Amelia L. Persico MBA, PharmD

Patients receiving treatment for cancer often have complex drug regimens that include analgesics, antineoplastic agents, maintenance medications for preexisting conditions, and medications for managing the adverse effects of cytotoxic chemotherapy and/or immunotherapy.

Over the past decade, approval and use of new oral chemotherapy agents has increased.

 Although these agents provide patients with the convenience of home treatment and ease of oral administration, they are subject to hepatic first-pass metabolism and enzymatic drug-drug interactions (DDIs), which are circumvented by intravenous agents. These and other DDIs can affect toxicities and reduce efficacy, if not diligently managed.

 Given the preponderance of patients in the United States with comorbid chronic pain and the pain associated with malignant disease, exploration of DDIs between analgesics and oral chemotherapy agents is warranted.

DDIs can occur via pharmaceutical, pharmacodynamic, or pharmacokinetic pathways.

 In pharmaceutical DDIs, drugs interact as a result of their chemical structure or physical properties.

 In pharmacodynamic drug interactions, there is an alteration in the expected pharmacologic effect as a result of overlapping mechanisms of action or toxicities of concomitantly administered medications.

 In pharmacokinetic drug interactions, one drug affects the absorption, distribution metabolism, and/or excretion of another.

 Pharmacokinetic drug interactions related to absorption frequently involve the cytochrome P450 enzymes of the liver, the p-glycoprotein (P-gp) efflux pump, and protein-binding displacement, such as albumin or alpha-glycoprotein.

Acetaminophen is often used to manage mild cancer pain, alone or combined with codeine/hydrocodone/oxycodone. It is metabolized primarily via glucuronidation and is therefore affected by potent inhibitors of glucuronidation, such as dasatinib, imatinib, and sunitinib. Imatinib carries a warning against exceeding 1300 mg per day of acetaminophen.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can be useful in managing mild to moderate and inflammatory cancer pain. Because of their efficacy in decreasing prostaglandin synthesis and inhibiting renal cyclooxygenase, NSAIDs can contribute to renal hypoperfusion and decreased clearance of methotrexate.

 They can also induce nephrotoxicity and thrombocytopenia. Caution is advised when NSAIDs are co-administered with any antineoplastic agents, and alternative therapy is recommended.

Opioid medications are commonly used to manage cancer pain. However, caution is advised when administering hydrocodone with imatinib or any other CYP3A4 inhibitor, as it increases the risk of opioid toxicity. Oxycodone interacts with aldesleukin, dasatinib, imatinib, nilotinib, and tamoxifen via CYP3A4 inhibition. Tramadol is a substrate of CYP2B6, CYP2D6, and CYP3A4. The active metabolite of tramadol, O-desmethyltramadol (M1), has more analgesia activity compared with tramadol. M1 is further metabolized via N-demethylation to N-desmethyltramadol (M2), which is next metabolized via CYP2B6 and CYP3A4. M3-M5 are subsequently glucuronidated to inactive forms.

 Therefore, administration with inhibitors or inducers of these enzymes, such as capecitabine and tamoxifen, significantly affects exposure to the active drug.

Codeine is another example of an analgesic that requires activation via metabolism. Much of its efficacy is rendered via metabolism to methyl morphine by CYP2D6.

 Co-administration with the tyrosine kinase inhibitor (TKI), nilotinib, a CYP2D6 inhibitor, nullifies the efficacy of codeine.

 Methadone serves as a unique example of drug metabolism, as it is a substrate of CYP2B6, CYP2C19, and CYP3A4. It is also a substrate of the P-gp transport system and is therefore subject to interaction with P-gp inducers and inhibitors. In addition to pharmacokinetic interactions, caution is advised when administering methadone with any anthracyclines, because of the overlapping cardiotoxicities. Tapentadol, which is uniquely poised to manage the combination of neuropathic and nociceptive pain that often afflicts patients with cancer, vastly metabolizes via glucuronidation and is not significantly affected by inducers and inhibitors of the CYP450 system.

Adjuvant therapies, such as anticonvulsants and antidepressants, used for pain management also have the potential for pharmacodynamic and pharmacokinetic interactions with oral chemotherapy. Enzyme-inducing antiepileptic drugs, such as carbamazepine, have known benefits in neuropathic pain, but their concomitant use with CYP450-dependent oral chemotherapy can result in toxicities or subtherapeutic serum levels.

 Nonenzyme-inducing antiepileptic drugs, such as gabapentin, pregabalin, and valproic acid, can also be efficacious in pain management, and they lack the DDI risks of enzyme-inducing agents.

 However, case reports have noted adverse events associated with carbamazepine and valproic acid—induced liver toxicity secondary to accumulation of the 10,11-epoxide metabolite from carbamazepine.

 Serotonin norepinephrine reuptake inhibitors, such as CYP2D6 substrate venlafaxine, can be beneficial in management of neuropathic cancer pain. However, enzymatic drug interactions are prevalent among this class as well.

Many targeted chemotherapy agents, such as crizotinib, lapatinib, and pazopanib, carry an increased risk of corrected QT interval (QTc) prolongation.

 The risk of QTc prolongation with TKIs ranges between 0% and 22.7%.

 In addition, antimetabolites capecitabine and fluorouracil carry a small risk of QTc prolongation.

Although the incidence of arrhythmia or sudden cardiac death as a result of torsades de pointes and QTc prolongation remains small, it is an important consideration in this patient population.

Six percent of patients with cancer present with QTc prolongation prior to initiation of chemotherapy. Furthermore, patients receiving chemotherapy are prone to electrolyte abnormalities secondary to diarrhea, emesis, mucositis, and poor nutrition.

 When buprenorphine, methadone, or tramadol are added to the regimen for pain or quetiapine for sleep, the risk for QTc prolongation is further compounded.

 Tricyclic antidepressants and venlafaxine, adjuvant analgesics, also carry the risk of QTc prolongation.

 It is also important to acknowledge that cardiac risks beyond QTc prolongation pervade multiple classes of antineoplastic agents and should be taken into consideration when part of an oncology regimen.

 In the event that multiple QTc-prolonging medications are indicated, baseline and follow-up EKG monitoring is prudent.

Management of drug interactions is one of the cornerstones of pharmacy practice. As more targeted oral chemotherapy agents become available each day, the onus remains on pharmacists to provide up-to-date therapeutic knowledge of the pharmaceutical, pharmacodynamic, and pharmacokinetic drug interactions between analgesics and chemotherapy. 

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Articles

Although these chemotherapy agents provide convenience and ease, they are subject to hepatic first-pass metabolism and enzymatic drug-drug interactions.