PBPK) model of PQR309. A baseline model was built with the physicochemical properties of the compound and pre-clinical PK data after iv and po administration. The model was then extended using PK data from cancer patients. Volume of distribution and renal clearance were calculated using the Lukacova and fup*GFR methods, respectively. Hepatic clearance was estimated from in vitro clearance obtained in hepatocytes and the intestinal absorption was calculated by the Advanced Compartmental Absorption and Transit (ACATTM) Model. Results The parameter sensitivity analysis showed that at fasted stomach pH of ∼1.5, PQR309 is fully dissolved and rapidly absorbed in the upper part of gastrointestinal tract leading to a distinct maximum plasma concentration (Cmax) and a predicted bioavailability of almost 100%. At a stomach pH of 4.0 dissolution is delayed and the absorption shifted towards distal parts of the gastrointestinal tract. The predicted bioavailability is still estimated to be good (> 75%), but the observed plasma concentration time profile is much shallower and the expected Cmax considerably reduced. Conclusions Our model predicts that concomitant administration of ARAs can impact PQR309 absorption and change its pharmacokinetic profile. The clinical relevance of this potential drug-drug interaction is unknown. In currently ongoing clinical studies co-medication of PQR309 with ARAs should be avoided until further clinical investigations confirm the model predictions and mitigation strategies are explored. Citation Format: Karin Jorga, Eva Huehn, Grace Fraczkiewicz, Debora Schmitz, Doriano Fabbro, Sasa Dimitrijevic. Concomitant administration of acid reducing agents can impact the pharmacokinetics of the balanced pan-PI3K and mTOR inhibitor PQR309. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 382.