Drug Interactions in Cancer Patients Requiring Concomitant Chemotherapy and Analgesics
The development of oral antineoplastic agents has revolutionized the treatment of cancer. They offer carefully selected patients the option of managing complex regimens at home.1 However, because these potential regimens may be complex and patients may be receiving other non-cancer chronic medications, this new trend requires pharmacovigilance. Compared to intravenously administered chemotherapy, oral agents undergo hepatic first-pass metabolism and are more likely to have drug interactions. Particularly with regard to chronic pain management, there are many interactions among some oral antineoplastics and various pain medications.
This article will focus on the one-third of the cancer patient population that is actively receiving cytotoxic chemotherapy on an outpatient basis who require ongoing analgesic therapy to control their pain.
What Are DDIs?
Drug–drug interactions (DDIs) are manifestations that occur when one drug either increases or decreases the efficacy of another drug due to pharmacological and/or pharmacokinetic interactions that arise.2 While the exact incidence of DDIs are unknown in cancer patients, it has been estimated that about one-third of cancer outpatients are at risk of developing a DDI.3 Approximately 20% to 30% of all adverse events (AEs) are caused by interactions between drugs.4 Drug interactions can be divided into different categories: pharmaceutical, pharmacokinetic (PK), and pharmacodynamicnamic (Table 1).5
The most common PK interactions in oncology are those that affect drug metabolizing enzymes: the cytochrome P450 (CYP450) enzymes, the efflux pump p-glycoprotein (P-gp), and protein-binding displacement (generally albumin or α-glycoprotein).6 A review of the literature found no publications examining the drug interactions between patients requiring cytotoxic chemotherapy and concurrent pain medications. Since cancer patients also may have multiple comorbid manifestations, it is important to know if and how the chemotherapy regimen can affect some of their non-neoplastic analgesic remedies. In this commentary, we thoroughly evaluate instances where chemotherapeutic agents utilized in the presence of pain medications can potentiate effects and induce toxicities or render medications less effective.
Chemotherapy and Drug Metabolism
Because the list of all chemotherapy agents is too extensive to publish here, we have highlighted the agents most commonly associated with potential DDIs with analgesic agents and their drug metabolism enzymes (Table 2).
Tyrosine Kinase Inhibitors
The tyrosine kinase inhibitors (TKIs) (imatinib [Gleevec], dasatinib [Sprycel], nilotinib [Tasigna], bosutinib [Bosulif], and ponatinib [Iclusig]) used in the treatment of chronic myelogenous leukemia (CML)7 are a class of medications involved in multiple drug interactions. These agents are metabolized extensively by the hepatic CYP450 enzymes. Imatinib is a substrate of CYP3A4 and CYP3A5. It is also a weak inhibitor of CYP2D6 and CYP2C9. Dasatinib, bosutinib, and ponatinib are substrates of CYP3A4 and the solubility of these drugs are pH-dependent. Ponatinib must be reduced to 30 mg daily when used concurrently with significant CYP3A4 inhibitors. Nilotinib is a CYP3A4 substrate as well as a competitive inhibitor of CYP2C8, CYP2C9, CYP2D6, and UDP glucuronosyltransferase 1A1 (UGT1A1).
Tamoxifen is a selective estrogen receptor modulator used in breast cancer treatment. It is metabolized extensively by CYP3A4, CYP3A5, CYP2C9, and CYP2D6. It is also an inhibitor of P-gp. The main metabolite found in plasma is N-desmethyl tamoxifen, a metabolite with similar activity as the parent drug formed by CYP3A4/5. Additional metabolites catalyzed by CYP2D6 are 4-hydroxytamoxifen and endoxifen, the latter of which is an active metabolite that may eventually be marketed as a new drug.8 Compared to tamoxifen, endoxifen and 4-hydroxytamoxifen have a 100-fold greater affinity for the estrogen receptor and 30 to 100-fold potency in suppressing any estrogen-dependent cell proliferation.9
Epidermal Growth Factor Receptor Inhibitors
Among the epidermal growth factor receptor (EGFR) inhibitors, erlotinib (Tarceva) and gefitinib (Iressa) represent high risk for common CYP450 interactions. Although we acknowledge that gefitinib has been removed from the US market, it still represents a significant potential for drug interactions because of its availability in Europe. Erlotinib is a major CYP3A4 substrate and undergoes extensive hepatic metabolism by this isoenzyme. It is also metabolized to a lesser extent by CYP1A2 and the extra-hepatic isoform CYP1A1. Gefitinib is predominantly metabolized by CYP3A4 to multiple metabolites, with only O-desmethyl gefitinib having exposure comparable to gefitinib.
Lapatinib (Tykerb) is a TKI that inhibits two EGFR inhibitors: ERB1 and ERB2 (HER2). It is both a substrate and an inhibitor of CYP3A4.
Vascular Endothelial Growth Factor Receptor Inhibitor
Pazopanib (Votrient) is an oral multikinase angiogenesis inhibitor. It inhibits vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α and -β, fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (kit), interleukin-2 receptor inducible T-cell kinase (itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms).10 Pazopanib is a substrate of P-gp and is indicated for renal cell carcinoma and soft-tissue sarcoma.
A single in vivo study showed that vemurafenib (Zelboraf), a BRAF inhibitor used in the management of malignant melanoma, is a moderate inhibitor of CYP1A2, a weak inhibitor of CYP2D6, and an inducer of CYP3A4.10 In vitro studies suggested that vemurafenib is both a substrate and inhibitor of CYP3A4 and P-gp, the result of which will elevate serum levels in the absence of a more potent 3A4 inducer.11
Pain Therapy and Drug Metabolism
Most medications used to treat cancer pain undergo extensive metabolism by the CYP450 system. The opioids that are least affected by CYP450 metabolism are morphine, hydromorphone, oxymorphone, and tapentadol (Nucynta). Morphine is a prototypical opioid analgesic substrate of UGT1A1 and depends on P-gp for gastric absorption and transport across the blood brain barrier.12 Fentanyl, on the other hand, is a weak substrate of CYP2D6, CYP3A4, and P-gp.13-15 Medications that inhibit or induce these enzymes may significantly increase or decrease drug exposure, respectively.13