Drug Interactions and the Pharmacist: Focus on

Drug Interactions

Drug Interactions and the Pharmacist: Focus on Everolimus Jennifer A Grabowsky

A

s Paracelsus stated, sola dosis facit venenum (only dose makes the poison), meaning that anything can be toxic if the dose or concentration is high enough. This is especially true for anticancer medications, which have a narrow therapeutic index. The dose needed to produce cytotoxicity in cancer cells is often at the threshold between therapeutic efficacy and excessive toxicity. Minor alterations in the concentration of anticancer drugs in the body can have a pronounced impact on the drug’s activity, adverse event profile, or both. Patients with cancer often are prescribed multiple medications for treatment of their disease, management of cancer-related or drug-related adverse events, and treatment of comorbidities. Therefore, they are at increased risk for drug interactions. Drug interactions can significantly alter the disposition or bioavailability of

Author information provided at end of text.

© 1967-2013 Harvey Whitney Books Co. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means without prior written permission of Harvey Whitney Books Co. For reprints of any article appearing in The Annals, please contact [email protected]

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OBJECTIVE: To evaluate everolimus drug-drug and drug-food interactions, with an

emphasis on patients with cancer.

DATA SOURCES:

Literature was accessed through PubMed (1990-March 2013) using Boolean combinations of the terms drug interactions, herb-drug interactions, food-drug interactions, everolimus, antineoplastic agents, hormonal, and breast neoplasms. In addition, reference citations from publications and the prescribing information for everolimus were reviewed.

STUDY SELECTION AND DATA EXTRACTION: All articles published in English, including human, animal, and in vitro studies, identified from the data sources were included.

DATA SYNTHESIS: Patients with cancer are at increased risk for drug interactions because of the multiple medications they are prescribed to treat their disease and comorbid conditions. Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is indicated for the treatment in adults with progressive neuroendocrine tumors of pancreatic origin that are unresectable, locally advanced, or metastatic; adults with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib; and, recently, postmenopausal women with advanced hormone receptor– positive, human epidermal growth factor receptor 2–negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole. As its use increases among patients with cancer, clinicians must be knowledgeable about potential drug and/or food/nutrient interactions and the mechanisms by which these interactions occur, to mitigate and prevent unwanted reactions and ensure patient safety.

CONCLUSIONS: Everolimus is a widely used oral mTOR inhibitor that has the potential for drug interactions that may affect therapeutic outcomes, produce toxicities, or both. This article provides a review of evidence-based literature, along with the prescribing information, to educate clinicians on the significance of these drug interactions and their impact on management with everolimus.

Ann Pharmacother 2013;47:1055-63.

Published Online, 11 Jun 2013, theannals.com, doi: 10.1345/aph.1R769

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anticancer therapies. The risk of drug interactions increases with the number of medications a patient takes, many of which are treatments for comorbid conditions rather than the cancer.1 In a cross-sectional study of patients with solid tumors, most drug interactions were among supportive care agents or medications used to treat comorbid conditions and only to a lesser extent among anticancer agents.2 Data collected by Hanigan et al. revealed that 96% of patients with cancer used prescription medications within 3 days before chemotherapy, 71% used over-the-counter medications, and 69% used vitamins, herbs, or supplements.3 In 2 studies, the median number of prescription medications taken per patient was approximately 5.1,3 The potential for drug interactions is high among ambulatory patients with cancer receiving intervals of systemic infused chemotherapy; however, oral chemotherapy places the patient at even greater risk for interactions, partly because of intestinal absorption and metabolism. Among adult outpatients, 27% (109/405) of those receiving systemic anticancer therapy for solid tumors of the breast, gastrointestinal tract, or genitourinary tract had at least 1 potential drug interaction (95% CI 23-31).1 The levels of severity ranged from major (9%) to moderate (77%) and were supported by scientific evidence obtained from clinical trials and case studies.1 Key to anticipating which drugs will interact is a solid understanding of the mechanism of action and pharmacokinetics of each drug. Everolimus is a macrolide antibiotic derivative initially used as an immunosuppressant in solid organ transplant; however, antitumor activity has led to investigation of its use in the oncology setting.4 Everolimus targets the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signal transduction pathway, which is constitutively activated in numerous solid and hematologic malignancies.5-7 mTOR is a serine/threonine protein kinase located immediately downstream of the PI3K/Akt pathway that plays a central role in cell growth, proliferation, survival, metabolism, and angiogenesis (Figure 1).8-10 mTOR integrates intracellular nutrient, energy, and redox levels with extracellular inputs (amino acids, nutrients, growth factors, cytokines) and as such is an important nexus in the overall functioning of the cell.9 Everolimus is approved for use in adults with progressive neuroendocrine tumors of pancreatic origin (pNET) that are unresectable, locally advanced, or metastatic; in adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib; in adults with renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery; in adults and children aged 3 years or older with subependymal giant cell astrocytoma associated with TSC requiring therapeutic intervention but who are not candidates for curative surgical resection; and in postmenopausal women with advanced 1056

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hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.11 Knowledge of potential interactions between everolimus and other drugs, foods, and nutrients will improve clinicians’ ability to detect and minimize these interactions, thereby improving patient outcomes and minimizing adverse reactions. Data Sources and Selection

Peer-reviewed and statistically vetted scientific human, animal, and in vitro studies published in English between 1990 and March 2013 were evaluated for this review. Literature was accessed through PubMed, using Boolean combinations of the terms drug interactions, herb-drug interactions, food-drug interactions, everolimus, antineoplastic agents, hormonal, and breast neoplasms. In addition, reference citations from publications and the prescribing information for everolimus were reviewed. Studies were assessed according to the level of scientific evidence provided for everolimusdrug or everolimus-herb and -food interactions. Drug Interactions

A drug-drug interaction is defined as the action of one drug on another drug’s efficacy (increased or decreased), toxicity, or both.1 Drug administration need not be concurrent; previous administration of one drug may alter the effects of another drug taken later. Drug interactions also can be the result of an interaction between a given drug and a food, dietary constituent, herb, drug formulation excipient, or environmental factor.12-16 Pharmacodynamic and/or pharmacokinetic interactions can occur with everolimus. Pharmacodynamic Interactions with Everolimus

Pharmacodynamic interactions with other chemical entities can alter the effect of the drug on the body and these effects can be additive, synergistic, or antagonistic. Evidence for synergistic antitumor activity in in vitro and preclinical models has demonstrated an effect greater than the addition of the 2 drugs.17 In in vitro studies, the combined antiproliferative activity of everolimus and letrozole was significantly greater (p < 0.001) than that of either drug alone.18 A synergistic antiproliferative response, defined as more pronounced cell-cycle arrest, was even detected at concentrations of drug that, when administered alone, resulted in partial inhibition of proliferation (ie, suboptimal drug concentrations). The drug combination also potentiated apoptotic cell death (p < 0.05). The antitumor and schedule-dependent effects of increasing doses of everolimus on human T-cell lymphoma cell lines, Hut-78 and Jurkat, treated with increasing


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doses of everolimus, alone or in combination with doxorubicin, etoposide, vincristine, or bortezomib, were examined by Huang et al.19 Cytotoxic synergism, defined based on in vitro growth inhibition and induction of apoptosis, was observed after concomitant use of doxorubicin and everolimus, bortezomib and everolimus, doxorubicin followed by everolimus, and bortezomib followed by everolimus. In contrast, cell exposure to everolimus followed by doxorubicin, bortezomib, or vincristine resulted in antagonistic effects. Pharmacokinetic Interactions with Everolimus

Pharmacokinetic interactions interfere with the absorption, distribution, metabolism, and elimination of a given drug. FACTORS AFFECTING DRUG ABSORPTION

For orally administered drugs, factors affecting the gastrointestinal tract (eg, food, agents that alter gastrointestinal motility, agents that alter gastrointestinal pH) may also af-

Drug Interactions and the Pharmacist: Focus on Everolimus

fect drug bioavailability and drug absorption may be increased, decreased, or delayed. Everolimus time to maximum concentration (tmax) is within 1 hour after daily oral everolimus 5 or 10 mg in patients with advanced solid tumors.20 In a study of healthy humans everolimus tmax was 0.5 hours after a single 4-mg dose.21 The elimination halflife (t1/2) was 30 ± 8 hours across a dose range of 5-70 mg.20 A similar t1/2 was seen in healthy humans: 32.2 ± 6.1 after a 4-mg dose.21 Oral bioavailability of everolimus is likely to be affected by P-glycoprotein (P-gp) because it is a substrate for this efflux pump.22 In healthy humans, a high-fat meal delayed everolimus tmax by 1.25 hours (median), reduced maximum concentration (Cmax) by 60%, and reduced area under the curve (AUC) by 16%.23 Everolimus was administered as two 1-mg tablets to fasting (10 hours overnight) individuals who remained fasting for 4 hours following everolimus administration23 and then was given to the same individuals after a standardized high-fat breakfast. Fasting values of pharmacokinetic variables were slightly greater than those in the fed state, except for tmax (median [range] 0.5 [0.5-2.0] vs 2.0 [0.5-6.0] hours, re-

Figure 1. PI3K/mTOR pathway. 4E-P1 = 4E-binding protein 1; AKT = protein kinase B; AMPK = adenosine monophosphate-activated protein kinase;

ATP = adenosine-5¢-triphosphate; EGF = epidermal growth factor; eIF4E = eukaryotic initiation factor 4E; Glut = glucose transporter; HIF = hypoxia inducible factor; IGF = insulin like growth factor; kRAS = v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; mTOR = mammalian target of rapamycin; PI3K = phosphatidylinositol 3-kinase; PTEN = phosphatase and tensin homolog; RAF = rapidly accelerated fibrosarcoma; Ras = rat sarcoma; S6K1 = ribosomal p70 56 kinase; TSC1 = tuberous sclerosis complex 1; TSC2 = tuberous sclerosis complex 2; VEGF = vascular endothelial growth factor. From Margariti N, et al. Overcoming breast cancer drug resistance with mTOR inhibitors. Could it be a myth or a real possibility in the short-term future? Br Canc Res Treat 2011 May;128:599-606. Copyright © Springer Science+Business Media, LLC. 2010. Reprinted by permission of Springer Publications.8

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spectively). Mean (SD) fasting versus fed values for other pharmacokinetic variables were Cmax, 17.9 (5.9) versus 7.1 (2.0) ng/mL; AUC0–∞,122 (52) versus 97 (19) ng • h/mL; and t1/2, 31.5 (6.4) versus 30.5 (4.9) hours, respectively.23 It has been suggested that the increased fat content in the meal may increase the absorption of drugs such as everolimus by increasing the gastric secretions, increasing biliary solubility of the drug, and/or by increasing the gastric residence time.24 Hence, everolimus should be administered consistently with or without food to minimize fluctuations in exposure.23 FACTORS AFFECTING DRUG DISTRIBUTION

Drug bound to plasma components, such as α-1 acid glycoprotein or human serum albumin (HSA), reduces the amount of unbound drug able to elicit a pharmacologic effect. Therefore, factors affecting protein binding or displacement from proteins can affect the proportion of unbound drug. In healthy individuals, HSA levels decline with age.25 In 20-year-old individuals, the HSA concentration was 52 g/L, and in 80-year-old people, it was 38 g/L.25 Approximately 75% of the plasma fraction of everolimus is protein bound.26 O’Reilly et al. conducted a comparative analysis of the pharmacokinetic profile of everolimus in mice, rats, and humans with advanced solid tumors of multiple types.27 Serum protein binding in the BALB/c nude mouse (5 mg/kg orally) was approximately 99.9% compared with 92% and 70% in the Lewis rat (5 mg/kg orally) and in patients with cancer (5 mg), respectively.27 The human data for the O’Reilly et al. comparative analysis were obtained from a study by O’Donnell et al.20 Erythrocyte partitioning was 2%, 60%, and 80% in the BALB/c mouse, Lewis rat, and patients with cancer, respectively.27 The differences in protein binding, blood cell partitioning, and bioavailability had little impact on tumor penetration when comparing the free fraction in plasma in the mouse or rat.27 These experimental animal models (especially the rat) are thought to correlate well with the pharmacokinetic profile in humans; however, the concentration of unbound drug in humans exceeds the doses needed to achieve antitumor activity.27 FACTORS AFFECTING DRUG METABOLISM

Interactions with Cytochrome P450 Enzymes or P-Glycoprotein

Metabolism-based drug interactions are a well-recognized and clinically relevant concern in evaluation of drug safety and efficacy. Factors increasing or decreasing metabolism, by induction or inhibition of cytochrome P450 (CYP450), P-gp transport, or both, are important with respect to everolimus therapy. P-gp (multidrug resistance protein 1 or adenosine triphosphate [ATP]–binding cassette, subfamily B, member 1) is an ATP-dependent efflux transport protein from the 1058

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ATP-binding cassette family of proteins.28,29 It acts as an efflux pump and plays a role in multidrug resistance as well as several physiologic processes. P-gp is located on the apical membrane of cells and actively extrudes substrates, preventing their absorption. To this end, P-gp protects the body from toxic or harmful species. CYP450 encompasses a superfamily of hemoprotein isoenzymes that play a major role in the metabolism of endogenous and exogenous compounds.30 They also play a role in the biosynthesis of endogenous compounds. In a mouse model with reduced levels of nicotinamide adenine dinucleotide phosphate–CYP450 reductase, the essential redox component of CYP450, total plasma cholesterol levels decreased 30% by 3 weeks of age and 80% by 2 months of age.31 In humans, a large proportion of CYP450 is located in the liver, but CYP450 is also located in extrahepatic tissue sites such as gut mucosa, brain, lung, and kidney.30 The net result is an increase in polarity to facilitate elimination and excretion of xenobiotics.30 CYP1, CYP2, and CYP3 are responsible for approximately 75% of drug metabolism; in particular, CYP1A2, CYP2 isoforms, CYP2D6, CYP2E1, and CYP 3A4 are major enzymes involved in drug metabolism.32 The specific isoenzymes implicated in everolimus metabolism are CYP3A5, CYP3A4, and, to a lesser extent, CYP2C8 (Table 111,33) in the gut and liver.34 Metabolic pathways include demethylation, hydroxylation, and ring degradation.26 A comparison of the relative amount of parent compound in blood after oral (1.5 mg/kg) and 2-hour intravenous (1.0 mg/kg) administration of everolimus suggests that intestinal metabolism (first-pass effect) accounts for a large percentage of metabolism.22 After intravenous dosing, 42.5% of the AUC was retained as parent compound (everolimus), and after oral dosing, 23% of the AUC was retained as parent compound.22 Troleandomycin, a well-known CYP3A4 inhibitor, and trimethoprim, a CYP2C8 inhibitor, reduced metabolism of everolimus by human liver microsomes 87.7 ± 10.7% and 4.2 ± 3.8%, respectively.34 Everolimus blood concentrations were increased by ketoconazole, a strong CYP3A4 inhibitor, in healthy humans. Ketoconazole coadministration with everolimus resulted in a maximum concentration increase of 3.9-fold (90% CI 3.4- 4.6), from 15 ± 4 ng/mL to 59 ± 13 ng/mL (Figure 2).35 Everolimus AUC increased 15.0-fold (90% CI 13.616.6), from 90 ± 23 ng • h/mL to 1324 ± 232 ng • h/mL. Everolimus t1/2 was prolonged by 1.9-fold, from 30 ± 4 hours to 56 ± 5 hours. It is recommended that use of ketoconazole, or other strong CYP3A4 inhibitors, be avoided if possible in everolimus-treated patients.11,36 Erythromycin, verapamil, and cyclosporine, moderate CYP3A4 inhibitors, increased the everolimus AUC 4.4-, 3.5-, and 2.7fold, respectively. Atorvastatin, a weak CYP3A4 inhibitor, had no effect on the everolimus AUC.36 Rifampin, a potent


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CYP3A4 inducer, significantly reduced everolimus concentrations. In an open-label, single-sequence, crossover study in healthy humans, administration of rifampin 600 mg/day for 8 days resulted in a 3-fold increase in enzyme activity (as measured by 6-β-hydroxycortisol urine concentration).21 Apparent clearance increased on average 172% (based on ratio of geometric mean) and Cmax, AUC, and t1/2 decreased by 58% (range, 14-73%), 63% (range, 0-82%), and 26%, respectively (p = 0.0001 for each). Participants had a high degree of variability (coefficient of variation, 52%); therefore, the results may not translate the same for all patients. A recent report, based on claims database review, shows that everolimus is frequently prescribed with other drugs that modulate the CYP and/or P-gp levels, resulting in


a potential decrease in efficacy or increase in toxicity of everolimus,37 highlighting the need for increased vigilance. The recommendations for everolimus use in patients additionally using strong CYP3A4 inducers or moderate/strong CYP3A4 inhibitors are listed in Table 1.11,33 Food-Drug and Complementary and Alternative Medicine-Drug Interactions

In addition to concomitant medication use, several hybrids of citrus fruit, wine, and medicinal herbs and herbal teas also affect CYP450 and P-gp activity and should be avoided when taking everolimus. Grapefruit and its juice (Citrus paradise); pomelo, shaddock, or pamplemousse (Citrus grandis); Seville orange (Citrus auranita); wine

Table 1. Clinically Relevant Cytochrome P450 Inducers and Inhibitors that Interfere with Everolimus and Recommendations for Dose Modifications11,33

Drug

Strong CYP3A4 inducers Carbamazepine Efavirenz Etravirine Nevirapine Oxcarbazepine Pentobarbital Phenobarbital Phenytoin Rifampin Rifabutin Rifapentine

Other CYP3A4 inducers

St. John’s wort (Hypericum perforatum) Strong CYP3A4 inhibitors

Amprenavir Atazanavir Clarithromycin Delavirdine Darunavir Fosamprenavir Indinavir Itraconazole Ketoconazole Lopinavir Nefazodone Nelfinavir Posaconazole Ritonavir Saquinavir Telithromycin Voriconazole

Moderate CYP3A4 and/or P-gp inhibitors

Aprepitant Cyclosporine Diltiazem Erythromycin Fluconazole Verapamil

Other CYP3A4 and/or P-gp inhibitors Grapefruit and grapefruit juice

P-gp = P-glycoprotein.

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Dose Modification

Avoid concomitant strong CYP3A4 inducers If pts. require coadministration, consider increasing the everolimus dose from 10 to 20 mg daily, using 5-mg increments; no clinical data are available on this dose adjustment in pts. receiving strong CYP3A4 inducers If the strong inducer is discontinued, everolimus dose should be returned to the dose used before initiation of the strong CYP3A4 inducer

Avoid during treatment with everolimus Avoid strong CYP3A4 inhibitors

Use caution when coadministered with a moderate CYP3A4 inhibitor or when administration of P-gp inhibitors cannot be avoided; if pts. require coadministration, reduce everolimus dose to 2.5 mg daily Everolimus dose increase from 2.5 to 5 mg may be considered based on pt. tolerance; if the moderate inhibitor is discontinued, a washout period of ~2-3 days should be allowed before everolimus dose is increased; treatment then should return to dose used before initiation of the moderate inhibitor Avoid during treatment with everolimus


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(Vitis vinifera); St. John’s wort (Hypericum perforatum); and herbal teas (chamomile [Matricaria recutita], peppermint [Mentha piperita], dandelion [Taraxacum officinale], guggul [Commiphora mukul], and goldenseal [Hydrastis canadensis]) have all documented interactions.38 Grapefruit and its juice, perhaps the most well-known food to interact with drug metabolism, contains 6¢,7¢-dihydroxybergamottin, a mechanism-based inhibitor of CYP450.38 Bergamottin is also the component in Seville orange juice that inhibits CYP3A4. Loss of CYP3A4 is irreversible and attributed to accelerated degradation of the enzyme.39 Isoenzymes of the subfamily CYP2C and CYP1A2 are also inhibited by grapefruit.38 As a result, the juice of these fruits increases the oral bioavailability of many CYP3A4 substrates.38,39 In vitro studies examining starfruit (Averrhoa carambola) have also demonstrated inhibition of CYP3A4 with a similar potency to grapefruit but by a different mechanism.40 Complementary and alternative medicine (CAM) use has increased in recent years, as more patients with cancer seek supplementary or alternative treatments for their disease. Among 115 patients with advanced breast cancer, 73% reported using at least 1 CAM product in the previous 6 months. The mean number of CAM products used was 3.9, and one of the most common was herbal medicine.41 Forty percent of CAM users reported using herbal medicine (95% CI 25-55) and 59% of users reported doing so with no physician or herbalist supervision.41 Interactions between CAM products and traditional medicines may occur through inhibition or induction of metabolizing enzymes, P-gp, or both. St. John’s wort is commonly used among patients with cancer for its purported antidepressant

properties.42 St. John’s wort or its constituents may induce expression of CYP3A or P-gp or inhibit enzyme activity. Few data are available on the use of CAM specifically with mTOR inhibitors; however, previous studies may predict potential interactions based on similar mechanisms. St. John’s wort is capable of inducing hepatic and intestinal CYP3A and intestinal P-gp. St. John’s wort may decrease everolimus exposure unpredictably and should therefore be avoided. In healthy individuals treated with St. John’s wort (0.15% standardized extract 600 mg 3 times daily for 16 days), P-gp expression increased 4.2-fold in peripheral blood lymphocytes versus baseline (p < 0.05).43 Hepatic and intestinal CYP3A expression increased 2.3-fold ± 0.7-fold and 2.4-fold ± 0.6fold, respectively, and intestinal P-gp expression increased 1.6-fold ± 0.5-fold in mice treated with St. John’s wort 1000 mg/kg/day.44 The extent of induction was dose dependent because higher doses (1250 mg/kg twice daily) further increased intestinal P-gp and CYP3A expression 3.1-fold ± 1.0-fold and 3.7-fold ± 1.3-fold, respectively. Use of St. John’s wort is not recommended in patients until specific dosing guidelines are established.45 Clinical data to support the safe and effective concomitant use of CAM products and Food and Drug Administration–approved medical treatments are lacking. Studies to more accurately assess the metabolism and CYP profiles of many herbal and CAM products are needed to establish evidence-based recommendations on safe use of these therapies. Everolimus Dosing Recommendations

Use of everolimus with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, ne-

Figure 2. Mean everolimus concentration profile after administration alone (open circles) and during ketoconazole coadministration (filled circles).

Bars represent 95% CIs. From Kovarik JM, et al. Blood concentrations of everolimus are markedly increased by ketoconazole. J Clin Pharmacol 2005 May;45(5):514-8. Copyright © 2005 by SAGE Publications. Reprinted by permission of SAGE Publications.35

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fazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) should be avoided (Table 1).11,33 Caution should be used when everolimus is coadministered with moderate CYP3A4 or P-gp inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem), and the recommended dose of everolimus (10 mg daily for advanced pNET, advanced RCC, and advanced hormone receptor–positive breast cancer) should be reduced to 2.5 mg daily. The reduced dose can be increased to 5 mg based on patient tolerance.11 If the moderate inhibitor is discontinued, 2-3 days of washout should be allowed before the everolimus dose is increased and the dose of everolimus should be returned to the one used before initiation of the moderate CYP3A4 or P-gp inhibitor. Concomitant use of everolimus with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) should be avoided. If patients require coadministration of a strong CYP3A4 inducer, the everolimus dose may be increased from an initial dose of 10 mg daily to 20 mg daily, in 5-mg increments. This recommendation is based solely on predictive models and not on clinical data with patients receiving strong CYP3A4 inducers. If the strong CYP3A4 inducer is discontinued, the everolimus dose should be returned to the one used before the CYP3A4 inducer’s initiation.

Summary

As our understanding of the pathophysiology of cancer evolves, so too does our approach to treating cancer. The aberrant pathways and altered cell signaling responsible for the initiation and progression of cancer continue to be the guides in drug development. As new molecular targets are identified and new anticancer medications are developed, there is the potential for new drug interactions to occur. Because one strategy to increase the effectiveness of anticancer treatments is combination therapy, the risk for drug interactions increases. Pharmacists are at the forefront of drug therapy. Across the spectrum of health care providers, pharmacists often have the most detailed knowledge of all medications taken by a patient and are therefore in a key position to mitigate and prevent drug interactions, as well as to counsel patients about them. The first step to minimizing drug interactions can be taken by obtaining a detailed and complete drug history, including CAM products. Factors such as demographics (age, race, sex), overall health status, CAM use, and dietary habits may have an impact on drug therapy. Although general guidelines regarding drug interactions can direct the proper use of medications, pharmacists must understand that each patient responds differently to a given drug. Pharmacists are responsible for recognizing the potential for drug interactions and preventing them. Specific treatment recommendations for everolimus are as follows: theannals.com


1. Patients should be counseled about the potential for drug interactions and instructed not to take any additional medications (prescription, over-the-counter, and herbal or other products) during everolimus treatment without prior consultation. 2. Concomitant administration of strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, erythromycin, fluconazole) or P-gp inhibitors should be avoided. 3. Concomitant administration of moderate CYP3A4 or P-gp inhibitors should be done with caution, and the dose of everolimus should be reduced. 4. Concomitant administration of strong CYP3A4 inducers should be avoided. If combined use cannot be avoided, the dose of everolimus may be increased. 5. Concomitant administration of CAM products should be avoided and patients should be educated on the potential consequences associated with these agents; consultation may be necessary to ascertain past or present use.

Jennifer A Grabowsky PharmD BCOP, Oncology Pharmacist, Early Phase Investigational Therapeutics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco Correspondence: Dr. Grabowsky, Jennifer.Grabowsky@ucsf medctr.org Reprints/Online Access: www.theannals.com/cgi/reprint/aph.1R769 Conflicts of interest: Author reported none

Acknowledgment: I thank Lauren D’Angelo PhD, Janardhan Sampath PhD, Matthew Grzywacz PhD, and ApotheCom (funded by Novartis Pharmaceuticals) for providing writing and editorial assistance.

© 1967-2013 Harvey Whitney Books Co. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means without prior written permission of Harvey Whitney Books Co. For reprints of any article appearing in The Annals, please contact [email protected]

References

1. Riechelmann RP, Tannock IF, Wang L, Saad ED, Taback NA, Krzyzanowska MK. Potential drug interactions and duplicate prescriptions among cancer patients. J Natl Cancer Inst 2007;99:592-600. 2. Riechelmann RP, del Giglio A. Drug interactions in oncology: how common are they? Ann Oncol 2009;20:1907-12. 3. Hanigan MH, la Cruz BL, Thompson DM, Farmer KC, Medina PJ. Use of prescription and nonprescription medications and supplements by cancer patients during chemotherapy: questionnaire validation. J Oncol Pharmacy Pract 2008;14:123-30. 4. Lebwohl D, Thomas G, Lane HA, et al. Research and innovation in the development of everolimus for oncology. Exp Opin Drug Discovery 2011;6:323-38. 5. Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004;10:8421-5. 6. Beeram M, Tan QT, Tekmal RR, Russell D, Middleton A, deGraffenried LA. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann Oncol 2007;18:1323-8. 7. Yee KW, Zeng Z, Konopleva M, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2006;12: 5165-73.


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Interacciones Farmacológicas y el Farmacéutico: Everolimus JA Grabowsky


Evaluar las interacciones entre fármacos y fármacosalimentos con everolimus, con especial énfasis en la población de pacientes oncológicos. Fuentes de inFORMACiÓn: Se realizó una búsqueda bibliográfica a través de la base de datos de PubMed (1990–marzo de 2013) mediante las combinaciones booleanas de los siguientes términos de búsqueda en inglés: drug interactions (interacciones farmacológicas), herb-drug interactions (interacciones productos herbales y fármacos), food-drug interactions (interacciones alimentos y fármacos), everolimus (everolimus), antineoplastic agents (agentes antineoplásicos), hormonal (hormonal), y breast neoplasms (neoplasias de mama). Asimismo, también se revisaron las referencias bibliográficas de las publicaciones y de la ficha técnica de everolimus. ObjetivOs:


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seLeCCiÓn de Fuentes de inFORMACiÓn y MÉtOdO de eXtRACCiÓn de

Se evaluaron todos los artículos identificados redactados en lengua inglesa de las fuentes de datos y se incluyeron estudios realizados en humanos, animales, e in vitro. sÍntesis: Los pacientes oncológicos presentan un riesgo mayor de interacciones farmacológicas debido las múltiples medicaciones prescritas para el tratamiento de su enfermedad y de los trastornos comórbidos. Everolimus, un inhibidor oral selectivo de mTOR (diana de la rapamicina en los mamíferos), está indicado para el tratamiento de adultos con tumores neuroendocrinos progresivos de origen pancreático no resecables, localmente avanzados, o metastáticos; adultos con carcinoma avanzado de células renales tras falta de respuesta al tratamiento con sunitinib o sorafenib; y, recientemente, mujeres postmenopáusicas con cáncer de mama avanzado con receptor humano positivo (HR+), y receptor 2 de factor de crecimiento epidérmico humano negativo (HER2-) en combinación con exemestano tras falta de respuesta al tratamiento con letrozol o anastrozol. Debido al aumento de su uso entre pacientes con cáncer, los facultativos deben tener conocimiento de sus interacciones potenciales con otros fármacos y/o alimentos/nutrientes y los mecanismos por los que se producen estas interacciones, con el fin de mitigar y prevenir las reacciones indeseables y asegurar la seguridad del paciente. COnCLusiOnes: Everolimus es un inhibidor mTOR oral de amplio uso que tiene el potencial de interacciones farmacológicas, el cual puede afectar al resultado terapéutico, producir toxicidades, o ambos. Este artículo proporciona una revisión de la literatura basada en la evidencia, junto con la ficha técnica, para formar a los facultativos sobre la importancia de estas interacciones farmacológicas y su impacto sobre el tratamiento con everolimus.

inFORMACiÓn:

RÉSUMÉ

Traducido por Enrique Soler Munoz

Les Interactions entre l’Évérolimus et les Médicaments, Aliments, et Plantes JA Grabowsky



Une recherche de littérature a été effectuée dans la banque de données PubMed (de 1990 au mois de mars 2013) en utilisant les mots-clés suivants: interactions médicamenteuses, interactions médicaments-aliments, interactions médicaments-plantes, évérolimus, agents antinéoplasiques, cancer du sein, cancers hormonaux. Les libellés réglementaires et les bibliographies des articles identifiés ont aussi été revus. sÉLeCtiOn de L’inFORMAtiOn et eXtRACtiOn des dOnnÉes: Tous les articles publiés en anglais, dont notamment les essais cliniques, les études animales et les études in vitro, ont été évalués. synthÈse des dOnnÉes: Les patients cancéreux sont plus à risque de développer des interactions médicamenteuses étant donné la panoplie de médicaments qu’ils reçoivent pour traiter leur cancer et les complications possibles de leur condition. L’évérolimus, un inhibiteur sélectif de mTOR (mammalian target of rapamycin –cible de larapamycine chez les mammifères) est indiqué 1) pour le traitement des tumeurs neuroendocrines pancréatiques, non résécables, localement avancés ou métastatiques; 2) le traitement du néphrocarcinome métastatique à cellules claires après l’échec d’un traitement par le sunitinib ou le sorafénib; et 3) chez les femmes ménopausées dans le traitement du cancer du sein avancé avec récepteurs hormonaux positifs et HER2 négatif, en association avec l’exémestane à la suite d’une récidive ou d’une progression de la maladie après un traitement par le létrozole ou l’anastrozole. Considérant que l’utilisation de l’évérolimus continue d’augmenter chez la population oncologique, les cliniciens doivent être à l’affût des différentes interactions possibles avec l’évérolimus et de leurs mécanismes sous-jacents, afin de pouvoir prévenir ou mitiger les réactions indésirables et ainsi promouvoir sa sécurité d’utilisation. COnCLusiOns: L’évérolimus est un agent oral qui possède un potentiel élevé d’interactions et son utilisation peut avoir un impact sur les bénéfices cliniques anticipés et/ou sur son profil d’innocuité. Cet article fait le point sur les données probantes disponibles à ce jour et sur l’impact réel que peuvent avoir ces différentes interactions au niveau clinique. sOuRCes d’inFORMAtiOn:

Traduit par Sylvie Robert

Évaluer et résumer les interactions que l’évérolimus peut avoir avec les médicaments, les aliments et les plantes chez une population oncologique.

ObjeCtiF:

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