US Pharm. 2009;34(7)(Oncology suppl):4-8.
ABSTRACT: Continuously administered oral chemotherapy agents are being used more commonly in cancer patients, increasing the potential for drug-drug interactions (DDIs). DDIs have the potential to increase toxicity or decrease effectiveness. Many DDIs involve the inhibition or induction of CYP450 enzyme activity in the liver. Potential DDIs involving several newer oral antineoplastic agents are discussed. Pharmacists have the opportunity to improve patient care by detecting the possibility of DDIs in cancer patients and by recommending dosing modifications, increased monitoring, or alternative treatments.
Developments in the treatment of cancer over the last several years have capitalized on discoveries concerning the mechanisms of cancer growth and metastasis. Many newer antineoplastic agents are administered orally, and most are given on a continuous basis rather than cyclically. Treatment with these newer agents and traditional chemotherapy drugs has allowed many cancer patients to obtain a response or disease stabilization. These conditions are allowing patients to be treated with oral antineoplastic agents for prolonged periods of time.
Drug-Drug Interactions (DDIs)
DDIs are a growing concern in cancer patients receiving chronic chemotherapy agents in addition to medications for other conditions. DDIs are an increasingly common cause of adverse effects in cancer patients. Patients who are elderly, have hepatic or renal impairment, have comorbid conditions, or are taking two or more medications are at higher risk for DDIs or their consequences.1-3 The estimated risk of experiencing a DDI is 50% when a patient takes five medications and rises to nearly 100% with seven medications.2 One group of researchers found that 67% of cancer inpatients were at risk for at least one DDI from their prescribed medications.4 It has been estimated that 20% to 30% of all adverse drug reactions are caused by DDIs.1,5
The detection and management of DDIs in cancer patients present a unique challenge. Chemotherapy agents usually have a narrow therapeutic window, allowing for very little blood-concentration variation before causing increased adverse effects or altering anticancer efficacy.2 Adverse effects caused by DDIs involving antineoplastic agents could be mistaken for symptoms of advancing cancer or side effects of other treatments. Because many of the newer oral chemotherapy agents were not studied in large numbers of patients before receiving FDA approval, the full extent of potential DDIs is not yet known.5
In addition, cancer patients are at risk for DDIs because of alterations in pharmacokinetic parameters caused by their disease state. Absorption may be affected by altered gastrointestinal function, and low albumin concentrations may cause changes in distribution characteristics. Changes may occur in organ permeability (e.g., ascites). The cancer, its treatment, or age-related changes may affect hepatic or renal function.1,2,4-6
Types of DDIs
DDIs can be categorized into three types of interactions: pharmaceutic, pharmacodynamic, and pharmacokinetic.1,2,5,7,8 Examples of pharmaceutic interactions include IV-line incompatibilities and inactivation of cisplatin if mesna (given to help prevent hemorrhagic cystitis due to ifosfamide) is added to the IV solution bag. Examples of pharmacodynamic interactions in cancer treatment are enhanced binding of fluorouracil (FU) to thymidylate synthetase with the addition of leucovorin and the potential reduction in aldesleukin activity if corticosteroids are used as antiemetics with this regimen. Pharmacodynamic interactions may be positive or negative.
In a pharmacokinetic interaction, one medication alters the absorption, distribution, metabolism, or excretion of another medication. Even though many newer antineoplastic agents are administered orally, clinically significant DDIs involving changes in absorption are infrequent. The majority of clinically significant interactions with these agents involve hepatic metabolism by the CYP450 system.1,2,4-6
The CYP450 system, a family of about 50 enzymes that metabolize many medications, is located primarily in the liver and to a lesser extent in the intestinal wall.2,6,9 Most medications are metabolized by 6 specific enzymes: CYP1A2, CYP2C9, CYP3A4, CYP2C19, CYP2D6, and CYP2E1. The first 3 enzymes have the most clinical significance. CYP3A4 metabolizes about 50% of all medications. Genetic and interpersonal variations in the activity of enzyme systems account for some variability in rates of drug metabolism.
Common DDIs can take the form of inhibition or induction of these metabolic pathways.1,2,6 An inhibitory medication reduces the metabolism of another drug by a competitive mechanism: Both drugs compete for the same pathway, and the clearance rate of one or both medications is slowed. Noncompetitive interactions occur when one medication irreversibly binds to or inactivates the metabolic enzyme, thus slowing clearance of other medications. These inhibitory enzymes can lead to excessively high concentrations of the second medication, leading to toxicity. Inhibitory interactions usually manifest fairly quickly, but the maximal effect of the interaction may not be seen until a new steady state has been reached.
Induction of metabolism occurs when one medication increases the production or activity of a CYP enzyme, leading to faster metabolism of another medication. This could lead to lower serum concentrations and a suboptimal effect or treatment failure. Induction DDIs may take several days or weeks to manifest completely.1,2,4-6
Interactions With Newer Oral Agents
For many of the newer oral antineoplastic agents, data regarding drug interactions are fairly limited. One team of investigators has formulated new guidelines for interpreting the potential for a DDI in a given patient situation.9 Clinically relevant interactions are more common under certain conditions, including medications with a single metabolic pathway; a steep dose-toxicity or dose-response curve; highly potent inhibitors or inducers; nonlinear pharmacokinetics; and other circumstances.1
Capecitabine: Capecitabine (Xeloda) is an oral fluoropyrimidine antineoplastic agent that is used primarily for the treatment of colorectal cancer and breast cancer.6,10-12 The usual dose is 1,250 mg/m2 po twice daily for 14 days every 3 to 4 weeks, although many patients require lower doses because of excessive toxicity. The most common adverse effects are hand-foot syndrome, nausea and vomiting, diarrhea, and myelosuppression. Capecitabine, a prodrug, is converted to FU in a multistep process in the liver. The final enzyme involved in the last step is expressed higher in tumor tissue than in normal tissue. FU is metabolized hepatically by dihydropyrimidine dehydrogenase.
The most common drug interaction reported for capecitabine is that seen with warfarin. Capecitabine/FU inhibits the CYP2C9 enzyme, which is responsible for the metabolism of the more potent S-isomer of warfarin. This can lead to substantial increases in international normalized ratio (INR) values and a high risk of bleeding complications. This interaction is even more problematic since capecitabine is given cyclically, resulting in widely fluctuating INR values and making it quite difficult to adjust warfarin doses. Consideration should be given to providing anticoagulation with a low-molecular-weight heparin (LMWH) instead of warfarin. If the warfarin must be continued, close monitoring and frequent INR checks are vital.10-13
Other drug interactions have been reported with capecitabine.2,9,11 Leucovorin may enhance the toxicity of capecitabine, as it does with FU. Leucovorin promotes the binding of FU with thymidylate synthetase and increases FU's effect and toxicity. Capecitabine may interact with phenytoin through its inhibition of CYP2C9. Elevated phenytoin concentrations associated with toxicity have been reported; close monitoring of phenytoin concentrations is recommended. Metronidazole may raise FU concentrations by reducing clearance. The patient should be carefully monitored for increased toxicity.
Lapatinib: Lapatinib (Tykerb) is a tyrosine kinase inhibitor used for the treatment of human epidermal growth factor 2 (HER2)/neu-overexpressing breast cancer.13-17 It inhibits both epidermal growth factor receptor (EGFR) and HER2. As a tyrosine kinase inhibitor, lapatinib works intracellularly and reduces the downstream effects of this pathway, including tumor cell proliferation, inhibition of apoptosis, and angiogenesis. Lapatinib is usually dosed at 1,250 mg po once daily. The most common adverse effects are hand-foot syndrome, nausea and vomiting, diarrhea, rash, anemia, and increased liver enzymes and bilirubin.
Lapatinib is extensively metabolized, primarily by the CYP3A4 pathway. In addition, it inhibits CYP2C8 and CYP3A4. Potential DDIs involve both of these pathways.13,15-17 Many medications inhibit the activity of the CYP3A4 enzyme (TABLE 1).1,13,18,19 Concurrent treatment with lapatinib and a CYP3A4 inhibitor may result in higher lapatinib concentrations and increased toxicity. Ketoconazole, a representative CYP3A4 inhibitor, has been shown to increase lapatinib's AUC three- to fourfold and increase its half-life almost twofold.16,17 If concurrent therapy with a strong CYP3A4 inhibitor is necessary, a lapatinib dose reduction to 500 mg po daily is recommended.
Metabolism of lapatinib also is affected by inducers of CYP3A4 activity (TABLE 2).13,18,19 If coadministration of a strong CYP3A4 inducer and lapatinib is necessary, the lapatinib dose should be increased slowly to 4,500 mg po daily as tolerated.
Lapatinib may alter the pharmacokinetics of other medications metabolized by CYP2C8 or CYP3A4 that have a narrow therapeutic window. This is because lapatinib can inhibit these pathways.19
Imatinib: Imatinib, a tyrosine kinase inhibitor that inhibits BCR-ABL, was the first targeted oral antineoplastic agent approved. It also inhibits other kinases, such as platelet-derived growth factor receptor (PDGFR), stem-cell factor, and c-Kit.2,3,6,20 Imatinib is used primarily for the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST). The usual starting dose ranges from 400 mg to 800 mg po daily. The most common adverse effects are edema, fatigue, nausea, diarrhea, arthralgia, and mild myelosuppression.
Imatinib is metabolized mainly by the liver, primarily by the CYP3A4 pathway. Other enzymes responsible for its metabolism are CYP1A2, CYP2D6, CYP2C9, and CYP2C19. There are many potential drug interactions with imatinib.2,3,6,8,13 As with lapatinib, CYP3A4 inhibitors have the potential for increasing imatinib concentrations and toxicity. CYP3A4 inducers may decrease concentrations of imatinib and potentially reduce its effectiveness. Unfortunately, there are no standard dosing-adjustment recommendations for these interactions.
Imatinib has other effects on the CYP system. It is a potent inhibitor of CYP3A4 and a weaker inhibitor of CYP2D6 and CYP2C9. Substrates of these enzymes include a number of commonly prescribed medications, including some beta-blockers; antidepressants; hydroxymethyl glutaryl coenzyme A reductase inhibitors; benzodiazepines; calcium channel blockers; cyclosporine; and some HIV medications.8,13,19 Patients receiving these therapies may be at risk for toxicity. In particular, warfarin metabolism may be reduced, leading to increased INR values and a higher risk of bleeding. Imatinib inhibits S-isomers and R-isomers through its alteration of CYP2C9 and CYP3A4. Since imatinib is given continuously rather than cyclically, it is possible through careful monitoring to adjust the warfarin dose downward to accommodate this interaction.
Dasatinib: Dasatinib (Sprycel) is a multiple tyrosine kinase inhibitor that has effects on BCR-ABL as well as on Src, c-Kit, and PDGFR.21,22 It is approved for the treatment of patients with CML or Philadelphia chromosome-positive (Ph+) acute lymphocytic leukemia (ALL) that is refractory to imatinib and patients who are intolerant to imatinib. The usual starting dose is 100 mg po daily or 70 mg po twice daily. The most common side effects are fluid retention, diarrhea, pleural effusions, and myelosuppression. The oral absorption of dasatinib is affected by pH-dependent solubility, and administration of dasatinib within 2 hours of antacids or with H2-blockers or proton-pump inhibitors can reduce dasatinib exposure by 50% to 60%.6,21,22
Dasatinib is metabolized hepatically, primarily by the CYP3A4 system. Its serum concentrations and toxicity may be increased if dasatinib is given concurrently with CYP3A4 inhibitors.4,13,21,22 If therapy with a potent CYP3A4 inhibitor is necessary, the dasatinib dose should be reduced to 20 mg and the patient should be closely monitored for side effects. In addition, because potent CYP3A4 inducers reduce dasatinib's concentration (up to 80%) and effectiveness, concurrent therapy is not recommended. If required, the dasatinib dose should be increased slowly. Dasatinib is a weak inhibitor of CYP3A4, and interactions with CYP3A4 substrates may be seen.18,19
Dasatinib has been reported to cause QT-interval prolongation. Concurrent use with another agent causing this effect could potentially result in arrhythmias.13,22
Nilotinib: Nilotinib (Tasigna) is used for the treatment of CML and Ph+ ALL, as it is a tyrosine kinase inhibitor that acts against BCR-ABL, c-Kit, and PDGFR.23,24 It is usually started at a dose of 400 mg po twice daily. The most common adverse effects are rash, nausea, headache, fatigue, and myelosuppression.
Nilotinib is metabolized primarily by CYP3A4, and interactions with inducers and inhibitors are expected.13,23,24 If treatment with a CYP3A4 inhibitor is required, the nilotinib dose should be reduced to 400 mg po once daily. If therapy with a CYP3A4 inducer is necessary, the nilotinib dose should be increased carefully, with close patient monitoring.
Nilotinib has been found to cause prolongation of the QT interval. Concurrent use with another agent causing this effect could potentially result in arrhythmias.13,23,24
Thalidomide: Thalidomide (Thalomid) is an antineoplastic agent used for the treatment of multiple myeloma because of its antiangiogenic and immunomodulatory actions.25 It is usually dosed at 200 mg po daily in the evening. The primary adverse effects are sedation, edema, thromboembolism, fatigue, neuropathy, rash, muscle weakness, tremor, and mild myelosuppression. Because it carries a risk of birth defects, thalidomide is available only through a restricted-access program. It is hydrolyzed in the plasma and is not metabolized by the liver.6,13
DDIs seen with thalidomide are primarily pharmacodynamic in nature. Thalidomide potentiates the sedative effects of benzodiazepines, opiates, hypnotics, and alcohol. The risk of venous thromboembolism (VTE) is substantially increased when thalidomide is given in conjunction with dexamethasone, doxorubicin, or other combination chemotherapy regimens.6,13,25,26 Prophylaxis with an LMWH or warfarin is recommended for most patients receiving thalidomide. The drug also has been associated with a higher risk of renal impairment when given concurrently with zoledronic acid.13 Careful monitoring is warranted.
Lenalidomide: Lenalidomide (Revlimid) shares the antiangiogenic, antiproliferative, and immunomodulatory actions of thalidomide. It is used for the treatment of multiple myeloma (starting dose 25 mg po daily for 21 of 28 days) and myelodysplastic syndrome (starting dose 10 mg po daily). Lenalidomide is free of many of the adverse effects of thalidomide, but it can cause neutropenia, thrombocytopenia, rash, hyperglycemia, and fatigue. Because of its structural similarity to thalidomide, lenalidomide is available only through a restricted-access program. As with thalidomide, the risk of VTE is increased when lenalidomide is given in conjunction with dexamethasone or combination chemotherapy. Appropriate antithrombotic therapy is not fully established, but prophylaxis with an LMHW, warfarin, or aspirin is recommended.27,28
Sorafenib: Sorafenib (Nexavar) is a tyrosine kinase inhibitor that affects vascular endothelial growth factor (VEGF), PDGFR, and other kinases. It is indicated for the treatment of renal-cell cancer and hepatocellular cancer, and is being investigated as therapy for other cancers.29-31 The usual starting dose is 400 mg po twice daily. The most common adverse effects are fatigue, rash or desquamation, hand-foot syndrome, diarrhea, and nausea.
Sorafenib is cleared hepatically, utilizing CYP3A4 as well as UGT1A9. Medications that potently inhibit CYP3A4 activity can increase sorafenib concentrations and toxicity; however, one study with ketoconazole did not substantially increase sorafenib concentrations.9,29-31 If concurrent therapy with a CYP3A4 inducer is required, sorafenib dose increases may be needed. Because sorafenib inhibits UGT1A9, concurrent therapy with doxorubicin or irinotecan may result in substantially increased exposure and toxicity.6,29-31 If combination therapy is necessary, the patient must be monitored closely.
Sunitinib: Sunitinib (Sutent) is indicated for the treatment of renal-cell cancer and GIST.29,30,32 It is a multityrosine kinase inhibitor with actions against VEGF, PDGFR, and other kinases. The usual starting dose is 50 mg po daily for 4 of 6 weeks.
Sunitinib is metabolized hepatically by CYP3A4. Administration of sunitinib with a potent CYP3A4 inducer may result in reduced sunitinib concentrations and efficacy; 2- and 4-fold increases in the Cmax and AUC have been observed with rifampin. A sunitinib dose increase to 87.5 mg po daily should be considered. Concurrent therapy with a CYP3A4 inhibitor may require a dose reduction to 37.5 mg po daily to avoid excess toxicity. When given with ketoconazole, the AUC and Cmax have been found to increase by about 50%.6,29,30,32 The most common side effects are fatigue, diarrhea, hand-foot syndrome, hypertension, decreased left ventricular ejection fraction, skin changes, and nausea.
Erlotinib: Erlotinib (Tarceva) is used primarily for the treatment of non-small-cell lung cancer and pancreatic cancer.33,34 It inhibits the action of the EGFR tyrosine kinase. The usual starting dose is 100 mg or 150 mg po daily, depending on the indication. The primary adverse effects are desquamating skin rash, diarrhea, fatigue, pruritus, anorexia, and bone pain.
Erlotinib is metabolized hepatically, primarily by CYP3A4 and to a lesser extent by CYP1A2. CYP3A4 inducers are likely to cause a decrease in erlotinib's concentrations and effectiveness. When tested with rifampin, the AUC decreased by about 60% to 70%.34 If concurrent therapy with erlotinib and a strong CYP3A4 inducer is necessary, a dose increase of 50 mg po daily should be considered. Elevated concentrations of erlotinib may occur when it is given with CYP3A4 inhibitors. When tested with ketoconazole, erlotinib concentrations were decreased by 60% to 70%. Dose decreases in increments of 50 mg should be considered, along with careful monitoring.
The oral absorption of erlotinib is pH-dependent; decreases in erlotinib absorption may occur when it is given with antacids, H2-blockers, and proton-pump inhibitors. These combinations should be avoided, if possible. In addition, erlotinib has been reported to increase INR values when it is used with warfarin.34 Close monitoring and adjustments of the warfarin dose are needed. When erlotinib is given with phenytoin, a decrease in erlotinib concentrations would be expected; in addition, an increase in phenytoin concentrations and toxicity has been reported with this combination.35
Many potential DDIs exist with newer oral chemotherapy agents. DDIs may affect concentrations of the oral chemotherapy agent or those of other medications. Pharmacists should carefully screen all medications given to cancer patients for potential interactions. They also should take steps to maximize the effectiveness of the antineoplastic agents or minimize toxicity. This may include monitoring, making dosing modifications, or recommending alternative treatments.
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