Abstract
Failure to recognize important features of a drug’s pharmacokinetic characteristics is a key cause of inappropriate dose and schedule selection, and can lead to reduced efficacy and increased rate of adverse drug reactions requiring medical intervention. As oral chemotherapeutic agents, tyrosine kinase inhibitors (TKIs) are particularly prone to cause drug-drug interactions as many drugs in this class are known or suspected to potently inhibit the hepatic uptake transporters OATP1B1 and OATP1B3. In this article, we provide a comprehensive overview of the published literature and publicly-available regulatory documents in this rapidly emerging field. Our findings indicate that, while many TKIs can potentially inhibit the function of OATP1B1 and/or OATP1B3 and cause clinically-relevant drug-drug interactions, there are many inconsistencies between regulatory documents and the published literature. Potential explanations for these discrepant observations are provided in order to assist prescribing clinicians in designing safe and effective polypharmacy regimens, and to provide researchers with insights into refining experimental strategies to further predict and define the translational significance of TKI-mediated drug-drug interactions.
Highlights
The economic burden of drug-related morbidity and mortality as a result of non-optimized medication therapy is estimated to be more than 16% of total US health care annual expenditures [1]
The organic anion transporting polypeptides OATP1B1 and OATP1B3 are examples of such transporters that can facilitate the uptake of a diverse array of xenobiotics, including many anticancer drugs, into the liver in advance of metabolism, and that are sensitive to inhibition by other medicines given concurrently
We provide an overview of this field of research in relation to tyrosine kinase inhibitors (TKIs), a rapidly expanding group of orally-administered drugs commonly used in the treatment of solid tumors and hematological malignancies, with particular emphasis on OATP1B1and OATP1B3-related mechanisms
Summary
The economic burden of drug-related morbidity and mortality as a result of non-optimized medication therapy is estimated to be more than 16% of total US health care annual expenditures [1]. Most TKIs are highly prone to cause DDIs [26], as patients receiving these agents are often subsequently treated for concomitant diseases, and because polypharmacy is highly prevalent [25] Comorbid conditions such as hypertension, chronic obstructive pulmonary disease, diabetes, cardiovascular disease, congestive heart failure, and peripheral vascular disease are frequently reported in the Pharmaceutics 2020, 12, 856 population of cancer patients [27], and this further increases the risk for potential DDIs. a recent study indicated that 97.1% of patients receiving treatment with TKIs were using at least one other drug simultaneously, with a median of 4 concurrent medications, and 47.4% experienced at least one potential TKI-mediated DDI [28]. The vast majority of orally-administered TKIs are eliminated from the body by enzyme-mediated metabolism, which occurs predominantly in the liver, followed by biliary or urinary excretion of the metabolites These processes require drugs to cross the selectively permeable biological membrane of hepatocytes and are dependent, at least in part, on interaction with membrane transporters. As hypertension and diabetes are among the prevalent comorbidities in cancer patients, many xenobiotic OATP1B1 and OATP1B3 substrate drugs are likely to be co-administrated with OATP-inhibitory TKIs, and clinically significant toxicities such as rhabdomyolysis, hyperkalemia, and hypoglycemia can be anticipated [39,40,41]
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