With the rapid and widespread use of tyrosine kinase inhibitors (TKIs) in oncology treatment, serious drug-drug interactions have been on the rise over the past few years, according to a new report. To ensure the safe use of TKIs, “each patient’s dosing needs to be evaluated,” commented Frank G.A, MD, PhD, from the Deifentel Hospital in the Netherlands, and colleagues in an article published in the July issue of The Lancet Oncology this year. The article provides a comprehensive overview of currently known and suspected interactions between TKIs and conventional prescription, over-the-counter, and herbal medications. The 15 TKIs approved by the FDA and the European Medicines Agency that have been evaluated to date are axitinib (Inlyta, Pfizer), crizotinib (Xalkori, Pfizer), dasatinib (Sprycel, Bristol-Myers Squibb-Otsuka Pharmaceuticals, USA), erlotinib (Troche, Osi Pharmaceuticals), gefitinib (ERSA AstraZeneca), imatinib (Gleevec, Novartis), lapatinib (Tykerb, GlaxoSmithKline), nilotinib (Tasigna, Novartis), pazopanib (Votrient, GlaxoSmithKline), regorafenib (Stivarga, Bayer), ruxolitinib (Jakafi, Insight), sorafenib (Doxorubicin, Bayer) , sunitinib (Sotan, Pfizer), vandetanib (Caprelsa, AstraZeneca), and verofinib (Zelboraf, Roche). The researchers provided detailed recommendations to guide oncologists, hematologists, and clinical pharmacists in managing drug-drug interactions during the treatment of TKIs in daily clinical practice. They noted that many “clinically relevant” drug interactions with TKIs have been identified, the majority involving altered drug bioavailability, primarily related to altered gastric pH from acid-suppressing drugs, metabolism due to cytochrome P450 isozymes, and prolonged QTc interval. Interactions with acid-suppressing drugs Acid-suppressing drugs such as proton pump inhibitors, H2 antagonists and acid-forming agents can significantly alter the absorption of most TKIs, which are weakly basic and exist in both ionized and non-ionized forms in the stomach. Acid-suppressing drugs will increase the gastric pH from 1 to 4, which will upset the balance between the two forms of TKIs and increase the insoluble non-ionized form, with the result that less drug is absorbed, leading to a decrease in blood levels. This interaction between TKIs and acid-making drugs is particularly important for crizotinib, dasatinib, erlotinib, lapatinib, and pazopanib. The investigators noted that the combination of these drugs can produce substantial changes in the absorption of oral TKIs. Therefore, the investigators recommend that, if possible, “the combination of these TKIs with proton pump inhibitors, H2 antagonists, and acid suppressants should be avoided, or at least staggered over several hours. Interactions between acid suppressants and other TKIs were less common. The investigators noted that proton pump inhibitors, H2 antagonists, and acid preparations could be used concomitantly with imatinib, axitinib, ruxolitinib, sorafenib, sunitinib, vandetanib, and virofenib. However, they separately note that nilotinib, which they recommend can be used concomitantly with proton pump inhibitors, but H2 antagonists must be taken 10 hours before nilotinib or 2 hours after nilotinib, and acid-makers need to be taken 2 hours before or 2 hours after nilotinib. They also noted that there are no clear data on possible interactions between regorafenib and acid-suppressing agents. Recommendations for dose adjustment The study goes on to highlight potential interactions between TKIs and drugs related to metabolism via cytochrome P450 isozymes. Particular attention should be paid to several drugs, particularly CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole) and CYP3A4 inducers (e.g., rifampin and enzalutamide), who have a significant effect on the blood concentration of any TKI, with the exception of sorafenib and vandetanib. In many cases, the result of this interaction is an increase in the blood concentration of TKIs, with a concomitant increase in drug toxicity. The steps we need to take are either to avoid the concomitant use of the two drugs or to reduce the dose of the TKI. In other cases, however, where the interaction results in a decrease in the blood level of the TKI, the dose of the TKI should be increased. The adjustment could be a 50% increase or decrease in the drug dose. The investigators have provided detailed recommendations for each TKI. The following drug combinations should be avoided: crizotinib + ketoconazole, gefitinib + itraconazole, vandetanib + rifampin, regorafenib + rifampin, and regorafenib + ketoconazole. The following TKI doses should be reduced when used concomitantly with ketoconazole: axitinib, dasatinib, erlotinib, lapatinib, nilotinib, pazopanib, ruxolitinib and sunitinib. The following TKI doses should be increased when used concomitantly with rifampicin: axitinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, nilotinib, ruxolitinib and sunitinib. Carbamazepine + lapatinib, carbamazepine + pazopanib, and phenytoin sodium + pazopanib, all three of which should be administered with a lower TKI dose. The investigators noted that the following combinations were “safe”: sorafenib + rifampin, sorafenib + ketoconazole, and vandetanib + itraconazole. Other drugs that affect the cytochrome P450 system include grapefruit, which acts as a CYP3A4 inhibitor. Grapefruit has been shown to increase the area under the curve (indicating higher blood concentrations) of sunitinib by 11% (Cancer Chemother Pharmacol. 2011;67:695-703) and nilotinib by 29% (J Clin Pharmacol. 2010;50:188-194). It is therefore recommended that grapefruit juice be avoided while taking sunitinib and nilotinib and not taken concomitantly with other TKIs. The investigators highlighted the potential interactions that occur during drug absorption when efflux transport P-glycoprotein is involved. Some TKIs (e.g., pazopanib, lapatinib, and gefitinib) are P-glycoprotein inhibitors and therefore can increase the bioavailability of other drugs that act as P-glycoprotein substrates (e.g., digoxin, irinotecan, and paclitaxel). It is also recommended that extensive therapeutic drug testing should be performed when TKIs that inhibit P-glycoprotein are combined with P-glycoprotein substrates with a narrow therapeutic window (e.g., digoxin, cyclosporine, and tacrolimus). Rare but potentially fatal interactions A rare but potentially fatal interaction is the prolongation of the QTc interval and subsequent tip-twisting ventricular tachycardia. TKIs that have been shown to cause QTc interval prolongation include crizotinib, gefitinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, vandetanib and verofinil. The researchers said clinical oncologists need to “better understand” the risks when QTc interval-prolonging drugs are used in conjunction with TKIs, and pharmacists need to regularly review the concomitant use of these QTc interval-prolonging drugs and CYP3A4 inhibitors. They note that “QTc interval prolonging drugs of particular concern are 5HT3 antagonists, antibiotics, antifungals and over-the-counter medications (e.g., domperidone) because they are commonly used in patients with concomitant TKIs.” ”Unless absolutely necessary,” TKIs that prolong the QTc interval and other drugs with similar effects “should be avoided concomitantly, and if they have to be used, an ECG should be performed 24 to 48 hours before the start of the combination and 1 week after,” the investigators suggest. Other Possible Interactions There have been reported cases of pharmacodynamic interactions of TKIs with other drugs. For example, imatinib can increase the toxicity of methotrexate by causing fluid retention, and sunitinib and imatinib can antagonize thyroxine therapy by interfering with thyroid hormones at the pituitary level. In addition, concomitant use of antibiotics that can affect the gastrointestinal flora may interfere with the hepatic-intestinal circulation of regorafenib and decrease regorafenib absorption. To improve the safety of TKIs in oncology treatment, a thorough evaluation of factors such as combination prescription drugs, herbal supplements, lifestyle foods and beverages (e.g. grapefruit juice), cardiovascular risk factors and physical examination is essential. To this end, close collaboration between oncologists, hematologists, clinical pharmacists, family physicians and cardiovascular specialists is imperative. The investigators recommend that “in cases of suspected interactions where pharmacokinetic data are not available, physicians and pharmacists should weigh the available evidence, extrapolate for individual patients with known pharmacokinetic data if possible, and closely monitor for toxic effects.”