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Changing the Drug Exposure of Small Molecule Tyrosine Kinase Inhibitors

Abstract

Tyrosine kinase inhibitors (TKIs) are a class of targeted oncologic therapies designed to inhibit the phosphorylation of tyrosine residues on cellular proteins typically involved in various cell signaling pathways. Particularly for small molecule TKIs, these drugs compete with ATP for binding in the intracellular catalytic domains of tyrosine kinases that possess specific mutations or that are overexpressed in cancer cells, which results in a constitutively active kinase. As the efficacy of TKIs is largely dependent on sufficient drug exposure in the body, pharmacokinetic interactions that alter systemic concentrations of TKIs can either reduce drug exposures to subtherapeutic levels, or raise drug exposures past toxicity limits.

Many of the small molecule TKIs are weakly basic drugs whose solubility decreases at an elevated pH. It is for this reason that TKIs are often advised in their labeling not to be co-administered with acid-reducing agents, such as proton pump inhibitors or H2-receptor antagonists, as prolonged usage of acid-reducing agents can result in an elevated fasting gastric pH, also known as hypochlorhydria. Additionally, many TKIs are extensively metabolized in the liver by cytochrome P450 enzymes. Therefore drug-drug interactions that impact mechanisms of hepatic uptake (i.e. uptake transporters) will result in a reduced hepatic clearance and an increased risk of drug toxicity.

Therefore we hypothesize that the drug disposition of small molecule TKIs can be affected by gastric pH and hepatic uptake transporters, which are viable targets for drug-drug interactions that may cause significant changes in drug exposure. The research presented herein evaluates the impact of gastric pH on the pharmacokinetics of dasatinib, a TKI with pH-dependent solubility, in healthy volunteers with rabeprazole (a proton-pump inhibitor)-induced hypochlorhydria, and proposes the use of betaine hydrochloride as a potential mitigation strategy. The research presented also utilizes the Biopharmaceutics Drug Disposition Classification System to predict mechanisms of hepatic uptake and the potential effects of hepatic uptake transporters on liver disposition of three selected TKIs: dasatinib, bosutinib, and vandetanib. Collectively, these studies aim to highlight potential areas of drug development for TKIs that may translate to more effective treatment of oncology patients.

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