Drug Absorption Interactions Between Oral Targeted Anticancer Agents and PPIs: Is pH-Dependent Solubility the Achilles Heel of Targeted Therapy?

Abstract

A majority of the novel orally administered, molecularly targeted anticancer therapies are weak bases that exhibit pH-dependent solubility, and suppression of gastric acidity with acid-reducing agents could impair their absorption. In addition, a majority of cancer patients frequently take acid-reducing agents to alleviate symptoms of gastroesophageal reflux disease, thereby raising the potential for a common but underappreciated drug-drug interaction (DDI) that could decrease the exposure of anticancer medication and result in subsequent failure of therapy. This article is a review of the available clinical literature describing the extent of the interaction between 15 orally administered, small-molecule targeted anticancer therapies and acid-reducing agents. The currently available clinical data suggest that the magnitude of this DDI is largest for compounds whose in vitro solubility varies over the pH range 1-4. This range represents the normal physiological gastric acidity (pH ~1) and gastric acidity while on an acid-reducing agent (pH ~4).

Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

“…The measured solubility and dissolution properties of LY3023414 were favorable for absorption if compared with published data for other PI3K/mTOR inhibitors (2,30,43). The compound was quite soluble near pH 2, which corresponds to the initial pH encountered by LY3023414 in the stomach, and remained soluble in simulated gastric and intestinal fluids.…”

“…The compound was quite soluble near pH 2, which corresponds to the initial pH encountered by LY3023414 in the stomach, and remained soluble in simulated gastric and intestinal fluids. The favorable solubility of LY3023414 between pH 4.5 and pH 7.5 is expected to minimize precipitation that can contribute to variable and lower absorption in the intestinal tract (29,30). Modeling in a gastroduodenal passage model indicated that absorption would be only slightly reduced by coadministration of gastric pH-altering proton-pump inhibitors.…”

“…The reason for this modest single-agent activity with other inhibitors is only partially understood. Besides patient selection and compensatory pathways, it has been reported that the solubility of oral PI3K/AKT/mTOR inhibitors may be limited under different pH conditions in the upper gastrointestinal tract, which in turn may affect their absorption and pharmacokinetic (PK) properties and thereby contribute to the variable activity observed (29,30).…”

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

“…These bind irreversibly to hydrogen potassium ATPase pumps and may elevate gastric luminal pH to as high as pH 7. 125 The duration of PPI-induced gastric acid suppression [125][126][127][128] may potentially be sustained for several days after therapy cessation. 129 Coadministration of an acid-reducing agent may markedly impair systemic absorption of many of the molecularly targeted agents (which exhibit pHdependent solubility), 128 potentially causing suboptimal tumor exposure and development of drug resistance pathways.…”

“…125 The duration of PPI-induced gastric acid suppression [125][126][127][128] may potentially be sustained for several days after therapy cessation. 129 Coadministration of an acid-reducing agent may markedly impair systemic absorption of many of the molecularly targeted agents (which exhibit pHdependent solubility), 128 potentially causing suboptimal tumor exposure and development of drug resistance pathways. 124,[130][131][132][133] This mechanism, from one class alone of drugs commonly coadministered with oral TKIs, adds further concerns to a dosing regimen of "one dose fits all" with oral TKIs.…”