With the rapid and widespread uptake of tyrosine kinase inhibitors (TKIs) in oncology over the past several years, serious drug–drug interactions are an "increasing risk," according a new report.
To guarantee the safe use of TKIs, "a drugs review for each patient is needed," write Frank G.A. Jansman, PharmD, PhD, from Deventer Hospital in the Netherlands, and colleagues in areview published in the July issue of the Lancet Oncology.
The review provides a comprehensive overview of known and suspected interactions between TKIs and conventional prescribed drugs, over-the-counter drugs, and herbal medicines.
All 15 TKIs approved to date by the US Food and Drug Administration or the European Medicines Agency are evaluated.
They are axitinib (Inlyta, Pfizer), crizotinib (Xalkori, Pfizer), dasatinib (Sprycel, Bristol-Myers Squibb and Otsuka America), erlotinib (Tarceva, Osi Pharmaceuticals), gefitinib (Iressa, AstraZeneca), imatinib (Gleevec, Novartis), lapatinib (Tykerb, GlaxoSmithKline), nilotinib (Tasigna, Novartis), pazopanib (Votrient, GlaxoSmithKline), regorafenib (Stivarga, Bayer), ruxolitinib (Jakafi, Incyte), sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer), vandetanib (Caprelsa, AstraZeneca), and vemurafenib (Zelboraf, Roche).
The authors offer specific recommendations to guide oncologists, hematologists, and clinical pharmacists in managing drug–drug interactions during treatment with TKIs in daily clinical practice.
They note that a number of "clinically relevant" drug interactions with TKIs have been identified. Most involve altered bioavailability related to altered stomach pH from acid-suppressive drugs, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval.
Interaction With Acid-Suppressive Drugs
Acid-suppressive drugs such as proton-pump inhibitors, H₂ antagonists, and antacids can profoundly alter the absorption of most TKIs. TKIs are weakly basic, and in the stomach they exists in both ionized and nonionized forms. An acid-suppressive drug will raise the stomach pH from about 1 to 4, which can shift the equilibrium between the 2 forms of TKIs toward the less soluble nonionized form; the result is that less drug is absorbed, leading to reduced concentrations in the blood.
This interaction between TKIs and acid-suppressive drugs is particularly important for crizotinib, dasatinib, erlotinib, gefitinib, lapatinib, and pazopanib. The concomitant use of these agents can result in a substantial alteration in the oral absorption of the TKI, the authors note. Therefore, if possible, the concomitant use of these TKIs with a proton-pump inhibitor, H₂ antagonist, or antacid "should be avoided, or the time of drug intake should be separated by several hours at least," the authors advise.
There is less interaction between acid-suppressive drugs and other TKIs. The authors note that proton-pump inhibitors, H₂ antagonists, and antacids can be used concomitantly with imatinib, axitinib, ruxolitinib, sorafenib, sunitinib, vandetanib, and vemurafenib.
However, they single out nilotinib, and advise that the concomitant use of proton-pump inhibitors is fine, but an H₂ antagonist should be taken 10 hours before or 2 hours after nilotinib, and an antacid should be taken 2 hours before or after nilotinibThey also note that there are no data available on potential interactions between regorafenib and acid-suppressive drugs.
Dose Adjustments Recommended
The authors move on to highlight potential interactions between TKIs and drugs that are metabolized by cytochrome P450 isoenzymes.
There are several drugs to watch out for. In particular, drugs that act as CYP3A4 inhibitors (such as ketoconazole, itraconazole, and voriconazole) or CYP3A4 inducers (such as rifampicin and enzalutamide) can have a large effect on the blood concentration of any TKI, with the exception of sorafenib and vandetanib.
In many cases, the result of this interaction is increased blood concentrations of the TKI, with resultant increased toxicity. The action required is either to avoid concomitant administration or to reduce the dose of the TKI. However, in other cases, the result of the interaction is a decrease in blood concentrations of the TKI, so an increased in dose is needed.
The dose adjustment can be a 50% increase or decrease. The authors provide detailed recommendations for each TKI.
Concomitant use of the following combinations should be avoided: crizotinib plus ketoconazole, gefitinib plus itraconazole, vandetanib plus rifampicin, regorafenib plus rifampicin, and regorafenib plus ketoconazole.
The dose of the TKI should be reduced when the following drugs are used in combination with ketoconazole: axitinib, dasatinib, erlotinib, lapatinib, nilotinib, pazopanib, ruxolitinib, and sunitinib.
The dose of the TKI might need to be increased when rifampicin is used in combination with axitinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, nilotinib, ruxolitinib, or sunitinib. The dose of TKI might need to be decreased with the combinations of carbamazepine plus lapatinib, carbamazepine plus pazopanib, and phenytoin plus pazopanib.
The authors note that the following combinations "can be used safely": sorafenib plus rifampicin, sorafenib plus ketoconazole, and vandetanib plus itraconazole.
Another substance that can interfere with the P450 system is grapefruit, which acts as a CYP3A4 inhibitor. Grapefruit has been shown to increase the area under the curve (denoting higher blood concentrations) of sunitinib by 11% (Cancer Chemother Pharmacol. 2011;67:695-703) and of nilotinib by 29% (J Clin Pharmacol. 2010;50:188-194). Thus, the authors recommend that grapefruit juice be avoided with sunitinib and nilotinib, and discourage it's consumption with other TKIs.
The authors highlight potential interactions that can occur at the point of drug absorption, when the p-glycoprotein efflux transporter is involved. Some TKIs (such as pazopanib, lapatinib, and gefitinib) act as inhibitors of this p-glycoprotein, and can therefore increase the bioavailability of other drugs that act as p-glycoprotein substrates (such as digoxin, irinotecan, and paclitaxel). The authors recommend extensive therapeutic drug monitoring when p-glycoprotein substrates with a narrow therapeutic window (such as digoxin, ciclosporin, and tacrolimus) are used in combination with TKIs that inhibit p-glycoprotein.
Rare Interaction, But Potentially Fatal
A rare but potentially fatal interaction is QTc prolongation and the subsequent development of Torsades de pointes.
The TKIs with demonstrated QTc prolongation are crizotinib, gefitinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, vandetanib, and vemurafenib.
Medical oncologists need to be "better informed" about the risk when coadministrating drugs that prolong the QTc interval and TKIs, the authors state.
Pharmacists need to routinely check for the concomitant use of such prolonging drugs and CYP3A4 inhibitors, they add. "Special attention should given to QTc interval-prolonging 5HT₃ antagonists, antibiotics, antifungals, and over-the-counter drugs (e.g., domperidone), because these drugs are frequently used by patients with cancer concomitantly with TKIs," they note.
"Unless absolutely necessary," the concomitant use of QTc interval-prolonging TKIs and other such drugs "should be avoided. If indicated, an ECG should be obtained 24 to 48 hours before and 1 week after initiating the concomitant therapy," the authors advise.
Other Possible Interactions
The authors note that there have been case reports describing pharmacodynamic interactions between TKIs and other drugs. For example, imatinib can increase methotrexate toxicity by causing fluid retention, and sunitinib and imatinib can antagonize levothyroxine treatment by interfering with thyroid hormones at the pituitary level.
In addition, the concomitant use of antibiotics that affect the flora of the gastrointestinal tract might interfere with the enterohepatic circulation of regorafenib and might decrease regorafenib absorption.
To improve the safety of TKIs in oncology, a thorough assessment of coprescribed drugs, herbal supplements, lifestyle food and drinks (e.g., grapefruit juice), cardiac risk factors, and physical examination" is needed, the authors conclude.
To do this, close collaboration between oncologists, hematologists, clinical pharmacists, family doctors, and cardiologists is imperative, they say.
"In case of a suspected interaction, and if pharmacokinetic data are not available, physicians and pharmacists should balance the available evidence, if possible, extrapolate available pharmacokinetic data for an individual patient, and monitor closely for toxic effects and response," they conclude.
The authors have disclosed no relevant financial relationships.
Lancet Oncol. 2014;15:e315-e326. Abstract
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