Cardiovascular drug interactions with tyrosine kinase inhibitors

147-154 Haouala 076.qxp:Layout 1 29.4.2010 8:53 Uhr Seite 147 Cardiovascular drug interactions with tyrosine
kinase inhibitors
Amina Haoualaa, Nicolas Widmera, Michael Montemurrob, Thierry Buclina, Laurent Decosterda
a Division of Clinical Pharmacology, Département de Médecine, CHUV, University hospital, Lausanne, Switzerland
b Multidisciplinary Oncology Centre, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
imatinib has revolutionised the treatment and progno- sis of chronic myeloid leukaemia (CML) and gastroin- Imatinib mesylate, a selective inhibitor of tyrosine ki- testinal stromal tumour (GIST) [2, 3].
nases, has excellent efficacy in the treatment of chronic Imatinib was designed [4] to inhibit the tyrosine myeloid leukaemia (CML) and gastrointestinal stromal kinase Bcr-Abl [5], a fusion oncoprotein resulting from tumour (GIST). Inducing durable responses and the translocation t(9;22)(q34;q11), which produces the achieving prolonged survival, it has become the stan- characteristic Philadelphia chromosome [5], the hall- dard of care for the treatment of these diseases. It has mark of CML and of some acute lymphoblastic opened the way to the development of additional tyro- sine kinase inhibitors (TKIs), including sunitinib, nilo- Imatinib was also found to be a potent inhibitor of tinib, dasatinib and sorafenib, all indicated for the two additional tyrosine kinases, namely KIT, involved treatment of various haematological malignancies and in the oncogenesis of GIST [7–9], and platelet-derived solid tumours. TKIs are prescribed for prolonged peri- growth factor receptor (PDGFR) involved in the patho- ods and are often taken by patients with – notably car- genesis of the hypereosinophilic syndrome [10].
diovascular – comorbidities. Hence TKIs are regularly Following imatinib, several other TKIs, including co-administered with cardiovascular drugs, with a con- sunitinib, nilotinib, dasatinib and sorafenib, have been siderable risk of potentially harmful drug-drug inter- developed and are now used in the treatment of various actions due to the large number of agents used in com- haematological malignancies, solid tumours including bination. However, this aspect has received limited GIST, advanced renal cell carcinoma (RCC) and attention so far, and a comprehensive review of the hepatocellular carcinoma (HCC), while showing prom- published data on this important topic has been lack- ising activity in other malignancies as well [11]. TKIs ing. We review here the available data and pharmaco- are extensively metabolised by cytochromes P450, logical mechanisms of interactions between commonly whose activity is characterised by a large degree of prescribed cardiovascular drugs and the TKIs mar- inter-individual variability [12]. Some of them are also keted at present. Regular updating of the literature on substrate or inhibitors of the drug transporters this topic will be mandatory, as will the prospective re- P-glycoprotein (Pgp = ABCB1), breast cancer resistance porting of unexpected clinical observations, given the protein (BCRP = ABCG2) and the organic cation car- fact that these drugs have been only recently mar- rier hOCT1 (SLC22A1). A given dose may therefore yield very different circulating concentration profiles Key words: tyrosine kinase inhibitor; drug interac- from one patient to another, thus favouring the selec- tions; targeted cancer therapy; cytochrome P-450 en- tion of resistant cellular clones in the event of sub-ther- zyme system; P-glycoprotein; gastrointestinal stromal apeutic drug exposure or the occurrence of undesirable tumour; chronic myeloid leukaemia, hepatocellular car- Identifying the most active and safest dosing schedule for individual patients to maximize thera- Introduction
peutic benefit has turned out to be a scientific and clin- Targeted cancer therapies have been designed to inter- act with particular proteins associated with tumour development or progression. Many of these agents are Division of Clinical Pharmacology – Laboratory Centre Hospitalier Universitaire Vaudois and University of Lausanne Cardiovascular Medicine 2010;13(5):147–154 147-154 Haouala 076.qxp:Layout 1 29.4.2010 8:53 Uhr Seite 148 ical challenge. Combination therapies have been in- (UpToDate online [20] and Cancer Care Ontario [21]) vestigated in various conditions, which certainly add a were screened, and abstracts of international and level of treatment complexity since overlapping toxici- national conferences, review articles and references ties and pharmacokinetic interactions must be care- given in identified articles were also scanned [22–24].
All relevant literature on pharmacokinetic or pharma- The small-molecule TKIs developed to date share a codynamic interactions was considered for inclusion in roughly similar safety profile and are generally better tolerated than traditional cytotoxic chemotherapies.
Drug interactions were either clinically docu- They are however administered over prolonged peri- mented or derived from considerations on proven or pu- ods, if not indefinitely, and are often taken by patients tative metabolic pathways, protein binding and trans- with comorbidities, notably cardiovascular disorders.
membrane transport of cardiovascular drugs and TKIs.
Thus, TKIs are likely to be administered simultane- When data on a particular combination were unavail- ously with other treatments, in particular cardiovas- able, potential interactions were predicted from the cular agents with a potential risk of harmful drug-drug reported disposition mechanisms of the agents.
Furthermore, there have been reports that TKIs Interaction between cardiovascular drugs
themselves may cause cardiotoxicity on their own [13– and tyrosine kinase inhibitors
15]. In some patients at least they cause symptomatic congestive heart failure or asymptomatic left ventricu- Table 1 (in 3 parts) summarises known or potential lar dysfunction [13, 15, 16]. TKIs do indeed to some ex- drug interactions between commonly prescribed car- tent inhibit normal variants of tyrosine kinases in non- diovascular drugs (lines) and the five major TKIs com- cancerous cells, which could explain such adverse mercially available at present (columns). Each cell effects. The actual importance of such toxicities re- indicates the type of interaction expected.
mains to be confirmed in additional studies.
Recently confronted with an increasing number of Interactions with imatinib
requests concerning drug interactions of TKIs with car- Imatinib is metabolised mainly by the cytochrome diovascular drugs, we have decided to review system- P450 (CYP) isoenzymes 3A4 and 3A5, while CYP1A2, atically the data available on pharmacological interac- CYP2D6, CYP2C9 and CYP2C19 play a minor role in tions between commonly prescribed cardiovascular its metabolism [25]. This TKI has also been shown to be agents and TKIs. Interactions between TKIs and a substrate of hOCT-1, Pgp and BCRP [19, 26–28].
cytochrome P450 inhibitors prescribed for a limited pe- However, a controversial report [29] suggests that ima- riod of time, such as antibiotics, antifungals [17], or in- tinib is an inhibitor rather than a substrate of BCRP.
ducers such as rifampicin [18], have been previously Hence interactions between imatinib and inhibitors of described and will not be the principal focus of the pres- BCRP [30] are not considered in this article. The ent review, which emphasises the potential interac- metabolites of imatinib are eliminated predominantly tions between TKIs and cardiovascular drugs taken through the bile, one metabolite (CGP 74588) showing indefinitely by patients presenting cardiovascular comparable pharmacological activity to the parent comorbidities. Table 1 has been devised as a tool to en- drug, but amounting to less than 20% of circulating able practitioners to improve safety in prescribing such imatinib concentration. The faecal to urinary excretion drug combinations. It does however not replace med- ratio is approximately 5:1 [25]. Interactions may occur ical evaluation and should be used in addition to thor- between imatinib and inhibitors or inducers of oughly weighed clinical judgment. Actually, most in- CYP3A4/5 and Pgp, leading to changes not only in the teractions do not represent true contraindications but plasma but also in the cell concentrations of imatinib.
rather call for appropriate dosage adjustment and For example, verapamil, a CYP3A4 and Pgp inhibitor [19], and carvedilol, a Pgp inhibitor, increase intracel- lular concentrations of imatinib by decreasing its me- Review of the literature
tabolism and inhibiting its efflux via Pgp, and hence may increase the cellular toxicity of imatinib.
Initial information was gathered from the official Swiss Moreover, this TKI may competitively inhibit the drug information source “Compendium Suisse des metabolism of drugs that are CYP3A4, CYP3A5, Médicaments 2009” [19]. In a second step, literature CYP2D6 and CYP2C9 substrates. Interactions of po- from Medline and evidence-based medicine reviews tential clinical relevance can thus occur with calcium was systematically searched using the following MeSH channel blockers such as verapamil and diltiazem, sub- terms: “drug interactions”, “cytochrome p450 enzyme strates of CYP3A4, whose circulating levels are in- system”, “p-glycoprotein”, “protein binding”, the re- creased when associated with imatinib [20, 21]. Inter- spective TKIs names and common cardiovascular actions with simvastatin, atorvastatin, amiodarone drugs. Additionally, two drug information databases and quinidine, involving the same P450 isoenzyme, Cardiovascular Medicine 2010;13(5):147–154 147-154 Haouala 076.qxp:Layout 1 29.4.2010 8:53 Uhr Seite 149 Table 1
Cardiovascular drugs interactions with tyrosine kinase inhibitors (first part).
The arrows 4 and 2 indicate an increase or decrease of drug concentration, respectively. Boldface text outlines interactions described clinically in the literature
(reference number), whereas standard characters represent potential interactions predicted from theoretical considerations (but not yet observed in the literature).
∅ means no interaction observed (reference number), and NE no interaction either reported or theoretically expected. The manufacturer mentions dasatinib as a substrate of Pgp,
confirmed by some [19, 20, 37], but not all recent experimental results [38]: interactions considered for this TKI and depending on Pgp are notified by *.
Finally, the warning sign
were added for interactions presumed to be of high clinical importance.
Pgp = drug transporter P-glycoprotein.
Imatinib
Dasatinib
Sunitinib
Sorafenib
Nilotinib
• Inhibition of CYP 2D6
• 2 of PR intervalb [21] NE
by imatinib:
2 metoprolol conc. [20]
• Inhibition of CYP 2D6
• 2 of PR intervalb [21] NE
by imatinib:
2 bisoprolol conc. [20]
• 2 of PR intervalb [21] • Inhibition of CYP 2C9 • Inhibition of Pgp
2 carvedilol conc. [19] 2 nilotinib conc.
• 2 of PR intervalb [21] NE
• Inhibition of CYP 2C9 • Inhibition of Pgp Cardiovascular Medicine 2010;13(5):147–154 147-154 Haouala 076.qxp:Layout 1 29.4.2010 8:53 Uhr Seite 150 Table 1
Cardiovascular drugs interactions with tyrosine kinase inhibitors (second part).
Imatinib
Dasatinib
Sunitinib
Sorafenib
Nilotinib
• Inhibition of CYP 3A4
• Inhibition of CYP 3A4
• Inhibition of
and Pgp by verapamil:
and BCRP by verapamil:
CYP 3A4 and BCRP
2 imatinib conc.
2 dasatinib conc. [20, 37]
by verapamil:
2 sunitinib conc.
• 2 of PR intervalb [21]
• Inhibition of CYP 3A4
• Inhibition of
by diltiazem:
CYP 3A4 by diltiazem:
2 dasatinib conc. [20]
2 sunitinib conc.
• Inhibition of CYP 3A4 • Inhibition of CYP 3A4
by imatinib:
• 2 of PR intervalb [21]
2 diltiazem conc. [20, 21] 2 diltiazem conc. [19, 20]
• Inhibition of CYP 3A4
• Inhibition of CYP 3A4
• 2 of PR intervalb [21] NE
by imatinib:
by dasatinib:
2 nifedipine conc.
2 nifedipine conc. [20]
• Inhibition of CYP 3A4
• Inhibition of CYP 3A4
• 2 of PR intervalb [21] NE
by imatinib:
by dasatinib:
2 amlodipine conc.
2 amlodipine conc. [20]
• Inhibition of CYP 3A4 • Inhibition of CYP 3A4 NE
• Inhibition of UGT 1A1 • Inhibition of Pgp by dasatinib:
by dasatinib:
2 simvastatin conc.
2 simvastatin conc. [19]
Inhibition of CYP 3A4 •
• Inhibition of UGT 1A1 • Inhibition of Pgp by imatinib:
2 atorvastatin conc.
Cardiovascular Medicine 2010;13(5):147–154 147-154 Haouala 076.qxp:Layout 1 29.4.2010 8:53 Uhr Seite 151 Table 1
Cardiovascular drugs interactions with tyrosine kinase inhibitors (third part).
Imatinib
Dasatinib
Sunitinib
Sorafenib
Nilotinib
• Thrombocytopenic
effect of dasatinib:
2 risk of bleeding [20]
• Thrombocytopenic
effect of dasatinib:
2 risk of bleeding [20]
• Inhibition of CYP 2C9
• Thrombocytopenic
• Inhibition of
• Inhibition of CYP 2C9
by imatinib:
effect of dasatinib:
CYP 2C9 by sorafenib: by sorafenib:
2 anticoagulation
2 risk of bleeding [20]
2 anticoagulation
2 anticoagulation
3 check PT/INR [19]
3 check PT/INR [19]
3 check PT/INR [19]
• Inhibition of
• Inhibition of CYP 2C9
CYP 2C9 by sorafenib: by sorafenib:
2 anticoagulation
2 anticoagulation
3 check PT/INR [19]
3 check PT/INR [19]
• Thrombocytopenic
effect of dasatinib:
2 risk of bleeding [20]
• Thrombocytopenic
effect of dasatinib:
2 risk of bleeding [20]
• 4 digoxin absorption
• 2 QT intervalb [21]
• 2 QT intervalb [21]
• 4 digoxin
• 4 digoxin
absorption [20]
absorption [20]
• 2 QT intervalb [21
a TKIs in general can cause thrombocytopenia, which is usually of no clinical relevance, please take that into consideration when coadministratingwith anticoagulant medication.
b Regular ECG controls are strongly recommended.
Cardiovascular Medicine 2010;13(5):147–154 147-154 Haouala 076.qxp:Layout 1 29.4.2010 8:53 Uhr Seite 152 may also be of clinical relevance [19–21, 31]. In pa- tinib dose be increased to 175% of the recommended tients taking imatinib these drugs should be avoided dose [40]. As shown in table 1, sunitinib was found to be whenever possible and replaced by safer alternatives one of the TKIs affecting the least the disposition of (e.g., pravastatin or sotalol) [20, 32].
cardiovascular drugs. An increase in PR interval can Finally, the interaction with quinidine, a known occur in association with beta-blockers and calcium inhibitor of hOCT-1, may paradoxically increase the channel blockers, and an increase in QT interval with circulating concentrations of imatinib but decrease the digoxine and amiodarone [21]. However, the only phar- exposure of target cancer cells known to express this macokinetic interactions found were with verapamil, carrier [19, 26]. With regard to all these mechanisms, diltiazem and amiodarone [20, 21, 40, 41].
it is worth noting that plasma concentrations of ima- tinib are correlated with efficacy and toxicity [33–36].
Interactions with sorafenib
A change in imatinib exposure due to a drug interac- Sorafenib is eliminated by a combination of CYP3A4– tion may therefore directly influence its therapeutic ef- mediated oxidative metabolism, phase II glucuronida- tion, and (possibly) biliary secretion, with glu- curonidated metabolites accounting for approximately Interactions with dasatinib
19% of an oral dose [42]. During co-administration with Dasatinib is metabolised to an active metabolite and ketoconazole, there was no increase in sorafenib expo- other inactive metabolites by the CYP3A4 isoenzyme, sure values, and no change in terminal elimination and was also reported to be a substrate of BCRP and half-life, compared to sorafenib alone [42]. The results Pgp [19, 20, 37], though this has recently been ques- suggest that sorafenib may be safely administered with tioned in pre-clinical models [38]. The active metabo- drugs known to inhibit CYP3A4/5–mediated metabo- lite does not appear to play a significant role in dasa- lism without dosage adjustment. However, sorafenib is tinib’s therapeutic activity. It has weak inhibitory ac- an inhibitor of UDP-glucurunosyl transferase (UGT) tivity against CYP3A4. Concomitant administration of 1A1, and 1A9, as well as CYP2C9, theoretically leading drugs that inhibit CYP3A4/5 and BCRP, such as vera- to an increase in plasma concentrations of CYP2C9 pamil, may lead to an increase in dasatinib exposure, substrates, such as torasemide, carvedilol, losartan, which raises the risk of cumulative cardiac toxicity.
acenocoumnarol and phenprocoumon [19]. Moreover, Conversely, concomitant administration of CYP3A4/5 aspirin, simvastatin and atorvastatin are substrates of inducers may lead to a reduction of as much as 80% in UGT1A1 and 1A9, and consequently their concentra- dasatinib exposure [38, 39]. In association with cardio- tion may increase when combined with sorafenib [19, vascular drugs, the same relevant interactions as with 43–45]. There are no data available describing clinical imatinib have been reported for dasatinib [19, 20], and concurrent use of the drugs concerned should also be Interactions with nilotinib
The risk of clinically relevant drug interactions with
Interactions with sunitinib
nilotinib is poorly documented. The drug undergoes In vitro studies have determined sunitinib metabolism metabolism by CYP3A4, and concomitant administra- to be mediated primarily by the CYP3A4 isozyme [40].
tion of strong inhibitors or inducers of CYP3A4/5 are Two N-deethylation steps are required to render suni- expected to increase or decrease nilotinib concentra- tinib inactive. An active metabolite is formed after the tions significantly. In healthy subjects receiving keto- first N-deethylation step mediated by CYP3A4. The ac- conazole, systemic exposure (AUC) to nilotinib was in- tive metabolite is further metabolised by CYP3A4, but creased approximately 3–fold [19]. This TKI is also a at a lower rate than in the first step, to form an inac- substrate of the efflux transporters Pgp and BCRP [19, tive metabolite (SU14335). An increase of about 50% in 28]. When administered with Pgp and BCRP in- total sunitinib exposure has been observed when suni- hibitors, increased concentrations of nilotinib are tinib was given concomitantly with ketoconazole, a po- tent CYP3A4/5 inhibitor [40]. To adjust for this At present, nilotinib is known to inhibit CYP2C9.
increase, it is recommended in patients receiving Acenocoumarol and phenprocoumon, substrates of strong CYP3A4/5 inhibitors that the sunitinib dose be CYP2C9, show increased concentrations, imposing reduced to 66% of the recommended dose [40]. Simi- careful monitoring of PT/INR [19]. A fact of note is that larly, healthy volunteers receiving rifampin, a strong nilotinib, also known to inhibit UGT1A1 [46], has been CYP3A4/5 inducer, had a 50% decrease in combined found to increase bilirubin levels, and the largest in- systemic exposure to sunitinib [40]. To adjust for this crease occurs in patients homozygous for the decrease, it is recommended in patients who require concomitant use of a CYP3A4/5 inducer that the suni- Cardiovascular Medicine 2010;13(5):147–154 147-154 Haouala 076.qxp:Layout 1 29.4.2010 8:53 Uhr Seite 153 Discussion
considered when physicians are looking for information on TKIs plasma drug exposure in their patients, when The treatment of cancer patients has shifted from tra- a drug interaction is suspected, or in the event of toxi- ditional, non-specific cytotoxic chemotherapy cycles to city, or lack of expected clinical response.
chronic treatment with molecular targeted therapies.
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