Pharmacokinetic drug drug interactions of tyrosine kinase inhibitors: A focus on cytochrome P450, transporters, and acid suppression therapy

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1 Received: 1 March 2016 Revised: 4 July 2016 Accepted: 4 July 2016 DOI: /hon.2335 REVIEW Pharmacokinetic drug drug interactions of tyrosine kinase s: A focus on cytochrome P450, transporters, and acid suppression therapy Caroline Gay 1 Delphine Toulet 1 Pascal Le Corre 1,2 1 Pôle Pharmacie, Service Hospitalo Universitaire de Pharmacie, CHU de Rennes, Rennes Cedex, France 2 Laboratoire de Pharmacie Galénique, Biopharmacie et Pharmacie Clinique, IRSET U1085, Faculté de Pharmacie, Université de Rennes 1, Rennes Cedex, France Correspondence Pascal Le Corre, Laboratoire de Pharmacie Galénique, Biopharmacie et Pharmacie Clinique, Faculté de Pharmacie, Université de Rennes 1, Rennes Cedex, France. pascal.le corre@univ rennes1.fr Abstract The extensive use of tyrosine kinase s (TKI's) in hematology and oncology has shown that these drugs have a significant potential for drug drug interactions. Since these drugs have a rather low therapeutic window, some drug interactions are of particular clinical relevance either on drug toxicity or on patient's response. Significant interactions occur with concomitant use of acid suppressive therapy leading to a decreased oral bioavailability. However, such interactions are drug dependent according to their solubility pattern and to the duration of action of acid suppressive therapy, which is coprescribed. Significant interactions occur by inhibition or induction of CYP450 3A4 which is the main metabolic pathway of TKIs. However, minor metabolic pathways should also be paid attention to. Interactions involving efflux and influx transporters should also be considered occurring for some TKIs. Genetic polymorphism in drug metabolism as well as in drug transport is a factor of variability in drug exposure, which could modulate the magnitude of drug drug interactions (DDIs). It should be noticed that TKIs can also be at the origin of drug interactions by altering the pharmacokinetics of coprescribed drugs. Since cancer patients are given many drugs either for supportive care or for the treatment of drug toxicity, and to the fact that the oldest patients are polymedicated, a clear understanding of DDIs with TKIs is of interest. The objectives of this review are to provide an overview of the mechanisms of DDIs with TKIs and to provide to physicians and pharmacists recommendations to manage these DDIs in their clinical practice. KEYWORDS acid suppression therapy, cytochrome P450, drug drug interactions, oral bioavailability, pharmacokinetics, transporters, tyrosine kinase s 1 INTRODUCTION Tyrosine kinase s (TKIs) are molecular targeted therapies allowing the disruption of signaling pathways responsible for the abnormal proliferation of cancer cells. 1 They have provided a significant breakthrough in the treatment of cancer either in hematology or in oncology, and their oral administration in outpatients has dramatically modified the landscape of cancer treatment. 2,3 These drugs are not definitely curative, while a recent report indicates that life expectancy of patients with chronic myeloid leukemia is approaching that of the general population, 4 and the current recommendations is to These authors contributed equally to this paper. prescribe them in a continuous fashion and indefinitely administration for most of the patients. On the whole, TKI's are better tolerated than intravenous antineoplastic agents. Indeed, cytotoxic drugs administered intravenously affect tissues with rapid cell division such as hair, skin, intestinal epithelium, and blood and are responsible for the main side effects. Nevertheless, TKI's have specific side effect profiles that differ from those observed with cytotoxic agents. Furthermore, their side effects are rather numerous and occur with a high frequency for some of them. 5 Cytotoxic agents are administered intravenously on a rather short time so that drug drug interactions (DDIs) are less likely, and usually not of clinical significance. However, TKI's are given chronically via oral Hematological Oncology. 2017;35: wileyonlinelibrary.com/journal/hon Copyright 2016 John Wiley & Sons, Ltd. 259

2 260 GAY ET AL. route so that their pharmacokinetics, and principally their bioavailability that depends on both absorption and first pass metabolism, can be altered by DDIs. Absorption can be reduced by coadministration of gastric acid reducing agents with a rather complex mechanism. Increase or decrease in the systemic exposure can result from induction or inhibition of transporters and/or metabolic enzymes, principally cytochromes (CYPs) at the intestinal and/or hepatic levels. 6 8 Furthermore, genetic polymorphism of transporters and CYPs can also modify the TKI's exposure. These DDIs may decrease the efficiency of treatments and/or increase adverse reactions, which can alter adherence in patients. 9,10 In addition to anticancer agents, patients are usually polymedicated as a result of age related comorbid conditions or of other supportive care drugs and complementary alternative medicines For these reasons, the patients have an increased risk of DDIs, and a clear understanding of DDIs with TKIs is of interest. The aims of this review are to provide an overview of the mechanisms of pharmacokinetic DDIs with TKIs and to provide physicians and pharmacists recommendations for the management of interactions in their clinical practice. 2 ABSORPTION OF TKIS AND GASTRIC ACID SUPPRESSION THERAPY Many drug related or patient related factors can influence oral absorption of drugs. Drug absorption depends on drug physicochemical properties (especially its solubility), intestinal permeability, and galenic formulation. Patient factors include gastric ph, gastric emptying rate, age, coexisting disease, efflux and uptake transporters in the intestinal tract. Given the interaction between TKIs and acid suppression therapy, the likelihood of a clinically significant interaction has to take into account the physicochemical properties of the drug and the nature of the acid suppressive agents used. Most TKIs are weak bases that have a ph dependent solubility. 15 This decreases their solubility in the gastrointestinal tract at the site of absorption in the jejunum (ph around 5 6) or in the ileum (ph around 7 8). Moreover, their poor solubility results also from a rather high lipophilicity, with the exception of ruxolitinib. Based on these characteristics, they belong to class II or IV of the Biopharmaceutic Classification System. 16,17 Another factor that should be taken into account is the value of dose per 250 ml. Indeed, if the solubility at ph 6.0 to 6.5 is higher than the concentration encountered in the gastrointestinal tract (dose per 250 ml), an interaction is unlikely. Basically, acid suppressive agents can be classified into 3 groups depending on their duration of action. Antacids neutralize gastric acidity and have a short duration of action, lasting around 2 hours post dosing. H2 blockers are competitive s of H2 receptors localized in gastric parietal cells. They reduce acid concentration and volume of gastric secretion with a dose dependent effect. The mean duration of action of ranitidine 150 mg and famotidine 20 mg is around 10 to 12 hours. Proton pump s act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase system of the gastric parietal cells. Duration of action is more than 24 hours. 18 Hence, according to the nature of the acid suppression therapy, the time interval in which TKIs with ph dependent solubility can be administered is different as illustrated in Figure 1. Table 1 summarizes the recommendations for TKI's administration with the different acid suppression therapies. For instance, imatinib does not have a ph dependent solubility and can be administered concomitantly with proton pump, H2 blockers, or antacid. Dasatinib has a ph dependent solubility and can be used in association with antacid or famotidine 20 mg after a specific time interval 10 to 12 hours after H2 blocker administration or 2 hours after antacid administration. 16 Crizotinib has a ph dependent solubility but a solubility at ph 6.0 to 6.5 higher than the value of dose per 250 ml so that there is no interaction with acid suppressive agents. 15 FIGURE 1 Mean duration of action of different acid suppression therapies

3 GAY ET AL. 2 TABLE 1 Interactions between TKIs and acid suppressive agents 15 18,47 50 Tyrosine Kinase Inhibitors pka Proton Pump Inhibitors H2 Blockers Antacid Afatinib Not studied Not studied Not studied Axitinib 4.8 Yes Yes Yes Bosutinib No No Yes, take antacid solution more than 2 h after bosutinib dose Cobimetinib Yes Not studied Not studied Crizotinib Pka1 = 5.6, Pka2 = 9.4 Dasatinib Pka1 = 3.1, Pka2 = 6.8, Pka3 = 10.8 Dabrafenib Pka1 = 6.6, Pka2 = 2.2, Pka3 = 1.5 Yes Yes Yes, take antacid solution 2 h before or after crizotinib dose No Yes, take famotidine 40 mg 2 h after dasatinib dose (12) No (FDA, EMA) Not studied Not studied Not studied Erlotinib 5.42 No Yes, take erlotinib 10 h after ranitidine 150 mg dose or take ranitidine 150 mg 2 h after erlotinib dose Gefitinib Pka1 = 5.4, Pka2 = 7.2 Take antacid solution 2 h before or after dasatinib dose Yes, antacid can be taken 4 h before or 2 h after the daily dose of erlotinib No No Yes, take antacid solution 2 h before or after gefitinib dose Ibrutinib 3.74 Not studied Not studied Not studied Idelalisib Pka1 = 1.6, Pka2 = 3.4, Pka3 = 9.8 Not studied Not studied Not studied No study with acid reducing agents was provided despite the ph dependent solubility. It was however accepted that the clinical data provided did not suggest a major impact of concomitant use of acid reducing drugs, and this together with the relatively flat exposure response relationship led to the conclusion that a specific study is not necessary. Imatinib 7.7 Yes Yes Yes Lapatinib No (EMA), yes (FDA) No (EMA), yes (FDA) No (EMA), yes (FDA) Nilotinib Pka1 = 2.1, Pka2 = 5.4 Pazopanib Pka1 = 2.1, Pka2 = 6.4, Pka3 = 10.2 Yes (EMA), no (FDA) Yes, take pazopanib at the same of proton pump s, in the evening, with no food (EMA), no (FDA) Yes, take nilotinib 10 h after famotidine 20 mg dose or take famotidine 20 mg 2 h after nilotinib dose Yes, take pazopanib 10 h after H2 blockers dose or take H2 blockers 2 h after pazopanib dose Ponatinib Pka1 = 2.77, Yes Yes Yes Pka2 = 7.8 Sorafenib Yes Not studied Not studied Sunitinib 8.95 Not studied Not studied Not studied Vandetanib Pka1 = 5.2, Yes Yes Yes Pka2 = 9.4 Vemurafenib Not studied Not studied Not studied Yes, take antacid solution 2 h before or after nilotinib intake Yes, take pazopanib 1 h before antacid dose. Take pazopanib 2 h after antacid dose Abbreviations: EMA, European Medicines Agency; FDA, Food and Drug Administration; TKI, tyrosine kinase. pka is the the symbol for the dissociation constant Ka at logarithmic scale between the ionized and unionized form of a molecule. 3 FIRST PASS EFFECT OF TKIS Cytochromes and drug transporters are located in several organs involved in the pharmacokinetics of drugs such as intestinal wall, liver, and kidneys. Given the location of these biological systems, the absorption as well as the elimination of drugs can be significantly affected. An updated and more comprehensive figure illustrates the potential sites of pharmacokinetic DDI with TKIs (Figure 2). Drug drug interactions withtkis are quite complex because these drugs can be both substrate of several CYPs (CYP3A4 being the major enzyme) and substrate of transporters (efflux or influx). Moreover, they can interfere with these biological systems by either induction or inhibition. Such a pattern could explain the variability of the interactions with TKIs. In Table 2, we have summarized the different enzymes and transporters (influx and/or efflux) involved in TKI pharmacokinetics. The clinical consequences of drug interactions depend on the magnitude of their impact on the systemic exposure (ie, area under the curve [AUC]). The intensity (strong, moderate, or weak) of metabolic inhibition or induction is defined by the Food and Drug Administration (FDA) based on the impact on AUC. 19 Indeed, a strong

4 262 GAY ET AL. FIGURE 2 Sites of pharmacokinetic drug drug interactions with tyrosine kinase s. The main transporters involved in the interactions are highlighted in red for a specific CYP is defined as an that increases the AUC of a substrate for more than 5 fold, or more than 80% decrease in clearance. For moderate and weak s, the increase is 2 fold to 5 fold, and 1.25 fold to 2 fold, respectively. Similarly, a strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate by more than 80%. For moderate and weak inductors, the decrease is 50% to 80% and 20% to 50%, respectively. Let us remind here that an inhibition is a quite immediate phenomenon (occurring in the 24 h post dosing) while an induction requires the synthesis of new proteins (enzymes or transporters), reaching its maximum at around 7 to 10 days. 20 Thus, in clinical practice, we have to pay particular attention to inhibition mechanisms at either enzyme level or transporter level. In Table 3, we report the DDIs with TKIs from the scientific literature with the mechanism involved, some recommendations from authors for dose adaptation, and the use of safer alternative therapy, which could be useful in daily practice. In our review, we found that TKIs are victims of DDIs in %, whereas they are responsible for DDIs in 39%. Thirty percent of studies have been conducted in healthy volunteers and 30% in patients (19% of whom are case reports). Cytochrome P450 is responsible for DDIs in 65%, transporters in 22%, competition acid glycoprotein binding in 2%, and phase 2 enzymes in 4% (Figure 3). The major cytochrome P450 and transporter involved in DDIs are CYP3A4 (62%) and P gp (14%), respectively. Cytochrome inhibition mechanisms are more frequent (60%) than CYP induction (40%). Concerning transporters, except afatinib, all DDIs are due to inhibition. The repartition of cytochrome P450 and transporters involved in DDIs is illustrated in Figure 4. While TKIs are implicated as victims in numerous DDIs, only a part of them should be considered of clinical significance. A 2 fold increase in their systemic exposure (AUC) or an 80% decrease in AUC might be considered as clinically significant. Furthermore, while much less known, protein kinase s may lead to DDIs as perpetrators. Indeed, bosutinib has been shown to inhibit CYP2C8, and time dependent CYP3A inhibition has been observed in vitro with crizotinib, dasatinib, erlotinib, gefitinib, nilotinib, pazopanib, sorafenib, and sunitinib. 21 These clinically significant interactions are shown in Table 4. Among these drugs, ibrutinib should be prescribed with caution given its particular sensibility to CYP3A4 s with recent clinically documented interaction. 22 Idelalisib as a perpetrator should be also prescribed with caution with drugs that are substrate of CYP3A4 with a case report of clinically significant interaction with diazepam. 23 Besides DDIs, fruit juice interactions may be considered given the large consumption of fruit juices and the oral administration of TKIs. If grapefruit juice (GFJ) has a significant y effect on intestinal CYP3A4, other fruit juices such as orange juice (OJ), apple juice and other beverages such as green tea have a minimal effect on the pharmacokinetics of CYP3A4 substrates. 24,25 Fruit juice (GFJ, OJ, and OJ) inhibition of the organic anion transporting polypeptides (influx transporter at the intestinal and hepatic levels) also led to significant drug interactions. Interactions of fruit juices with P gp have also been reported, but the effect is minimal with no evidence of clinically relevant interactions. 26,27 Very recently, inhibition of fruit juices and green tea on BCRP has been demonstrated in vitro with dasatinib as a dual substrate of P gp and BCRP. 28 This work suggested that ingredients in GPJ and OJ strongly inhibit BCRP so that TKIs fruit juice interactions may be of concern.

5 GAY ET AL. 263 TABLE 2 CYPs and transporters involved in TKI pharmacokinetics 6 8,17, 49 Cytochrome Transporters Major CYPs Minor CYPs Inhibitor Inducer P gp BCRP MRP OATP OAT OCT Afatinib Negligible Substrate and moderate Substrate and Axitinib CYP3A4, CYP3A5 CYP1A2, CYP2C19, UGT1A1 CYP1A2, CYP2C8 Substrate Strong Bosutinib CYP3A4 UGT Strong Weak substrate Strong. OATP1B1 substrate Strong Cobimetinib CYP3A4 UGT2B7 CYP3A4, CYP2D6 Substrate Moderate Crizotinib CYP3A4, CYP3A5 CYP2D6, CYP2C19 Dasatinib CYP3A4 CYP2C8, FMO 3, and UGT Erlotinib CYP3A4 CYP1A2, CYP2C8, CYP1A1, CYP2D6 Gefitinib CYP3A4, CYP2D6 CYP3A, CYP2B6, UGT1A1, UGT2B7 CYP3A, CYP2C8, CYP2C9, UGT Strong substrate Strong CYP3A4 Strong substrate Weak CYP1A1, CYP3A4, CYP2C8 CYP1A1 CYP2D6, CYP2C19 Strong substrate Strong Strong substrate Inhibitor OCT1 and OCT2 Strong substrate Moderate Strong substrate Strong Strong substrate Strong hoct1 substrate MRP7 OAT3 substrate OCT2 substrate OCT1 OCT1 and OCT2 Ibrutinib CYP3A4 CYP2D6 Idelalisib CYP3A4 UGT1A4 Substrate Strong Imatinib CYP3A4 CYP2D6, CYP2C9, CYP2C19, CYP1A2 Lapatinib CYP3A4 CYP2C8, CYP2C19, CYP2C9, CYP1A2, CYP2D6 Nilotinib CYP3A4 CYP2C8, CYP2C9, CYP1A1, CYP1A2, CYP2D6 CYP3A4/5, CYP2D6, CYP2C9, CYP2C8 CYP3A, CYP2C8 CYP3A4, CYP2C8, CYP2C9, CYP2D6, UGT1A1 Strong substrate Strong Strong substrate Strong CYP2B6, CYP2C8, CYP2C9 Weak substrate Strong Substrate Strong Strong substrate Strong Strong substrate Strong inhibiton Strong substrate Strong OATP1B1 and OATP1B3 substrate MRP4 substrate MRP7 MRP7 OAT1A2 and OATP1B3 substrate OATP1B1 OCT1: substrate and MRP7 OCT1 and OCT3 (Continues)

6 264 GAY ET AL. TABLE 2 (Continued) Cytochrome Transporters Major CYPs Minor CYPs Inhibitor Inducer P gp BCRP MRP OATP OAT OCT Pazopanib CYP3A4 CYP1A2, CYP2C8 CYP2D6, CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 Regorafenib CYP3A4 UGT1A9 CYP2C9; CYP2B6; CYP3A4; CYP2C8 Moderate substrate Inhibitor Strong substrate Inhibitor OATP1B1 Inhibitor Inhibitor Ruxolitinib CYP3A4, CYP2C9 CYP3A4 Inhibitor Inhibitor Sorafenib CYP3A4 CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 Substrate Inhibitor Substrate Inhibitor MRP2 substrate and MRP4 Sunitinib CYP3A4 CYP1A2 Strong substrate Strong Strong substrate Strong MRP2 and MPR4 Vandetanib CYP3A4 FMO 1, FMO 3 CYP2D6 CYP3A4, CYP2C9, CYP1A2 Inhibitor Strong substrate Strong OCT2 Vemurafenib CYP3A4 CYP1A2, CYP2D6 CYP3A4, CYP2B6 Strong substrate Weak Substrate Strong Abbreviations: CYP, cytochrome; TKI, tyrosine kinase.

7 GAY ET AL. 265 TABLE 3 Drug drug interactions with TKIs reported in the literature Tyrosine kinase Generate/ Undergo Drug drug interaction Study Mechanism Consequences Recommendations Ref. Afatinib Undergoes Rifampicin Healthy subjects P gp induction AUC diminution of afatinib by 33,8% and Cmax diminution by 21,6% Increase the afatinib dose at 10mg daily Ritonavir Healthy subjects P gp inhibition Afatinib dose 1hour after the ritonavir dose: afatinib AUC is increased by 47, 6% Afatinib dose 6h after the ritonavir dose: afatinib AUC is increased by 10,8% Strong P gp dosed once daily: take it 12h apart from afatinib dose Strong P gp dosed twice daily: take it 6h apart from afatinib dose Generates P gp substrate Moderate P gp inhibition No clinical effect is expected Axitinib Undergoes Rifampicin Healthy subjects Strong CYP3A4 induction AUC diminution of axitinib by 79%Cmax diminution by of axitinib 71% Ketoconazole Healthy subjects Strong CYP3A4 inhibition AUC augmentation of axitinib 2,06 fold Generates Cyclophosphamide In vitro Antiangiogenic activity of axitinib Reduction of the concentration of cyclophosphamide active metabolite in tumor cells by 60% Increase axitinib dose by steps with toxicity monitoring Decrease initial axitinib dose by 2mg twice daily with toxicity monitoring Bosutinib Generates CYP2C8 substrate In vitro Bosutinib is a time dependent of CYP2C8 Augmentation of CYP2C8 substrate AUC by 1,2 fold No clinical effect of this drugdrug interaction is expected 21 Undergoes Ketoconazole Healthy subjects Strong CYP3A4 inhibition Bosutinib AUC is increased by 8 fold Bosutinib dose reduction is required with patient monitoring of side effect Valproic acid In Vitro Downregulation of c Src, growth inhibition and induction programmed cell death by valproic acid. Animal Valproic acid enhances bosutinib cytotoxicity in patient with colorectal cancer Rifampin Healthy subjects CYP3A induction AUC diminution of bosutinib by 92%Cmax diminution of bosutinib by 86% Cobimetinib Generates Dextrometorphane Patient CYP2D6 inhition No change in dextrometorphane exposure Midazolam Patient CYP3A4 inhibiton No change in midazolam exposure Undergoes Itraconazole Animal CYP3A4 inhibition AUC augmentation of cobimetinib by 5.6 fold Healthy volunteers CYP3A4 inhibition AUC augmentation of cobimetinib by 6.7 fold Association between bosutinib and moderate CYP3A inducers should be avoided. No drug drug interaction is expected with CYP3A4 and CYP 2D6 substrates Cobimetinib should not be used with strong CYP3A4 s (EMA) FDA 59 FDA (Continues)

8 266 GAY ET AL. TABLE 3 (Continued) Tyrosine kinase Generate/ Undergo Drug drug interaction Study Mechanism Consequences Recommendations Ref. Cmax augmentation of cobimetinib by 3.2 fold Moderate CYP3A4 PKPB model CYP3A4 inhibition AUC augmentatipn of cobimetinib by 3 4 fold Weak CYP3A4 (Fluvoxamine) PKPB model CYP3A4 inhibition No change in cobimetinib exposure is expected Rifampin Animal CYP3A4 induction AUC diminution of cobimetinib by 80% PKPB CYP3A4 induction AUC diminution of cobimetinib by 83% Efavirenz PKPB CYP3A4 induction AUC diminution of cobimetinib by 72% Crizotinib Undergoes Ketoconazole Strong CYP3A4 inhibition AUC augmentation of crizotinib by 2 fold Rifampicin Strong CYP3A4 induction AUC diminution of crizotinib by 82% and Cmax by 69% Generates Doxorubicin In vitro P gp inhibition Increase intracellular concentration of doxorubicin Patients treated with 60mg daily of cobimetinib: if the association with a moderate CYP3A is unavoidable, cobimetinib dose recommended is 20mg daily.patients treated with 20mg or 40mg of cobimetinib, association with moderate CYP3A4 s should be avoided. (FDA) Cobimetinib should not be used with strong CYP3A4 inducers (EMA) Toxicity monitoring. Avoid the association, if possible Increase crizotinib dose gradually. Patient must be monitored carefully P gp substrate P gp inhibition Crizotinib can increase plasma concentration of P gp substrate Midazolam PKPB CYP3A4 inhibition Increase of midazolam AUC by 3,7 fold and midazolam Cmax by 2 fold Dabrafenib Generates Midazolam In vitro CYP3A4 inhibition midazolam AUC decreases by 74% Undergoes Ketoconazole In vivo CYP3A4 inhibition Dabrafenib AUC increases by 71% Caution must be exercised with P gp substrate with narrow therapeutic window Caution must be exercised with CYP3A4 substrate with narrow therapeutic window Caution must be exercised with concomitant use of CYP 3A4substrate with narrow therapeutic range Dabrafenib should not be used with strong CYP3A4 s Gemfibrozil In vivo CYP2C8 inhibition (Continues)

9 GAY ET AL. 267 TABLE 3 (Continued) Tyrosine kinase Generate/ Undergo Drug drug interaction Study Mechanism Consequences Recommendations Ref. Dabrafenib AUC increases by 47% Dabrafenib should not be used with strong CYP2C8 s Dasatinib Undergoes Ketoconazole Patients Strong CYP3A4 inhibition Augmentation of AUC dasatinib by 4,86 fold and Cmax by 3,64 fold Rifampicin Patients Strong CYP3A4 induction Diminution of dasatinib AUC by 82% Generates Paracetamol In vitro Inhibition of hepatic glucuronidation by dasatinib Augmentation of paracetamol AUC by 1,06 fold. Simvastatin CYP3A4 inhibition Augmentation of simvastatin AUC by 20% Erlotinib Undergoes Ketoconazole Healthy subjects Strong CYP3A4 inhibition Augmentation of erlotinib AUC and Cmax by 2 fold. Reduce dasatinib dose by 20 40mg daily Increase dasatinib dose by 20mg step with toxicity monitoring of the patient. No clinical impact is expected in vivo Caution must be exercised with CYP3A4 substrate with narrow therapeutic windows Decrease erlotinib dose by 50mg steps if toxicity appears and the association is needed Ciprofloxacin Healthy subjects CYP1A2 inhibition by ciprofloxacin Enzyme inducing antiepileptic drugs Augmentation of erlotinib AUC by 33% Patients Strong CYP3A4 induction Diminution of erlotinib AUC by 2 fold Clinical impact is expected to be minimal. Toxicity monitoring is recommended Use non enzyme inducing antiepileptic drug Diminution of erlotinib exposure by 33% to 71% Rifampicin Healthy subjects Strong CYP3A4 induction Diminution of erlotinib AUC by 3 to 5 fold Fenofibrate Case report CYP3A4 induction Plasma concentration of erlotinib is decreased by 2,5 fold Erlotinib Generates Phenytoin Case report Unknown mechanism: CYP2C9 or CYP2C19 inhibition by erlotinib competitive inhibition of the Phenytoin concentration is increased by 3 fold If the combination with enzyme inducing antiepileptic drugs is needed, possibly to increase erlotinib dose by until mg daily with toxicity monitoring Increase the erlotinib dose to 300mg dailly with toxicity monitoring. If it's well tolerated after 2 weeks increase the dose to 450mg daily Therapeutic drug monitoring of erlotinib should be considered in patients with early disease progression. Therapeutic drug monitoring of phenytoin even after erlotinib discontinuation (Continues)

10 268 GAY ET AL. TABLE 3 (Continued) Tyrosine kinase Generate/ Undergo Drug drug interaction Study Mechanism Consequences Recommendations Ref. clearance of phenytoin by the CYP450, increase in unbound phenytoin Simvastatin Case report Competitive effect of simvastatin and erlotinib on CYP3A4 Rhabdomyolysis Prescribe pravastatin (renal excretion, no CYP mediated metabolism Warfarin Case report Unknown mechanism INR augmentation INR monitoring Gefitinib Undergoes Itraconazole Healthy subjects Strong CYP3A4 inhibition Augmentation of gefitinib AUC and Cmax by 78% and 51% respectively Toxicity monitoring. No clinical data available about the starting dose Rifampicin Healthy subjects Strong CYP3A4 induction Diminution of gefitinib AUC and Cmax by 83% and 65% respectively Avoid the concomitant use with strong CYP3A4 inducers. If the combination is needed, increase the gefitinib dose to 500mg daily Enzyme inducing antiepileptic drug Patients Strong CYP3A4 induction Diminution gefitinib AUC by 70% Phenytoin Patients CYP 3A4 induction in intestine Diminution of gefitinib AUC and Cmax by 47% and 26% respectively Sorafenib Patients Unknown mechanism Diminution of gefitinib AUC and Cmax by 38% and 26% respectively Generates Metoprolol Patients CYP2D6 inhibition Augmentation of metoprolol AUC by 35% Therapeutic drug monitoring of gefitinib at the beginning of the treatment. Caution should be exercised with CYP2D6 substrate with narrow therapeutic window Warfarin Patients Unknown mechanism INR augmentation INR monitoring Ibrutinib Undergoes Ketoconazole Healthy subjects Strong CYP3A4 inhibition Augmentation of ibrutinib AUC and Cmax by 29 fold and 24 fold respectively Verapamil Case report CYP3A4 inhibition Patient admitted because of severe diarrhea Strong CYP3A4 inducers Healthy subjects Strong CYP3A4 induction Ibrutinib plasma concentration is decreased by 92% and AUC by 90% Association should be avoided. Ibrutinib dose interruption or modification is warranted when treatment of a patient on ibrutinib requires administration of strong or moderate CYP3A s. Ibrutinib was discontinued for 5 days. Verapamil was stopped. as an alternative antihypertensive drug was prescribed (lercanidipine) Avoid strong CYP3A4 inducers. Alternative drugs must be proposed (Continues)

11 GAY ET AL. 269 TABLE 3 (Continued) Tyrosine kinase Generate/ Undergo Drug drug interaction Study Mechanism Consequences Recommendations Ref. Idelalisib Undergoes Ketoconazole Patients Strong CYP3A4 inhibition Augmentation of idelalisib AUC and Cmax by 79% and 26% respectively Rifampicin Patients Strong CYP3A4 induction Diminution of idelalisib AUC and Cmax by 75% and 58% respectively Generate Midazolam Patients CYP3A4 inhibition Augmentation of midazolam AUC and Cmax by 437% and138% respectively If patients are taking concomitant strong CYP3A s, monitor for signs of Idelalisib toxicity. Follow dose modifications for adverse reactions. Avoid coadministration of Idelalisib with strong CYP3A inducers, such as rifampin, phenytoin, St. John's wort, or carbamazepine. Avoid coadministration of Idelalisib with CYP3A substrates, as Idelalisib is a strong CYP3A Diazepam Case report CYP3A4 inhibition Altered mental status and respiratory failure Imatinib Generates Simvastatin Patients CYP3A4 inhibition Augmentation of simvastatin AUC and Cmax by 3,5 fold and by 2 fold Ciclosporin CYP3A4 inhibition Augmentation of ciclosporin AUC and Cmax by 20% and by 23% Paracetamol In vitro Inhibition of hepatic glucuronidation by imatinib Imatinib may increase paracetamol hepatotoxicity Idelalisib and diazepam were discontinued. Idelalisib was reinitiated after patient recovery. Lorazepam was introduced instead of diazepam Prescribe pravastatin.caution must be exercised with CYP3A4 substrate with narrow therapeutic window. No clinical impact is expected, but others authors recommends cyclosporine dose reduction in case of co administration with imatinib Effects of imatinib on the pharmacokinetics of paracetamol dosed 1000mg daily is well tolerated in association with imatinib 400mg daily Levothyroxin Case report Unknown mechanism Thyroid function test are altered Metoprolol Patients CYP2D6 inhibition Augmentation of metoprolol AUC by 23% Increased levothyroxine dose by 2 fold with monitoring of thyroid function test in post thyroidectomy patients. Caution should be exercised if imatinib is associated with CYP2D6 substrate with narrow therapeutic window (Continues)

12 270 GAY ET AL. TABLE 3 (Continued) Tyrosine kinase Generate/ Undergo Drug drug interaction Study Mechanism Consequences Recommendations Ref. Vincristine Patients CYP3A inhibition Imatinib increases vincristine toxicity Nilotinib Patients P gp inhibition Imatinib increase intracellular concentration of nilotinib Synergistic association. Warfarin In vitro CYP2C9 inhibition Risk of bleeding Avoid the association. Low molecular weight or standard heparin can be used Imatinib Undergoes Rifampicin Healthy subjects Strong CYP3A4 induction Reduction of imatinib AUC and Cmax by 74% and 54% Phenytoin Patients Strong CYP3A4 induction Carbamazepine and phenytoin: reduction of imatinib concentration by 68% Carbamazepine In association with strong CYP3A4 inducers, increase imatinib dose by at least 50% Use non enzyme inducing antiepileptic drug if possible. If the combination is needed, increase imatinib dose at least 50% Topiramate Topiramate: reduction of imatinib concentration by 48% Phenytoin Patients Strong CYP3A4 induction Reduction of imatinib AUC by 80% St. John's wort Healthy subjects Strong CYP3A4 induction Reduction of imatinib AUC by 30 32% Ketoconazole Healthy subjects Strong CYP3A4 inhibition Augmentation of imatinib AUC and Cmax by 40% ans 26% Ketoconazole Animal Strong CYP3A4 inhibition Augmentation of imatinib AUC and Cmax by 63,4% and 28,8% Itraconazole No modification with itraconazole Voriconazole Augmentation of imatinib Cmax by 36,8% Kétoconazole Animal CYP3A4 inhibition Augmentation of imatinib AUC by 35% in association with ketoconazole and primaquine Primaquine Competition for alpha 1 glycoprotein acid binding between primaquine and imatinib Avoid the association Avoid the association If the association is needed, regular monitoring for toxic effect Monitoring of toxic effect and dose adjustment may be required Monitoring of toxic effect and dose adjustment may be required (Continues)

13 GAY ET AL. 271 TABLE 3 (Continued) Tyrosine kinase Generate/ Undergo Drug drug interaction Study Mechanism Consequences Recommendations Ref. Gemfibrozil Healthy subjects OATP1A2 and OATP2B1 inhibition (reduction of imatinib absorption) Reduction of imatinib Cmax by 35%, imatinib AUC is unchanged 97 CYP2C8 inhibition (diminution of active metabolites) Ginseg Case report P gp inhibition Hepatotoxicity in patient treated with imatinib who regularly take ginseng CYP3A4 inhibition Do not use ginseng of other over the counter herbal product. 98 Clindamycin Patients Competition between both drugs for alpha 1 acid glycoprotein binding. Reduction of imatinib AUC and Cmax by 3 fold Lapatinib Generates Vinorelbine Patients CYP3A4 inhibition Reduction of vinorelbine clearance by 30 40% This combination is generally well tolerated Topotecan In vitro BCRP inhibition Augmentation of topotecan AUC by 18% Reduce the topotecan dose by 40% decrease the toxicity 100 Animal OATP1B1 inhibition Patients Cimetidine In vitro BCRP inhibition Reduction of BCRP mediated transport by 82% Digoxine In vitro P gp inhibition Reduction of Pgp mediated transport by 74% Undergoes Ketoconazole Healthy subjects CYP3A4 inhibition Augmentation of lapatinib Cmax by 114% and lapatinib AUC by 257% Carbamazepine Healthy subjects CYP3A4 induction Reduction of lapatinib Cmax and AUC by 59% and 72%. Use BCRP substrat with caution Use P gp substrat with caution Lower the lapatinib dose to 500 mg once daily Gradually increase the lapatinib dose to 4500 mg once daily and monitor for liver toxicity Nilotinib Generates Warfarin Healthy subjects CYP2C9 inhibition Nilotinib has no effect on single dose warfarin pharmacokinetics Paclitaxel Animal P gp inhibition Augmentation of paclitaxel AUC by 36% Warfarin and nilotinib may be used concurrently as needed Nilotinib can be combined with conventional chemotherapeutic drugs as well as other TKIs that are substrates of ABCB1 and ABCG2 in patients with MDR mediated by ABC transporters to attain improved anticancer responses Doxorubicin In vitro P gp inhibition 105 (Continues)

14 272 GAY ET AL. TABLE 3 (Continued) Tyrosine kinase Generate/ Undergo Drug drug interaction Study Mechanism Consequences Recommendations Ref. Nilotinib reduces intracellular concentration of doxorubicin by 1.3 fold MRP 1 inhibition Undergoes Rifampicin Healthy subjects CYP3A4 induction Reduction of nilotinib Cmax and AUC by 64% and 80% Increase the dose gradually dependent on toxic effects and effectiveness 106 Ketoconazole Healthy subjects CYP3A4 inhibition Augmentation of nilotinib Cmax and AUC by 84% and 201% Pazopanib Generates Paclitaxel Patients CYP3A4 inhibition Reduction of paclitaxel clearance of 14% augmentation of paclitaxel Cmax by 31% Undergoes Ketoconazole Patients CYP3A4 inhibition Augmentation of pazopanib Cmax and AUC by 45% and 66% Phenytoin Patients CYP3A4 induction Reduction of pazopanib Cmax and AUC by 50% and 30%. Carbamazepine Lower nilotinib dose to 400 mg once daily Reduce the pazopanib dose 400 mg once daily if concomitant administration with a CYP34A Gradually increase the pazopanib dose in 200 mg steps depending on toxicity Regorafenib Undergoes Rifampicin Healthy subjects CYP3A4 induction Reduction of regorafenib Cmax and AUC by 50% and 20%. Avoid the combination with strong CYP3A4 inducers; if unavoidable, gradually increase the regorafenib dose and monitor toxic effects 14 Ketoconazole Healthy subjects CYP3A4 inhibition Augmentation of regorafenib Cmax and AUC by 33% and 40%. Ruxolitinib Undergoes Rifampicin Healthy subjects CYP3A4 induction Reduction of ruxolitinib Cmax and AUC by 52% and 71%. Avoid the combination with strong CYP3A4 s; if unavoidable, regorafenib toxicity should be monitored Increase the ruxolitinib dose gradually depending on toxic effects and efficacy Ketoconazole Healthy subjects CYP3A4 inhibition Augmentation of ruxolitinib Cmax and AUC by 33% and 91% Sorafenib Generates Midazolam Patients CYP3A4 induction Reduction of midazolam AUC by 15% Reduce the ruxolitinib dose by 50% and haematological toxicity should be monitored extensively (twice a week) Clinical and, where possible, drug level monitoring may still be appropriate (Continues)

15 GAY ET AL. 273 TABLE 3 (Continued) Tyrosine kinase Generate/ Undergo Drug drug interaction Study Mechanism Consequences Recommendations Ref. Gefitinib Patients CYP3A4 induction Diminution of gefitinib AUC by 38% Docetaxel In vivo OATP1B1 inhibition Diminution of docetaxel clearance In vitro Doxorubicin Patients UGT1A1 inhibition Augmentation of doxotubicin AUC by 21%. 111 Irinotecan Patients UGT1A1 inhibition Augmentation of irinotecan AUC by 26 42%. 112 Undergoes Rifampicin In vivo CYP3A4 induction Diminution of sorafenib exposure by 37%. Combination can be used safely In vitro Patients Sirolimus Patients Possible interaction due to effects on ABC or SLC transporters No clinically significant differences in Cmax Felodipine Case report CYP3A4 inhibition Augmentation of sorafenib plasma concentration by 3 fold Sirolimus can be safely combined with sorafenib Sunitinib Undergoes Rifampicin In vitro CYP3A4 induction Reduction of sunitinib Cmax and AUC by 23% and 46%. Healthy subjects Patients Gradually increase the sunitinib dose in 12,5 mg steps, with a maximum of 87,5 mg once daily, dependent on indication 116 Ketoconazole In vitro CYP3A4 inhibition Augmentation of sunitinib Cmax and AUC by 49% and 51%. Reduce the sunitinib dose to a maximum of 25 mg once daily 116 Healthy subjects Patients Ciprofloxacin Animal CYP3A4 inhibition Augmentation of sunitinib Cmax by 82% Sirolimus Patients interaction due to effects on ABC or SLC transporters No clinically significant differences in Cmax Levofloxacin Animal P gp inhibition Augmentation of sunitinib Cmax by 58% Use with caution in association with ciprofloxacin. Moxifloxacin could be an alternative (no change in pharmacokinetic parameters Sirolimus can be safely combined with sunitinib Be particularly carefully observed for possible adverse reactions (Continues)

16 274 GAY ET AL. TABLE 3 (Continued) Tyrosine kinase Generate/ Undergo Drug drug interaction Study Mechanism Consequences Recommendations Ref. Moxifloxacin seems to be the most appropriate in combination with sunitinib (insignificant influence on pharmacokinetics) Clarithromycin Animal CYP 3A4 inhibition Diminution of sunitinib AUC and Cmax by 24.7% and 2.2% No significant effect of oral azithromycin or clarithromycin on the pharmacokinetic profile of sunitinib. No clinical effect is expected. 118 Azithromycin Animal No interaction with CYP 3A4 is expected Augmentation of sunitinib Cmax by 13.6% and diminution of sunitinib AUC by 0.7% Vandetanib Generates Cisplatin Patients OCT2 inhibition Augmentation of cisplatin Cmax and AUC by 43% and 33% Metformin Healthy subjects OCT2, MATE1, and MATE2K inhibition Intracellular accumulation of metformin Metformin Healthy subjects OCT2 inhibition Augmentation of metformin Cmax and AUC by 50% and 74%. Diminution of cisplatin clearance by 52% Vandetanib could be safely administered with carboplatin May require additional monitoring of metformin, with dose adjustments where necessary Digoxin Healthy subjects P gp inhibition Augmentation of digoxin Cmax and AUC by 29% and 23%. Diminution of digoxine clearance by 9%. Undergoes Rifampicin Healthy subjects CYP3A4 induction Reduction of vandetanib AUC by 40% Itraconazole Healthy subjects CYP3A4 inhibition Augmentation of vandetanib AUC by 9%. Everolimus In vitro P gp inhibition Augmentation of brain concentration of vandetanib by 3 4 fold and cellular accumulation by 220% May require additional monitoring of digoxin, with dose adjustments where necessary CYP3A4 inducers should therefore be avoided during vandetanib treatment Combination can be used safely Further clinical investigation for employing everolimus as an efflux modulator in adjunct to vandetanib monotherapy for the treatment of recurrent brain tumors BCRP inhibition Vemurafenib Undergoes Cobimetinib CYP3A4 inhibition No change is vemurafenib exposure No clinically relevant pharmacokinetics drug interaction Abbreviations: AUC, area under the curve; EMA, European Medicines Agency; FDA, Food and Drug Administration; INR, international normalized ratio; PBPK, physiologically based pharmacokinetic; SLC, solute carrier., Not Applicable

17 GAY ET AL. 275 predictive of the systemic exposure of some TKIs. Moreover, polymorphism in influx transporters (eg, OCTN1, OCTN2, and OATP1A2) may play a role in the disposition and outcome of TKIs. 41,42 Influx and efflux transporters play an increasing role in the field of oncology as a result of their contribution to interindividual variability in the pharmacokinetics as well as the clinical outcome of TKIs. 6 5 DISCUSSION FIGURE 3 Molecular target involved in drug drug interactions with tyrosine kinase s 4 POLYMORPHISM 4.1 Cytochrome P450 Cytochrome P450 supergene family is the most important system involved in the biotransformation of drugs. Metabolism mediated by cytochrome P450 isoenzymes is known to play a major part in the biotransformation of anticancer agents in vivo, and they play an important role in the interindividual variability in drug response. About 40% of CYP450 dependent drug metabolism is catalyzed by polymorphic enzymes. Polymorphisms in genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 can impact the therapeutic outcome or adverse reactions Cytochrome P450 polymorphisms are already well documented in the literature and are beyond the scope of this review. However, it should be noted that the magnitude of DDIs has been shown to vary depending on genotype status of the patients (extensive or poor metabolizer). Indeed, the interaction is more significant in patients with CYP2C19 extensive metabolism as shown with fluvoxamine and omeprazole. Indeed, even a single oral low dose of fluvoxamine increased omeprazole exposure in extensive metabolizers but did not increase omeprazole exposure in poor metabolizers Drug transporters Impact of transporter polymorphism is more and more studied, particularly in oncology As shown above, 22% of DDIs in our review dealt with transporters. Drug transporters are categorized into 2 superfamilies: ATP binding cassette (ABC) transporters and solute carrier transporters. A representation of drug transporters location is shown in Figure 2 with indication of those involved in TKI disposition. The ABC transporters are responsible for xenobiotic efflux. Most tyrosine kinase s are P gp (ABCB1) substrates, and some of them are also P gp s (Table 1), leading to potential DDIs (either as precipitant drug that causes the interaction or as an object drug whose systemic exposure is altered by the interaction). The influence of polymorphisms in genes encoding for influx and efflux drug transporters on the pharmacokinetics as well as on the outcome of drug treatment of cancer is of concern. A functional significance of variants in ABCB1 and ABCG2 has been shown to be Tyrosine kinase s are currently used extensively in oncology and hematology. However, serious DDIs occur, some of them leading to treatment interruption by the patient himself. Coprescription of drugs that induce or inhibit TKI's metabolic pathways is quite significant. It has been recently reported that coprescription of drugs that may decrease TKIs effectiveness ranged approximately from 25% to 60%, while coprescription of drugs that may increase TKI toxicity ranged from 25% to 75%. 43 Hence, management of DDIs in everyday practice remains a great challenge. The prevalence proportion of acid suppressive agents use has been estimated to be around 20% to 35% of cancer patients for all types of cancer with PPI as the most commonly used (between 65% and 80%). 44 Given the wide availability of acid suppressive agents, the prevalence is likely underestimated. As shown above, it is clear that interactions betweentkis and acid suppression therapy are very complex. The complexity arises from the specific physicochemical properties of a specific TKI (ph dependent solubility, value of dose per 250, and lipophilicity) and on the pharmacology of the acid suppressive agents, namely, their duration of action allowing to find a window of administration minimizing the interaction. Hence, professionals should be aware of such interactions and that there is no general rule but case by case information. Hence, they should refer to recommendations from health authorities and from peer reviewed scientific information when considering the coprescription of acid suppression therapy. It should be noticed, according to Yu et al, 18 that there is some discordance between European Medicines Agency and FDA about DDIs between acid suppressive agents and TKIs (eg, pazopanib). The major CYP involved in TKI metabolism is CYP3A4, and its interactions are rather well described. However, this is not the case for those affecting the minor CYP pathways. Even if these minor metabolic pathways are less studied, they can be significantly involved when the major CYP pathway is inhibited, and this minor CYP becomes then a major metabolic pathway. Moreover, drug interactions with minor CYPs should be studied given the fact that synergistic inhibitions on both major and minor pathways may have a paramount effect on drug concentrations. Cytochrome interactions are complex with sometimes concentration dependent and timedependent effects. Patients treated by TKIs can present fungal or bacterial infections that are treated by azole antifungals or macrolides, some of them being potent CYP3A4 s. There are subtle differences in the CYP3A4 inhibition potential within azole antifungal and macrolides agents. Hence, in the clinical practice, it is important to analyze these CYPbased interactions with caution to avoid them. Practitioners should

18 276 GAY ET AL. FIGURE 4 Repartition of cytochromes, transporters, and phase 2 enzyme in drug drug interactions with tyrosine kinase s TABLE 4 Drug drug interactions of TKI as victims and as perpetrators to be considered as clinically significant (ie, interactions resulting in a 2 fold increase or a 50% decrease in AUC. Interactions of higher impact with either a 5 fold increase or a 80% decrease in AUC are indicated in bold) TKI as Victim Inhibitor Inductor Axitinib Ketoconazole Rifampicin Bosutinib Ketoconazole Rifampicin Cobimetinib Itraconazole Rifampicin Moderate CYP3A4 Efavirenz Crizotinib Ketoconazole rifampicin Dabrafenib Ketoconazole gemfibrozil Dasatinib Ketoconazole Rifampicin Erlotinib Ketoconazole Enzymeinducing antiepileptic drugs Gefitinib Itraconazole Rifampicin Enzymeinducing antiepileptic drugs Ibrutinib Ketoconazole verapamil Rifampicin Idelalisib Ketoconazole Rifampicin Imatinib Rifampicinphenytoin Lapatinib Ketoconazole Carbamazepine Nilotinib Ketoconazole Rifampicin Ruxolitinib Rifampicin TKI as Perpetrator (Metabolic Inhibition) Crizotinib Dabrafenib Erlotinib Idelalisib Imatinib Substrate Midazolam Midazolam Phenytoin Midazolam Simvastatin Abbreviations: AUC, area under the curve; TKI, tyrosine kinase. also keep in mind the dual roles of TKIs on CYP, and especially on CYP3A4. Indeed, when given with other drugs, TKIs may not only be the victims in drug interactions but also play a role as perpetrators influencing the pharmacokinetics of coadministered drugs. However, CYP3A4 interactions of TKIs as perpetrators currently appear to be generally modest. 6 Many TKIs are known to be substrate and/or of efflux or influx transporters (Table 2) and were responsible for 22% of DDIs in our review with different clinical impact (Table 3). In contrast to metabolic enzymes that are mainly present at the intestinal and hepatic levels, transporters are present in organs and tissues affecting drug distribution and excretion as well as in some types of tumor cells. Hence, transporter based interactions may have different consequences because of increase in tissue distribution, especially in the brain. The interested reader may refer to a recent review highlighting the impact of transporter interactions. 6 Whatever the origin of a potential drug interaction (enzyme or transporter based), when a high risk association cannot be avoided because it is not possible to withhold a beneficial drug from a patient, a dose individualization of TKI may be useful either by therapeutic drug monitoring or by toxicity adjusted dosing to improve patient's response or reduce drug toxicity. Polymorphism of either metabolic enzymes or transporters adds another degree of complexity in the field of pharmacokinetic variability of TKIs, and its impact on the magnitude of DDI has not been yet fully documented. The clinical integration in daily practice of patient pharmacogenetic information on transporters and metabolic enzymes could be a further step toward personalized therapy in oncology care to reduce interindividual and intraindividual pharmacokinetic variability. In conclusion, regulatory agency should pay attention to drug information update so as to give actualized information to health care professional to help them in their daily practice. While there is a regular flow of scientific knowledge ontki DDIs, summary of product characteristic is not comprehensive. For instance, in our review, around 25% of DDIs were not described in the product labeling information of imatinib. Since TKIs are relatively new marketed drugs, the clinical evidence supporting DDIs is rather limited for some TKIs. Hence, health care professionals may not readily identify the most significant deleterious associations and should refer to regulatory agency information and to actualized peer reviewed sources for potential DDIs. It