Clinically relevant drug interactions with multikinase inhibitors: a review

Abstract

Multikinase inhibitors (MKIs), including the tyrosine kinase inhibitors (TKIs), have rapidly become an established factor in daily (hemato)-oncology practice. Although the oral route of administration offers improved flexibility and convenience for the patient, challenges arise in the use of MKIs. As MKIs are prescribed extensively, patients are at increased risk for (severe) drug-drug interactions (DDIs). As a result of these DDIs, plasma pharmacokinetics of MKIs may vary significantly, thereby leading to high interpatient variability and subsequent risk for increased toxicity or a diminished therapeutic outcome. Most clinically relevant DDIs with MKIs concern altered absorption and metabolism. The absorption of MKIs may be decreased by concomitant use of gastric acid-suppressive agents (e.g. proton pump inhibitors) as many kinase inhibitors show pH-dependent solubility. In addition, DDIs concerning drug (uptake and efflux) transporters may be of significant clinical relevance during MKI therapy. Furthermore, since many MKIs are substrates for cytochrome P450 isoenzymes (CYPs), induction or inhibition with strong CYP inhibitors or inducers may lead to significant alterations in MKI exposure. In conclusion, DDIs are of major concern during MKI therapy and need to be monitored closely in clinical practice. Based on the current knowledge and available literature, practical recommendations for management of these DDIs in clinical practice are presented in this review.

Keywords: cytochrome P450 enzyme; drug transporters; drug–drug interaction; gastric acid suppression; metabolism; multikinase inhibitor.

Figure 1.

Working mechanism of the drug–drug interaction with an ASA: MKIs are arranged according to the clinical relevance and magnitude of the interaction in a descending order, with the most relevant interactions on top of the list. A PPI increases stomach pH after intake and thereby decreases absorption of MKIs and therefore bioavailability of MKIs. ASA, acid-suppressive agent; DDI, drug–drug interaction; MKI, multikinase.

Figure 2.

Distribution of drug transporters and metabolizing enzymes: A complete overview of all the drug transporters and metabolizing phase I and phase II enzymes are presented in this figure for the main organs involved in the pharmacokinetics of drugs. BCRP, breast cancer resistance protein (ABCG2); CYP, cytochrome P450 iso-enzyme, MATE, multi-antimicrobial extrusion protein; MRP, multidrug resistance associated protein; OAT, organic anion transporters; OATP, organic anion transporting peptides; OCT, organic cation transporters; P-gp, P-glycoprotein (ABCB1); UGT, UDP-glucuronosyltransferase.