Drug Interactions With Commonly Prescribed Oral Chemotherapeutic and Targeted Agents

Many malignancies currently have oral medication options for cancer therapy. The use of oral therapy can avoid complex intravenous (IV) regimens that negatively affect patient quality of life.¹ According to the literature, cancer patients favor oral medications over IV chemotherapy.² Many of the newly approved anticancer agents are administered orally, suggesting a paradigm shift from IV administration.³ While oral medications for cancer therapy offer improved quality of life and convenient and flexible administration for patients, many agents have the potential for overlapping drug toxicities and drug interactions (DDIs). In addition, oncology patients may be at an increased risk for DDIs due to malabsorption, malnutrition, and other disease states, as well as complex medication regimens.⁴

Many of the more commonly used oral cancer therapy agents include the newer tyrosine kinase inhibitors (TKIs), including but not limited to dasatinib, erlotinib, imatinib, lapatinib, nilotinib, sorafenib, and sunitinib. Capecitabine is also a commonly used oral chemotherapy agent and is included in this review. Each of these agents exhibits clinically significant DDIs as reported in the literature. The interactions of imatinib, nilotinib, and dasatinib were recently reviewed and published in a number of comprehensive tables.⁵ It is important to consider the pharmacokinetic and pharmacodynamic properties of the chemo - therapeutic or targeted agent and any concomitant medications to explore the potential for DDIs not yet reported in the literature, as many of these medications have been available for only a short time.

Methods
A systematic search of MEDLINE was performed using the following MeSH terms: drug interactions, cytochrome p450, P-glycoprotein, ABCB1, organic cation transporter 1, protein binding, glucuronidation, UGT, and warfarin, along with the aforementioned drug names. The official drug monographs were also used.⁶ This review is organized by characterizing drug interactions as either pharma cokinetic or pharmacodynamic.⁷ Pharmacokinetic interactions include changes in the absorption, distribution, or metabolism of a drug due to another drug. Pharmacodynamic changes include changes to the patient’s re sponse to a drug, without pharmacokinetic changes.

Pharmacokinetic Interactions
Absorption
A number of mechanisms are involved in the absorption of drugs, including disruption of gastrointestinal (GI) micro - flora required for absorption, changes in the gut pH, and interactions mediated by drug transporters. Sorafenib absorption is dependent on GI microflora. Oral neomycin has been implicated in alterations of the GI microflora, leading to decreased sorafenib absorption.6 Oral antimicrobials expected to alter the GI microflora should therefore be used with caution. Dasatinib,⁶ erlotinib,^6,8 and nilotinib6 display pH-dependent solubility, and an increase in stomach pH by acid-lowering medications decreases their absorption. For example, proton pump in hibitors have been shown to decrease absorption more than histamine receptor antagonists. Antacids may be used, but their dosing should be separated from administration of the aforementioned TKIs by several hours. In these cases, the indication for acidlowering medications should be thoughtfully considered.

Drug transporters such as ATP-binding cassette proteins (ABCB1) or P-glycoprotein (P-gp) and organic cation transporters (OCT1) also play a role in drug interactions with oral chemotherapeutic and targeted agents. As an efflux transporter on endothelial cells of the brain capillaries, P-gp can modulate drug concentrations within the brain; as a transporter on hepatocytes, and on epithelial cells in the small intestine, P-gp can also modulate systemic and intracellular drug concentrations.⁹ Dasatinib,⁵ erlotinib,¹⁰ imatinib,⁵ lapatinib,⁶ nilotinib,⁶ and sunitinib¹¹ are substrates of P-gp. Brain and intracellular concentrations of these agents can be increased with P-gp inhibitors such as atorvastatin, diltiazem, fluconazole, hydrocortisone, propranolol, tacrolimus, tamoxifen, and verapamil.^6,7 Inducers of P-gp (rifampin, St. John’s wort) may decrease concentrations of these agents by increasing efflux.^6,7 Lapatinib and nilotinib also inhibit P-gp, increasing drug concentrations of other P-gp substrates. This interaction should be monitored carefully in patients also receiving agents with a narrow therapeutic window, such as digoxin, cyclosporine, and tacrolimus. For example, digoxin and lapatinib coadministration has been reported to increase digoxin levels by 2.8-fold, suggesting the need for close monitoring.⁶

OCT1 is another drug transporter that has been shown to modulate drug interactions among TKIs in vitro. This influx transporter is predominantly located on the membrane between the portal vein and hepatocytes,⁹ where drugs are metabolized and enter systemic circulation. Imatinib is a substrate for OCT1, and intracellular concentrations can be decreased by inhibitors such as prazosin.¹² Imatinib and erlotinib have also been shown to be inhibitors of OCT1. Metformin influx into hepatocytes, a major site of action, has been shown to be OCT1 dependent, and inhibition of OCT1 by imatinib and erlotinib may decrease efficacy of metformin, although in vivo data are not available.¹³

Distribution
All of the TKIs included in this review have reported protein binding greater than 90%, mainly to albumin.⁶ While displacement DDIs with other agents have not been reported, TKIs are potentially implicated in DDIs with other agents with high protein binding, such as phenytoin and warfarin. In a case report of phenytoin toxicity, the protein- binding interaction between phenytoin and erlotinib was reasonably postulated as a potential contributor of the toxicity.¹⁴

Metabolism
Phase 1 Reactions
Phase 1 hepatic metabolism reactions include oxidation, demethylation, and hydrolysis of drugs by hepatic microsomal enzymes, which include the cytochrome (CYP) P450 isoenzymes.⁷ The CYP isoenzymes are often implicated in DDIs, and oral chemotherapeutic and targeted agents are no exception. Many of these drug interactions require dosage adjustments, and all warrant increased monitoring for adverse effects.

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Capecitabine is a prodrug, activated and metabolized by tissue enzymes. However, capecitabine is an inhibitor of CYP2C9 and therefore potentially increases concentrations of CYP2C9 substrates. Case reports of phenytoin toxicity with capecitabine use have been published.¹⁵ A case report of warfarin and capecitabine coadministration resulting in a supratherapeutic international normalized ratio (INR) has also been published.¹⁶ Therefore, patients receiving phenytoin and warfarin with capecitabine should be closely monitored for potential toxicity. Dasatinib is metabolized by CYP3A4. Inducers of CYP3A4 should be avoided due to decreased concentrations of dasatinib. When coadministered, rifampin decreased both Cmax and AUC of dasatinib by approximately 80%.6 Inhibitors of CYP3A4 should also be avoided due to increased concentrations of dasatinib. 6 Dasatinib also inhibits the metabolism of CYP3A4 and should be used cautiously with other CYP3A4 substrates. Patients should be monitored closely for adverse effects of these agents.

Erlotinib is metabolized by CYP1A2 and CYP3A4. Erlotinib concentrations can be decreased by inducers of CYP1A2 or CYP3A4. Decreased erlotinib concentrations have been reported in current cigarette smokers, suggesting higher doses may be required for these patients. A phase 1 study determined that a higher dose of erlotinib (300 mg daily) can be tolerated in smokers for 14 days.¹⁷ Erlotinib concentrations can be increased by inhibitors of CYP1A2 and CYP3A4, such as ciprofloxacin, which may increase erlotinib concentrations more than other agents.⁶ Interactions with erlotinib are also possible with other CYP3A4 substrates, as both agents can compete for sites on the enzyme for metabolism. For example, simvastatin and phenytoin have been implicated in interactions through this mechanism.¹⁴ A case report of rhabdomyolysis with the use of erlotinib and simvastatin was published, implicating the decreased clearance of simvastatin due to competition for metabolism by CYP3A4 as the precipitating factor.¹⁸

Imatinib is metabolized by CYP3A4, CYP1A2 (minor), CYP2C9 (minor), and CYP2C19 (minor). Imatinib concentrations can be decreased by inducers of CYP3A4.⁶ Inhibitors of CYP3A4 should also be used with caution due to increased concentrations of imatinib.⁶ As previously discussed, imatinib is also a P-gp substrate. Agents that are dual inhibitors of P-gp and CYP3A4 (verapamil, clarithromycin, erythromycin, cyclosporine, ketoconazole, and fluconazole) may increase both systemic and intracellular concentrations of imatinib. Imatinib also inhibits CYP2C9, and CYP3A4 should be used with caution with other CYP3A4 or CYP2C9 substrates. Patients receiving concomitant warfarin therapy should also be monitored closely for increases in INR, as the metabolic pathway for warfarin includes both CYP2C9 and CYP3A4. Although a report of 8 patients receiving concomitant warfarin and imatinib included no INR deviations or bleeding events, patients should still be monitored closely for the effects of this interaction.¹⁹

Lapatinib is metabolized by CYP3A4. Studies in healthy subjects indicate that concentrations of lapatinib are increased 2-fold by the CYP3A4 inhibitor ketoconazole and decreased more than 50% by the CYP3A4 inducer carbamazepine.²⁰ Lapatinib doses may need to be adjusted for other CYP3A4 inhibitors and inducers. Lapatinib also inhibits CYP3A4 and should be used cautiously with other CYP3A4 substrates.⁶ Nilotinib is another agent metabolized by CYP3A4. Inhibitors of CYP3A4 may increase nilotinib concentrations, while inducers of CYP3A4 may decrease nilotinib concentrations. Nilotinib inhibits the metabolism of CYP3A4 and CYP2C9. The CYP3A4 inhibition is evidenced by increased midazolam concentrations in the presence of nilotinib. Substrates of CYP2C9 can also be increased due to concomitant nilotinib administration.6 The potential interaction between nilotinib and warfarin should be monitored closely in patients receiving both agents.

Much of the data regarding the metabolism of sorafenib is in vitro data. In vitro, sorafenib is metabolized by CYP3A4 and inhibits CYP2C9, CYP2C19, CYP3A4, and CYP2D6.⁶ However, in vivo, sorafenib concentrations were unchanged in the presence of ketoconazole, a CYP3A4 inhibitor.⁶ Similar studies found no differences in the concentrations of midazolam, a CYP3A4 substrate; omeprazole, a CYP2C19 substrate; or dextromethorphan, a CYP2D6 substrate.²¹ A single report implicates the calcium channel blocker felodipine (a CYP3A4 substrate) as the precipitating agent in a patient with sorafenib levels increased 3-fold, suggesting competition for the CYP3A4 enzyme.²² Reports indicating increased effects of warfarin, most likely mediated by CYP2C9 inhibition by sorafenib, have also been published.^23,24 While inhibition of CYP2C19, CYP3A4, and CYP2D6 has been reported in vitro, it may not be seen clinically. However, concomitant CYP3A4 inhibitors/inducers and substrates of CYP2C19, CYP3A4, and CYP2D6 with a narrow therapeutic window should be used with caution with sorafenib, as individual variability may play a role.

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Finally, sunitinib and an active metabolite SU12662 are also metabolized by CYP3A4, but these agents do not induce or inhibit the metabolism of any other CYP enzymes. In the presence of the CYP3A4 inhibitor ketoconazole, sunitinib AUC was increased by 50%.6 SU12662 concentrations were also increased in the presence of ifosfamide, another CYP3A4 inhibitor.²⁵ When using sunitinib with other CYP3A4 inhibitors, including grapefruit juice,²⁶ dose reductions should be considered. In the presence of rifampin, sunitinib concentrations were decreased.⁶ St. John’s wort should not be used with sunitinib, and when used with other CYP3A4 inducers, dose increases of sunitinib should be considered.

Phase 2 Reactions
The second phase of hepatic metabolism includes glucuronidation and sulfation reactions to form inactive water-soluble metabolites for elimination. Glucuro - nida tion occurs through UDP-glucuronosyltransferase (UGT) enzymes, and interactions are well described in vitro.^27,28 The clinical implications of these interactions are currently not known. Sorafenib metabolism by UGT1A9 is inhibited by valproic acid and is competitive with other substrates such as propofol and acetaminophen.^6,29 Sorafenib also inhibits UGT1A9 and UGT1A1, increasing propofol and irinotecan concentrations, respectively.⁶ Nilotinib and imatinib also inhibit UGT1A1 metabolism, increasing concentrations of UGT1A1 substrates such as carvedilol, levothyroxine, acetaminophen, and raloxifene.^6,28,30

Pharmacodynamic Interactions
Prolongation of QTc Interval
A number of medications are known to prolong the QTc interval, including some of the TKIs. Prolongation of the QTc interval can place patients at risk for arrhythmias, including torsades de pointes and sudden cardiac death. Utilization of multiple medications with the propensity to cause QTc prolongation can increase the risk for these cardiac complications. Dasatinib, nilotinib, lapatinib, and sunitinib all prolong the QTc interval.⁶ Other commonly used medications that prolong the QTc interval include digoxin, quinolone antibiotics, methadone, and antipsychotics. Use of these agents with the aforementioned TKIs should be done with additional EKG monitoring.

Conclusion
Oral chemotherapy agents offer the convenience of dosing from home and can improve patient quality of life. It is important to consider the potential for DDIs for patients who receive these medications to avoid increased toxicity from TKI therapy and other medications or additive side effects with other agents.

References

1. O’Neill VJ, Twelves CJ. Oral cancer treatment: developments in chemotherapy and beyond. Br J Cancer. 2002;87:933-937.
2. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997;15:110-115. \
3. Aisner J. Overview of the changing paradigm in cancer treatment: oral chemotherapy. Am J Health Syst Pharm. 2007;64(suppl 5):S4-S7.
4. Riechelmann RP, Saad ED. A systematic review on drug interactions in oncology. Cancer Invest. 2006; 24:704-712.
5. Haouala A, Widmer N, Duchosal MA, et al. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011;117:e75-e87.
6. US National Library of Medicine. DailyMed. http://dailymed.nlm.nih.gov. Accessed October 13, 2011.
7. Hartshorn EA, Tatro DS. Principles of drug interactions. In: Tatro DS, ed. Drug Interaction Facts 2008: The Authority on Drug Interactions. St Louis, MO: Wolters Kluwer Health, Inc; 2008.
8. Duong S, Leung M. Should the concomitant use of erlotinib and acid-reducing agents be avoided? The drug interaction between erlotinib and acid-reducing agents. J Oncol Pharm Pract. Published online August 17, 2010. doi:10.1177/1078155210381794.
9. Eechoute K, Sparreboom A, Burger H, et al. Drug transporters and imatinib treatment: implications for clinical practice. Clin Cancer Res. 2011;17:406-415.
10. de Vries NA, Buckle T, Zhao J, et al. Restricted brain penetration of tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. Invest New Drugs. Published online October 21, 2010. doi:10.1007/s10637- 010-9569-1.
11. Tang SC, Lagas JC, Lankheet NA, et al. Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinab coadministration. Int J Cancer. 2012;130:223-233.
12. Engler JR, Frede A, Saunders VA, et al. Chronic myeloid leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 activity. Leukemia. 2010;24:765-770.
13. Minematsu T, Giacomini KM. Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther. 2011;10:531-539.
14. Grenader T, Gipps M, Shavit L, et al. Significant drug interaction: phenytoin toxicity due to erlotinib. Lung Cancer. 2007;57:404-406.
15. Brickell K, Porter D, Thompson P. Phenytoin toxicity due to fluoropyrimidines (5FU/capecitabine): three case reports. Br J Cancer. 2003;89:615-616.
16. Janney LM, Waterbury NV. Capecitabine-warfarin interaction. Ann Pharmacother. 2005;39:1546-1551.
17. Hughes AN, O’Brien ME, Petty WJ, et al. Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers. J Clin Oncol. 2009;27:1220-1226.
18. Veeraputhiran M, Sundermeyer M. Rhabdomyolysis resulting from pharmacologic interaction between erlotinib and simvastatin. Clin Lung Cancer. 2008; 9:232-234.
19. Breccia M, Santopietro M, Loglisci G, et al. Concomitant use of imatinib and warfarin in chronic phase chronic myeloid leukemia does not interfere with drug efficacy [letter]. Leuk Res. 2010;34:e224-e225.
20. Smith DA, Koch KM, Arya N. Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects. Br J Clin Pharmacol. 2009;67:421-426.
21. Flaherty KT, Lathia C, Frye RF, et al. Interaction of sorafenib and cytochrome P450 isoenzymes in advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. Published online February 25, 2011. doi:10.1007/s00280-011-1585-0.
22. Gomo C, Coriat R, Faivre L, et al. Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2011;29:1511-1514.
23. Moretti LV, Montalvo RO. Elevated International Normalized Ratio associated with concurrent use of sorafenib and warfarin. Am J Health Syst Pharm. 2009;66:2123-2125.
24. Laber DA, Mushtaq M. Compassionate use of sorafenib in patients with advanced renal cell cancer. Clin Genitour Cancer. 2009;7:34-38.
25. Hamberg P, Steeghs N, Loos WJ. Decreased exposure to sunitinib due to concomitant administration of ifosfamide: results of a phase I and pharmacokinetic study on the combination of sunitinib and ifosfamide in patients with advanced solid malignancies. Br J Cancer. 2010;102:1699-1706.
26. van Erp NP, Baker SD, Zandvliet AS, et al. Marginal increase of sunitinib exposure by grapefruit juice. Cancer Chemother Pharmacol. 2011;67:695-703.
27. Liu Y, Ramírez J, House L, et al. Comparison of the drug-drug interactions potential of erlotinib and gefitinib via inhibition of UDP-glucuronosyltransferases. Drug Metab Dispos. 2010;38:32-39.
28. Williams JA, Hyland R, Jones BC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004;32:1201-1208.
29. Ethell BT, Anderson GD, Burchell B. The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases. Biochem Pharmacol. 2003;65:1441-1449.
30. Liu Y, Ramírez J, Ratain MJ. Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors. Br J Clin Pharmacol. 2011;71:917-920.
31. Morgan RG. Leucovorin enhancement of the effects of the fluoropyrimidines on thymidylate synthase. Cancer. 1989;63(6 suppl):1008-1012.
32. Di Gennaro E, Piro G, Chianese MI, et al. Vorinostat synergises with capecitabine through upregulation of thymidine phosphorylase. Br J Cancer. 2010;103:1680-1691.
33. Shah SR, Martin R, Dowell JE, et al. Comparison of the 5-fluorouracil-warfarin and capecitabine-warfarin drug interactions. Pharmacotherapy. 2010;30:1259-1265.
34. Thomas KS, Billingsley A, Amarshi N, et al. Elevated international normalized ratio associated with concomitant warfarin and erlotinib. Am J Health Syst Pharm. 2010;67:1426-1429.