Elsevier

The Lancet Oncology

Volume 15, Issue 8, July 2014, Pages e315-e326
The Lancet Oncology

Review
Drug–drug interactions with tyrosine-kinase inhibitors: a clinical perspective

https://doi.org/10.1016/S1470-2045(13)70579-5Get rights and content

Summary

In the past decade, many tyrosine-kinase inhibitors have been introduced in oncology and haemato-oncology. Because this new class of drugs is extensively used, serious drug–drug interactions are an increasing risk. In this Review, we give a comprehensive overview of known or suspected drug–drug interactions between tyrosine-kinase inhibitors and other drugs. We discuss all haemato-oncological and oncological tyrosine-kinase inhibitors that had been approved by Aug 1, 2013, by the US Food and Drug Administration or the European Medicines Agency. Various clinically relevant drug interactions with tyrosine-kinase inhibitors have been identified. Most interactions concern altered bioavailability due to altered stomach pH, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval. To guarantee the safe use of tyrosine-kinase inhibitors, a drugs review for each patient is needed. This Review provides specific recommendations to guide haemato-oncologists, oncologists, and clinical pharmacists, through the process of managing drug–drug interactions during treatment with tyrosine-kinase inhibitors in daily clinical practice.

Introduction

To improve effectiveness and reduce adverse events of cancer treatment, specific targets have been identified in oncology in the past decade. One of the most promising groups in targeted therapy are the tyrosine-kinase inhibitors.1 Tyrosine kinases are key components of signal transduction pathways in the cell that relay information about conditions in the extracellular domain or the cytoplasm to pass on to the nucleus. As a result, tyrosine-kinase inhibitors affect gene transcription and DNA synthesis. Many tumour cells show abnormal activity of specific tyrosine kinases and are therefore an appealing target in oncology.1

All tyrosine-kinase inhibitors are given orally, which makes administration flexible and convenient, and improves quality of life. Another advantage of oral administration is that the tyrosine-kinase inhibitors are often taken on a continuous daily basis (compared with intermittent use of most chemotherapy), which usually improves the exposure time of the tumour to the active drug.

Although tyrosine-kinase inhibitors have some advantages compared with traditional chemotherapy, new challenges have arisen in the use of these novel targeted drugs. First, tyrosine-kinase inhibitors have specific toxicity profiles that differ from those of cytotoxic drugs.2 Toxic effects can be severe (eg, cardiovascular side-effects) and some tyrosine-kinase inhibitors can even cause secondary tumours (eg, vemurafenib). Because the tyrosine-kinase inhibitors are used chronically and are metabolised by cytochrome P450 (CYP) isozymes, patients given these drugs are at substantial risk of having drug–drug interactions. Furthermore, because of the oral administration route of tyrosine-kinase inhibitors, new drug–drug interactions concerning gastrointestinal absorption have become apparent (eg, cotreatment with proton pump and tyrosine-kinase inhibitors).

Drug–drug interactions might be associated with serious or even fatal adverse events, or can lead to reduced therapeutic effects of either drug. Interactions can be classified into those that are pharmacokinetic and those that are pharmacodynamic.3 Pharmacokinetic interactions arise when absorption, distribution, metabolism, or elimination of the involved drugs are altered, leading to changes in the amount and duration of drug availability at receptor sites. The most common pharmacokinetic drug–drug interactions concern absorption (incomplete drug absorption is a risk of drug interaction) and metabolisation by the cytochrome P450 isozymes. Pharmacodynamic interactions usually refer to an interaction in which active compounds change each other's pharmacological effect. The effect can be synergistic, additive, or antagonistic.

In this Review we give an overview of existing data of known or suspected drug–drug interactions between tyrosine-kinase inhibitors approved by the US Food and Drug Administration or the European Medicines Agency and conventional prescribed drugs, over-the-counter drugs, and herbal medicines. Furthermore, we provide specific recommendations to guide oncologists, haemato-oncologists, and clinical pharmacists through the process of managing drug–drug interactions during treatment with tyrosine-kinase inhibitors in daily clinical practice.

Section snippets

Pharmacokinetic drug interactions: absorption

Gastrointestinal absorption of a drug depends on its inherent characteristics (eg, solubility), but can also be affected by drug–drug interactions. At the absorption level, these interactions mainly take place with tyrosine-kinase inhibitors that have incomplete absorption (eg, bioavailability <50%, first pass effect, or dependence on influx or efflux transporters). Important factors that can affect absorption of tyrosine-kinase inhibitors are a change in stomach pH due to coadministration of

Pharmacokinetic drug interactions: distribution

Distribution is largely measured by blood flow and the binding affinity for the plasma proteins albumin and α1-acid glycoprotein. If two drugs that are both highly bound to plasma proteins (>90%) are combined, one drug can displace the other from its protein binding site, therefore increasing the concentration of unbound drug (figure 1).

Although axitinib, lapatinib, and vemurafenib are all highly bound to plasma proteins (≥99%), and should theoretically be most susceptible for drug–drug

Pharmacokinetic drug interactions: metabolism

Phase 1, mostly oxidative, metabolism by cytochrome P450 enzymes (CYPs) is the most important route of drug metabolism of drugs in vivo. Although some drugs are also metabolised by enterocyte CYP3A4 enzymes, the main site of metabolism in the human body is the liver (figure 1).

CYP enzymes can be inhibited in two ways: (1) competitive binding of two substrates at the same CYP-enzyme binding site and (2) uncompetitive inhibition of CYP enzymes by an inhibitor coadministered with a substrate for

Axitinib

The effects of strong CYP3A4 inhibition and induction on axitinib exposure have been thoroughly investigated. However, the effect on Cmax and the area under the curve of moderate CYP3A4 inhibitors (eg, fluconazole) needs to be assessed in future studies. CYP1A2 and CYP2C19 have a minor role in axitinib elimination and so the risk of a clinical relevant drug–drug interaction via inhibition or induction of these enzymes is negligible. Furthermore, the effect of drug-transporter inhibitors (eg,

Pharmacokinetic drug interactions: elimination

Drug–drug interactions related to elimination generally occur due to renal impairment, either caused by the parent drug or during concomitant use of other nephrotoxic comedication. Most tyrosine-kinase inhibitors are eliminated by liver metabolism and subsequently excreted in faeces as metabolites or unchanged, with minor contributions of renal clearance. Because tyrosine-kinase inhibitors are largely eliminated by hepatic metabolism, drug–drug interactions that take place through changes in

Pharmacodynamic interactions

Pharmacodynamic drug–drug interactions can happen when the pharmacological effect of one drug is changed by another through action on mechanisms associated with the same physiological process or effect. Although pharmacodynamic interactions can be used intentionally (eg, methotrexate and folic acid), they can also be harmful (eg, cisplatin and lisdiuretics).

Some case reports describe pharmacodynamic interactions between tyrosine-kinase inhibitors and other drugs. For instance, imatinib can

Prolongation of the QTc interval

Many classic anticancer drugs can prolong the QTc interval (eg, anthracyclines). This prolongation is also frequently reported with use of tyrosine-kinase inhibitors,5, 6 which is probably caused by interaction with hERG K+ channels. This interaction results in a change in electrical flow and delayed pulse conduction, and therefore, QTc prolongation (figure 2).74 The potential of a tyrosine-kinase inhibitor to prolong the QTc interval is usually related to its chemical structure and plasma

Recommendations for clinical practice

In the past few years, tyrosine-kinase inhibitors have rapidly become an established part of oncology practice, but have also presented new challenges, such as the increased risk of drug–drug interactions.

Apart from sorafenib and vandetanib, tyrosine-kinase inhibitors' exposures are greatly affected by CYP3A4 inhibitors and inducers, and clinical intervention is often needed (table 3). Furthermore, acid-reducing drugs, such as proton-pump inhibitors, can profoundly affect the bioavailability of

Search strategy and selection criteria

We screened the existing scientific literature about known or suspected drug–drug interactions between US Food and Drug Administration (FDA) and European Medicines Agency (EMA)-approved tyrosine-kinase inhibitors and conventional prescribed drugs, over-the-counter drugs, and herbal medicines. We identified references through searches of PubMed and Embase with the search terms [Drug interaction] OR [Drug combination] AND [Drug name]. We identified additional information was in the summary

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