Arq Bras Cardiol Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia hK75cdBpqNwbSsYWmZXFKtD S0066-782X2014002300007 S0066-782X2014005040138 00007 10.5935/abc.20140138 Original Articles Prevention of Pazopanib-Induced Prolonged Cardiac Repolarization and Proarrhythmic Effects Akman Tulay 1 2 Erbas Oytun 3 Akman Levent 4 5 Yilmaz Ahmet U. 6 Tepecik Education and Research Hospital Department of Medical Oncology Tepecik Education and Research Hospital, Department of Medical Oncology Dokuz Eylul University Institute of Oncology Department of Basic Oncology Dokuz Eylul University, Institute of Oncology, Department of Basic Oncology Ege University Medical School Department of Physiology Ege University Medical School, Department of Physiology Ege University Medical School Department of Obstetrics and Gynecology Ege University Medical School, Department of Obstetrics and Gynecology Ege University Institute of Health Sciences Department of Stem Cell Ege University, Institute of Health Sciences, Department of Stem Cell Izmir University Medical Park Hospital Department of Medical Oncology Izmir University, Medical Park Hospital, Department of Medical Oncology Mailing Address: Tulay Akman, Gaziler Caddesi, No: 468. Yenisehir. Postal Code 35100. Izmir. Turkey. Email: tulaytuzel@gmail.com

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 12 09 2014 11 2014 103 5 403 409 27 04 2014 01 07 2014 04 07 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Background:

Pazopanib (PZP) may induce prolonged cardiac repolarization and proarrhythmic effects, similarly to other tyrosine kinase inhibitors.

 Objectives:

To demonstrate PZP-induced prolonged cardiac repolarization and proarrhythmic electrophysiological effects and to investigate possible preventive effects of metoprolol and diltiazem on ECG changes (prolonged QT) in an experimental rat model.

 Methods:

Twenty-four Sprague-Dawley adult male rats were randomly assigned to 4 groups (n = 6). The first group (normal group) received 4 mL of tap water and the other groups received 100 mg/kg of PZP (Votrient® tablet) perorally, via orogastric tubes. After 3 hours, the following solutions were intraperitoneally administered to the animals: physiological saline solution (SP), to the normal group and to the second group (control-PZP+SP group); 1 mg/kg metoprolol (Beloc, Ampule, AstraZeneca), to the third group (PZP+metoprolol group); and 1mg/kg diltiazem (Diltiazem, Mustafa Nevzat), to the fourth group (PZP+diltiazem group). One hour after, and under anesthesia, QTc was calculated by recording ECG on lead I.

 Results:

The mean QTc interval values were as follows: normal group, 99.93 ± 3.62 ms; control-PZP+SP group, 131.23 ± 12.21 ms; PZP+metoprolol group, 89.36 ± 3.61 ms; and PZP+diltiazem group, 88.86 ± 4.04 ms. Both PZP+metoprolol and PZP+diltiazem groups had significantly shorter QTc intervals compared to the control-PZP+SP group (p < 0.001).

 Conclusion:

Both metoprolol and diltiazem prevented PZP-induced QT interval prolongation. These drugs may provide a promising prophylactic strategy for the prolonged QTc interval associated with tyrosine kinase inhibitor use.

 Arrhythmias, Cardiac / therapy Pyrimidines / adverse effects Heart Conduction System / physiology Heart / physiology Introduction

Multi-targeted tyrosine kinase inhibitors (TKI) have become important for the treatment of several malignancies in the past few years1. Sorafenib is a Raf kinase inhibitor that inhibits vascular endothelial growth factor receptors 1, 2 and 3 (VEGFr-1, -2, and -3, respectively), platelet-derived growth factor receptor b (PDGFr-b), Fms-like tyrosine kinase-3 (Flt-3), and c-kit. Sunitinib inhibits VEGFr-1, -2, and -3, PDGFr-a and -b, c-kit, Flt-3, colony-stimulating factor type 1, and glial cell line-derived neurotrophic factor (GDNF) receptor (RET)2. Pazopanib is a potent multi-targeted TKI targeting VEGFr, PDGFr, and c-kit2,3. There are lots of ongoing trials with pazopanib in different types of tumors. Pazopanib has shown monotherapy activity in advanced renal cell cancer (RCC) patients and is approved for the treatment of advanced RCC patients4.

While exploring the therapeutic index of TKIs, oncology investigators are confronted with drug adverse effects such as cardiac toxicities5. QT prolongation has drawn attention because of the risk of serious cardiac arrhythmias, such as torsade de pointes, and may be associated with ventricular arrhythmia and sudden cardiac death6.

In several studies, QTc prolongation has been observed with TKIs such as sunitinib7,8, vandetanib7,9,10, dasatinib7, crizotinib11. However there are limited data about QTc prolongation with pazopanib treatment. Metoprolol is a class 2 antiarrhythmic agent according to the Vaughan-Williams classification and a member of the group of drugs called beta-blockers12. Diltiazem is a class 4 antiarrhythmic agent and a member of the non-dihydropyridine group of drugs known as calcium channel blockers12. This study was aimed to demonstrate that pazopanib induced prolonged cardiac repolarization and to investigate the possible corrective effects of metoprolol and diltiazem on electrocardiographic changes in an experimental model.

 Methods

After receiving the Animal Ethics Committee's consent, the experiments performed in this study have been carried out according to the rules in the Guide for the Care and Use of Laboratory Animals adopted by National Institutes of Health (USA). Animals were fed ad libitum and housed in pairs in steel cages, in a temperature-controlled environment (22 ± 2 ºC) with 12-h light/dark cycles. The experimental procedures were approved by the Ege University Committee for Animal Research. All animal studies strictly conformed to the animal experiment guidelines of the Committee for Humane Care.

Electrocardiograms (ECG) were recorded on male rats under anesthesia in the prone position. Electrodes consisted of 26-gauge needles placed subcutaneously for 1 cm. Standard limb leads were constructed from electrodes placed at the paws. Rats were anesthetized with a combination of 40 mg/kg of ketamine hydrochloride (Alfamine®, Ege Vet, Alfasan International B.V., Holland) and 4 mg/kg of xylazine hydrochloride (Alfazyne®, Ege Vet, Alfasan International B.V., Holland), intraperitoneally administered. Under anesthesia, ECG was taken in lead I (DI) (Biopac MP 150). Data were evaluated using Biopac Student Lab Pro software, version 3.6.7 (BIOPAC Systems, Inc.), and the parameters were as follows: QT interval, T-wave duration, and heart rate. For the calculation of QTc, Fridericia formula was used.

The rats were randomly assigned to four groups (n = 6). Table 1 shows detailed information about the groups. The first group (normal group) received 4 mL of tap water, while the other groups received 100 mg/kg of pazopanib, perorally, via orogastric tubes. Tablets containing 200 mg of pazopanib (Votrient®, GlaxoSmithKline) were crushed and suspended in tap water to yield a concentration of 10 mg/mL. According to the weight of each rat, suspended drug solution was completed to 4 mL with tap water. Three hours after the oral administration of pazopanib, the animals received intraperitoneally: physiological saline solution (SP), to the normal group and to the second group (control-PZP+SP group); 1 mg/kg of metoprolol (Beloc, Ampule, AstraZeneca), to the third group (PZP+metoprolol group); and 1 mg/kg of diltiazem (Diltiazem, Mustafa Nevzat), to the fourth group (PZP+diltiazem group). One hour after administering those drugs, and under anesthesia, the QTc interval was calculated by recording ECG on lead I. The observer (O.E.) who measured the QT intervals was blind to laboratory data. The QT interval was determined from the onset of the QRS complex to the end of the T wave. Six consecutive beats were evaluated, and the arithmetic means of RR and QT were obtained.

Detailed description of the groups
Groups Beginning of the study (orogastric tube) 3 hour later (intraperitoneal) 1 hour later
Group 1 (normal group) (n=6) Tap water SP ECG records are taken
Group 2 (control-PZP+SP group) (n=6) PZP SP
Group 3 (PZP+metoprolol) (n=6) PZP Metoprolol
Group (PZP+diltiazem) (n=6) PZP Diltiazem

PZP: pazopanib; SP: physiological saline solution.

 Statistical analysis

Results were given as mean ± standard error of the mean (SEM). Shapiro-Wilk test was used for checking normal distributions. All variables had normal distribution. One-Factor Analysis of Variance (ANOVA) was used to assess the groups with normally distributed continuous variables. Bonferroni adjustment for multiple comparisons was performed. Data analyses were performed using the SPSS software, version 15.0, for Windows (Chicago, IL, USA).

A p value < 0.05 was accepted as statistically significant, and a p value < 0.001, as highly statistically significant.

 Results

Figure 1 shows the ECGs of all groups, and Table 2 summarizes the QTc intervals of all groups.

a) ECG of normal group rats receiving only saline solution without pazopanib (PZP); b, c, d) ECG changes in rats receiving saline solution, metoprolol and diltiazem after 3 hours of PZP administration; b) QT prolongation in control group rats receiving only saline solution after PZP administration; c) QT-interval shortage in the PZP+metoprolol group; and d) QT-interval shortage in the PZP+diltiazem group. QT intervals are shown in the black areas. The values of QTc intervals of all groups
Groups QTc (ms) Heart rate (beats per minute) T duration (ms) QT duration (ms)
Normal 99.93 ± 3.62 266 ± 21.69 28.33 ± 1.21 60.83 ± 0.98
Control-PZP+SP 131.23 ± 12.21** 231.33 ± 67.95 47 ± 4.09** 85 ± 9.33**
PZP+metoprolol 89.36 ± 3.61†† 164.67 ± 27.04† 29.33 ± 2.73†† 64 ± 0.89††
PZP+diltiazem 88.86 ± 4.04†† 176.67 ± 9.30† 29.67 ± 1.36†† 62 ± 1.78††

PZP: pazopanib; SP: physiological saline solution.

p < 0.001 control group compared with normal group

p < 0.05 diltiazem or metoprolol group compared with control group

p < 0.001 diltiazem or metoprolol group compared with control group

The QTc interval was significantly longer in the control-PZP+SP group then in the normal group (131.23 ± 12.21 ms vs 99.93 ± 3.62 ms, respectively) (p < 0.001).

Both metoprolol and diltiazem treatments significantly shortened the QTc intervals when compared with that of the control-PZP+SP group (89.36 ± 3.61 ms, 88.86 ± 4.04 vs 131.23 ± 12.21 ms, respectively) (p < 0.001).

 Discussion

Several molecular-targeted therapy drugs, such as multi-targeted TKIs, histone deacetylase inhibitors, vascular-disrupting agents, farnesyl protein transferase (FTPase) inhibitors, protein kinase C inhibitors, and Src/Abl kinase inhibitors, have been found to have an effect on the QT interval13.

Long QT syndrome (LQTS) is either an inherited (congenital) or acquired disorder of the electrical system of the heart. Congenital LQTS usually results from disorders in the cardiac membrane sodium or potassium ion channels14. The clinical course of patients with LQTS is variable, owing to incomplete penetrance of QT elongation, which may or may not cause arrhythmias. Patients with LQTS may be classified into three main categories of risk for developing life-threatening cardiac events, such as torsade de pointes and cardiac arrest, as follows: very high risk, high risk, and low risk. Patients at low risk may have just QT prolongation, the risk of life-threatening cardiac events being 0,5%15. The major electrolyte imbalances associated with prolonged QT interval are hypocalcemia, hypophosphatemia, hypokalemia, and hypomagnesemia16. Usually the pharmacologic agents that cause significant QT prolongation have potassium channel blocking effects predominantly affecting the delayed rectifier repolarizing current, IK (which is the sum of two kinetically and pharmacologically distinct types of IK current components: a rapid, IKr, and a slow, IKs, component), which has a major role in the electrical activity of cardiac ventricular myocytes. IKr plays a major role in the termination of the plateau phase of the action potential and in driving cell membrane repolarization17,18. Dysfunction of these channels is determined in certain forms of inherited and acquired LQTS19.

In vitro studies have suggested that most QT-prolonging drugs block the IKr component that is encoded by hERG (human ether-a-go-go-related gene) in humans. Although functional IKr current has been found in many species, such as dogs, guinea pigs, and rabbits, there is very little (if any) functional IKr or hERG-like current in the rat ventricle20. Studies with macrolide antibiotics in rats have shown good agreement between QT-interval prolongation assessments based on rat ECG data and the clinical findings of human beings; however, those results should be carefully assessed and the existence of differences between rats and humans should be kept in mind21.

Cancer patients may be particularly prone to QT prolongation, because many of them (16% to 36%) have baseline ECG abnormalities and use concomitant drugs, such as antiemetics, antifungals or antibiotics, that can enlarge the QT interval7,9. In addition, cancer patients often have symptoms such as nausea, vomiting, diarrhea, and decreased oral intake, which may lead to electrolyte disturbances, placing the patient at risk for QT prolongation7,22.

TKIs have played an important role in the treatment of several malignancies in the past few years and provided a significant improvement in patients' outcome1. The use of small molecule vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) has shown to increase the risk and the incidence of fatal adverse events (FAEs) in patients being treated for cancer. Compared with 0.7% for controls, the incidence of FAEs associated with the use of VEGFr-TKI was 1.5%. Cardiotoxicity is the second most common cause of FAEs1. The use of TKIs in the past decade has revealed a new spectrum of pro-arrhythmogenic adverse effects, QT-interval prolongation being one the most important ones7,9. QT-interval prolongation has been observed in several trials with the use of molecular-targeted agents, and QT-interval prolongation has drawn attention because of its risk of malignant cardiac arrhythmia and sudden cardiac death23.

QT-interval prolongation has been associated with several multi-targeted TKIs, such as sunitinib, vandetanib, and nilotinib7,9,10,24. In clinical studies, 2% (11/558) of patients receiving pazopanib have experienced QT-interval prolongation. Torsade de pointes has been reported in less than 1% (2/977) of those receiving pazopanib in monotherapy studies. In a randomized clinical trial, 3 of 290 patients receiving pazopanib have had post-baseline QTc-interval values between 500 and 549 ms. None of the patients receiving placebo have had post-baseline QTc-interval values greater than or equal to 500 msec25. Despite these findings French et al26 have conducted a series of detailed experiments examining the potential cardiotoxicity of sunitinib, sorafenib and pazopanib in rodents under dobutamine challenge, and have found no biochemical, mitochondrial, heart rate, ECG or echocardiographic changes in radial and circumferential strain with 12-hour monitoring. However, in a recent clinical study evaluating the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors, supratherapeutic concentrations were achieved with pazopanib administration over 8 days, which produced a concentration-dependent decrease in heart rate and a concentration-independent prolongation of the QTc interval27.

Medical therapy with beta-blockers is considered to be first-line prophylactic therapy in LQTS. According to current guidelines, there is a class I indication for beta-blockers treatment among patients with a clinical diagnosis of LQTS28,29. Different beta-blockers have similar effectiveness in preventing cardiac events in patients with LQTS30. In a different study, the authors have shown that pretreatment with diltiazem and propranolol reduce the epinephrine-induced QTc-interval prolongation31. In an animal study, the authors have put forward the beneficial effects of calcium-channel blockers in cardiac failure and LQTS30. Furthermore, proarrhythmia and QT-interval prolongation have been predominantly demonstrated with class Ia, class Ic, and class III antiarrhythmic agents32,33. Due to the above-mentioned reasons, we selected metoprolol and diltiazem in our study34.

In the present study, we evaluated pazopanib-induced QT-interval prolongation in an experimental rat model. First, we demonstrated QTc-interval prolongation in rats treated with pazopanib alone. Three hours following drug administration, the control-group rats, which had been given pazopanib and saline solution injection intraperitoneally, showed QTc-interval elongation, thus supporting the previous studies that had shown the association of TKIs and ECG abnormalities7,9. Secondly, this study showed that the QT-prolonging effect of pazopanib can be reverted by some drugs. The PZP+metoprolol and PZP+diltiazem groups did not show QTc-interval elongation compared to the control-PZP+SP group. On the other hand, QTc intervals of both groups were significantly shorter than that of the control group, while similar results were obtained in the PZP+metoprolol and PZP+diltiazem groups. Based on the study results, both metoprolol and diltiazem were considered effective in preventing the QT-prolonging effect of pazopanib.

Treatment with QT-prolonging TKIs is frequently necessary for cancer patients. The therapy risks must be weighed against benefits. Treatment must start with withdrawal of the precipitating medication. Underlying risk factors should be assessed, administration of the possible precipitating drug must be ceased and reversible conditions, such as metabolic abnormalities, must be corrected before drug initiation34. Concurrent use of multiple QT-prolonging drugs should be avoided. Patients should be advised about the proarrhythmic risk. Periodic monitoring with ECG and close follow-up are essential for early detection and treatment in high risk patients with a history of QT-interval prolongation, patients taking antiarrhythmics, or individuals with relevant preexisting disease, such as bradycardia and electrolyte imbalances35.

Our study shows some limitations. First, this is an experimental study on rats. The question of whether or not these experimental results are also relevant to humans in the clinical setting and have therapeutic implications needs to be further investigated. Second, in our study, no ventricular stability test was performed. Because of this limitation, the potential prophylactic effects of the drugs against proarrhythmia cannot be evaluated according to our results. Therefore, different studies with specific models of ventricular stability are needed for the recommendation of these drugs for prophylactic use.

A better knowledge about potential cardiac side effects of pazopanib and the identification of patients at higher risk are required to reduce cardiotoxicity with that agent. In the present study, the preventing effects of metoprolol and diltiazem on pazopanib-induced QT-interval prolongation were evaluated.

In conclusion, both metoprolol and diltiazem significantly shortened pazopanib-induced QT-interval prolongation. Although metoprolol and diltiazem prevented QT-interval prolongation, long-term studies including ventricular stability test in different models can provide evidence for the prophylactic use of those drugs in high risk patients treated with pazopanib.

Author contributions

Conception and design of the research and Obtaining financing: Akman T, Erbas O, Akman L, Yilmaz AU; Acquisition of data, Analysis and interpretation of the data and Statistical analysis: Akman T, Erbas O, Akman L; Writing of the manuscript and Critical revision of the manuscript for intellectual content: Akman T, Yilmaz AU.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any thesis or dissertation work.

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Barsheshet A Dotsenko O Goldenberg I Genotype-specific risk stratification and management of patients with long QT syndrome Ann Noninvasive Electrocardiol 2013 18 6 499 509 Schwartz PJ. Pharmacological and non-pharmacological management of the congenital long QT syndrome: the rationale. Pharmacol Ther. 2011;131(1):171-7. Schwartz PJ Pharmacological and non-pharmacological management of the congenital long QT syndrome: the rationale Pharmacol Ther 2011 131 1 171 177 Darbar D, Smith M, Mörike K, Roden DM. Epinephrine-induced changes in serum potassium and cardiac repolarization and effects of pretreatment with propranolol and diltiazem. Am J Cardiol. 1996;77(15):1351-5. Darbar D Smith M Mörike K Roden DM Epinephrine-induced changes in serum potassium and cardiac repolarization and effects of pretreatment with propranolol and diltiazem Am J Cardiol 1996 77 15 1351 1355 Redfern WS, Carlsson L, Davis AS, Lynch WG, Mackenzie I, Redfern WS, et al. Relationships between preclinical cardiac electrophysiology, clinical QT-interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res. 2003;58(1):32-45. Redfern WS Carlsson L Davis AS Lynch WG Mackenzie I Redfern WS et al Relationships between preclinical cardiac electrophysiology, clinical QT-interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development Cardiovasc Res 2003 58 1 32 45 Stanton MS, Prystowsky EN, Fineberg NS, Miles WM, Zipes DP, Heger JJ. Arrhythmogenic effects of antiarrhythmic drugs: a study of 506 patients treated for ventricular tachycardia or fibrillation. J Am Coll Cardiol. 1989;14(1):209-15. Stanton MS Prystowsky EN Fineberg NS Miles WM Zipes DP Heger JJ Arrhythmogenic effects of antiarrhythmic drugs: a study of 506 patients treated for ventricular tachycardia or fibrillation J Am Coll Cardiol 1989 14 1 209 215 Shantsila E, Watson T, Lip GY. Drug-induced QT-interval prolongation and proarrhythmic risk in the treatment of atrial arrhythmias. Europace. 2007;9 Suppl 4:iv37-44. Shantsila E Watson T Lip GY Drug-induced QT-interval prolongation and proarrhythmic risk in the treatment of atrial arrhythmias Europace 2007 9 Suppl 4 iv37 iv44 Brana I, Tabernero J. Cardiotoxicity. Ann Oncol. 2010;21 Suppl 7:vii173-9. Brana I Tabernero J Cardiotoxicity Ann Oncol 2010 21 7 vii173 vii179 Prevenção da Repolarização Cardíaca Prolongada e dos Efeitos Pró-arrítmicos Induzidos por Pazopanibe Akman Tulay 1 2 Erbas Oytun 3 Akman Levent 4 5 Yilmaz Ahmet U. 6 Tepecik Education and Research Hospital Department of Medical Oncology Tepecik Education and Research Hospital, Department of Medical Oncology Dokuz Eylul University Institute of Oncology Department of Basic Oncology Dokuz Eylul University, Institute of Oncology, Department of Basic Oncology Ege University Medical School Department of Physiology Ege University Medical School, Department of Physiology Ege University Medical School Department of Obstetrics and Gynecology Ege University Medical School, Department of Obstetrics and Gynecology Ege University Institute of Health Sciences Department of Stem Cell Ege University, Institute of Health Sciences, Department of Stem Cell Izmir University Medical Park Hospital Department of Medical Oncology Izmir University, Medical Park Hospital, Department of Medical Oncology Correspondência: Tulay Akman, Gaziler Caddesi, No: 468. Yenisehir. Postal Code 35100. Izmir. Turkey. Email: tulaytuzel@gmail.com Fundamento:

Pazopanibe (PZP) pode induzir prolongamento da repolarização cardíaca e efeitos pró-arrítmicos, à semelhança de outros inibidores da tirosina quinase. Objetivos: Demonstrar prolongamento da repolarização cardíaca e efeitos eletrofisiológicos pró-arrítmicos induzidos pelo PZP, assim como investigar possíveis efeitos de metoprolol e diltiazem na prevenção de alterações no ECG (prolongamento do intervalo QT) em um modelo experimental em ratos.

 Métodos:

Ratos Sprague-Dawley adultos machos (24) foram designados de modo aleatório para quatro grupos (n = 6). O primeiro grupo (normal) recebeu 4 ml de água da torneira, enquanto os demais receberam 100 mg/kg de PZP (comprimido de Votrient®) através de sonda orogástrica. Após 3 horas, os animais receberam por via intraperitoneal: solução salina, para o grupo normal e para o segundo grupo (controle-PZP+SP); 1 mg/kg de metoprolol (Beloc, Ampola, AstraZeneca), para o terceiro grupo (PZP+metoprolol); e 1mg/kg de diltiazem (Diltiazem, Mustafa Nevzat), para o quarto grupo (PZP+diltiazem). Uma hora após a administração desses medicamentos, e sob anestesia, calculou-se o intervalo QTc registrando-se o ECG em DI.

 Resultados:

Os valores médios do intervalo QTc foram: grupo normal, 99,93 ± 3,62 ms; grupo controle-PZP+SP, 131,23 ± 12,21 ms; grupo PZP+metoprolol, 89,36 ± 3,61 ms; e grupo PZP+diltiazem, 88,86 ± 4,04 ms. Os grupos PZP+metoprolol e PZP+diltiazem apresentaram intervalos QTc significativamente mais curtos comparados aos do grupo controle-PZP+SP (p < 0,001).

 Conclusão:

Ambos metoprolol e diltiazem evitaram o prolongamento do intervalo QT induzido por PZP. Tais medicamentos podem ser uma promissora estratégia para evitar o prolongamento do intervalo QTc associado ao uso de inibidores da tirosina quinase.

 Arritmias Cardíacas / terapia Pirimidinas / efeitos adversos Sistema de Condução Cardíaco / fisiologia Coração / fisiologia Introdução

Os inibidores da tirosina quinase (TKIs) dirigidos a múltiplos alvos tornaram-se importantes para o tratamento de várias malignidades nos últimos anos1. Sorafenibe é um inibidor da Raf quinase que inibe os receptores do fator de crescimento endotelial vascular 1, 2 e 3 (VEGFr-1, -2 e -3, respectivamente), o receptor do fator de crescimento derivado de plaqueta (PDGFr-b), a tirosina quinase-3 semelhante a Fms (Flt-3) e c-kit. Sunitinibe inibe VEGFr-1, -2 e -3, PDGFr-a e -b, c-kit, Flt-3, fator estimulante de colônia de granulócitos tipo 1, e receptor do fator neurotrófico derivado da glia (RET)2. Pazopanibe é um potente TKI dirigido a múltiplos alvos, tais como VEGFr, PDGFr e c-kit2,3. Há muitos estudos em andamento com pazopanibe em diferentes tipos de tumores. Pazopanibe mostrou-se ativo em monoterapia para pacientes com câncer avançado de células renais, para cujo tratamento foi aprovado4.

Ao explorarem o índice terapêutico dos TKIs, os pesquisadores de oncologia confrontam-se com efeitos adversos dos medicamentos, como a toxicidade cardíaca5. O prolongamento do intervalo QT tem chamado atenção devido ao risco de graves arritmias cardíacas, como torsade de pointes, podendo associar-se com arritmia ventricular e morte súbita cardíaca6.

Vários estudos relataram prolongamento do intervalo QTc com o uso de TKIs, tais como sunitinibe7,8, vandetanibe7,9,10, dasatinibe7 e crizotinibe11. No entanto, dados sobre a ocorrência de prolongamento do intervalo QTc com o tratamento com pazopanibe são limitados. Metoprolol é um agente antiarrítmico classe 2 segundo a classificação de Vaughan-Williams e membro do grupo dos betabloquedores12. Diltiazem é um agente antiarrítmico classe 4, pertencente ao grupo dos medicamentos não diidropiridina, conhecidos como bloqueadores dos canais de cálcio12. Este estudo teve por objetivo demonstrar que pazopanibe induz prolongada repolarização cardíaca, assim como investigar os possíveis efeitos corretivos do metoprolol e diltiazem nas alterações eletrocardiográficas em um modelo experimental.

 Métodos

Após a aprovação pelo Comitê de Ética em Pesquisa em Animais, os experimentos foram realizados segundo as regras do Guia de Cuidados e Uso de Animais de Laboratório adotado pelo National Institutes of Health Norte-Americano. Os animais receberam dieta sem restrições e foram alojados aos pares em gaiolas de aço, em ambiente com temperatura controlada (22 ± 2 ºC) e ciclos de claro/escuro de 12 horas. Os procedimentos experimentais foram aprovados pelo Comitê de Pesquisa Animal da Universidade de Ege. Todos os estudos animais atenderam rigorosamente às diretrizes de experimento animal do Comitê para Cuidados Humanizados.

Os eletrocardiogramas (ECG) foram registrados em ratos machos anestesiados na posição de pronação. Os eletrodos consistiram em agulhas de calibre 26 colocadas por 1 cm no subcutâneo. As derivações padrão nos membros foram construídas a partir de eletrodos colocados nas patas. Os ratos foram anestesiados com uma combinação de 40 mg/kg de cloridrato de quetamina (Alfamine®, Ege Vet, Alfasan International B.V., Holanda) e 4 mg/kg de cloridrato de xilazina (Alfazyne®, Ege Vet, Alfasan International B.V., Holanda), administrados por via intraperitoneal. O ECG foi registrado sob anestesia na derivação DI (Biopac MP 150). Os seguintes parâmetros foram avaliados usando-se o programa Biopac Student Lab Pro, versão 3.6.7 (BIOPAC Systems, Inc.): intervalo QT, duração da onda T e frequência cardíaca. Utilizou-se a fórmula de Fridericia para calcular o intervalo QTc.

Os ratos foram designados de modo aleatório para quatro grupos (n = 6), que são detalhados na Tabela 1. O primeiro grupo (grupo normal) recebeu 4 ml de água potável, enquanto os demais receberam 100 mg/kg de pazopanibe através de sonda orogástrica. Comprimidos contendo 200 mg de pazopanibe (Votrient®, GlaxoSmithKline) foram esmagados e suspensos em água potável até a concentração de 10 mg/ml. De acordo com o peso de cada rato, a solução do medicamento em suspensão foi complementada até 4 ml com água potável e administrada através de sonda orogástrica. Três horas após a administração oral de pazopanibe, os animais receberam por via intraperitoneal: solução salina (SP), para o grupo normal e para o segundo grupo (grupo controle-PZP+SP); 1 mg/kg de metoprolol (Beloc, Ampola, AstraZeneca), para o terceiro grupo (grupo PZP+metoprolol); e 1mg/kg de diltiazem (Diltiazem, Mustafa Nevzat), para o quarto grupo (grupo PZP+diltiazem). Uma hora após a administração desses medicamentos, e sob anestesia, calculou-se o intervalo QTc registrando-se o ECG em DI. Um observador (O.E.), cego para os dados de laboratório, mediu os intervalos QT do início do complexo QRS até o final da onda T. Seis batimentos consecutivos foram avaliados, e as médias aritméticas dos intervalos RR e QT foram obtidas.

Descrição detalhada dos grupos
Grupos Início do estudo (sonda orogástrica) 3 horas depois (intraperitoneal) 1 hora depois
Grupo 1 (normal) (n=6) Água potável SP ECG são registrados
Grupo 2 (controle-PZP+SP) (n=6) PZP SP
Grupo 3 (PZP+metoprolol) (n=6) PZP Metoprolol
Grupo (PZP+diltiazem) (n=6) PZP Diltiazem

PZP: pazopanibe; SP: solução salina.

 Análise estatística

Os resultados foram apresentados como média ± erro padrão da média (EPM). Utilizou-se o teste de Shapiro-Wilk para testar as distribuições normais. Todas as variáveis apresentaram distribuição normal. Usou-se Análise de Variância de um fator (ANOVA) para avaliar os grupos com variáveis contínuas de distribuição normal. O teste de Bonferroni para múltiplas comparações foi realizado. A análise dos dados foi realizada com o programa SPSS, versão 15.0, para Windows (Chicago, IL, EUA).

Adotou-se o valor de p < 0,05 como estatisticamente significativo, e o valor de p < 0,001 como altamente significativo.

 Resultados

A Figura 1 mostra os ECGs de todos os grupos, e a Tabela 2 resume os intervalos QTc de todos os grupos.

a) ECG do grupo normal de ratos que receberam apenas solução salina sem pazopanibe (PZP); b,c,d) Alterações do ECG em ratos que receberam solução salina, metoprolol e diltiazem 3 horas após a administração de PZP; b) Prolongamento do intervalo QT no grupo controle de ratos que receberam apenas solução salina após a administração de PZP; c) Encurtamento do intervalo QT no grupo PZP+metoprolol; d) Encurtamento do intervalo QT no grupo PZP+diltiazem. Os intervalos QT são mostrados nas áreas negras. Valores dos intervalos QTc em todos os grupos
Grupos QTc (ms) Frequência cardíaca (bpm) Duração da onda T (ms) Duração do QT (ms)
Grupo normal 99,93 ± 3,62 266 ± 21,69 28,33 ± 1,21 60,83 ± 0,98
PZP+SP (controle) 131,23 ± 12,21** 231,33 ± 67,95 47 ± 4,09** 85 ± 9,33**
PZP+metoprolol 89,36 ± 3,61†† 164,67 ± 27,04† 29,33 ± 2,73†† 64 ± 0,89††
PZP+diltiazem 88,86 ± 4,04†† 176,67 ± 9,30† 29,67 ± 1,36†† 62 ± 1,78††

PZP: pazopanibe; SP: solução salina; bpm: batimentos por minuto.

p < 0,001 grupo controle comparado ao grupo normal

p < 0,05 grupo diltiazem ou metoprolol comparado ao grupo controle

p < 0,001 grupo diltiazem ou metoprolol comparado ao grupo controle.

O intervalo QTc foi significativamente mais longo no grupo controle-PZP+SP do que no grupo normal (131,23 ± 12,21 ms vs 99,93 ± 3,62 ms, respectivamente) (p < 0,001).

Tanto o tratamento com metoprolol quanto o tratamento com diltiazem encurtaram significativamente os intervalos QTc em comparação aos do grupo controle-PZP+SP (89,36 ± 3,61 ms, 88,86 ± 4,04 vs 131,23 ± 12,21 ms, respectivamente) (p < 0,001).

 Discussão

Vários medicamentos da classe 'terapia molecular alvo-dirigida', tais como os TKIs dirigidos a múltiplos alvos, inibidores da histona desacetilase, agentes dirigidos a alvos vasculares, inibidores da proteína farnesil transferase (FTPase), inibidores da proteína quinase C, e inibidores da quinase Src/Abl, mostraram ter um efeito no intervalo QT13.

A síndrome do QT longo (SQTL) é um distúrbio do sistema elétrico do coração que pode ser hereditário (congênito) ou adquirido. A SQTL congênita em geral resulta de distúrbios nos canais iônicos de sódio ou potássio da membrana cardíaca14. A evolução clínica dos pacientes com SQTL varia, devido à incompleta penetrância do prolongamento do intervalo QT, que pode ou não causar arritmias. Quanto ao risco de desenvolvimento de eventos cardíacos que ameaçam a vida, tais como torsade de pointes e parada cardíaca, os pacientes com SQTL podem ser classificados nas seguintes três categorias principais: risco muito alto, risco alto e risco baixo. Aqueles com baixo risco podem apresentar apenas prolongamento do intervalo QT, sendo o risco de eventos cardíacos que ameaçam a vida de 0,5%15. Os principais desequilíbrios eletrolíticos associados com intervalo QT longo são hipocalcemia, hipofosfatemia, hipocalemia e hipomagnesemia16. Em geral, os agentes farmacológicos que causam significativo prolongamento do intervalo QT apresentam efeitos bloqueadores dos canais de potássio que afetam predominantemente a corrente repolarizante retificadora tardia, IK (que é a soma de dois componentes distintos cinética- e farmacologicamente: um rápido, IKr, e outro lento, IKs), que desempenha importante papel na atividade elétrica dos miócitos ventriculares cardíacos. O componente IKr tem papel principal na finalização da fase de platô do potencial de ação e na orientação da repolarização da membrana celular17,18. Ocorre disfunção desses canais em determinadas formas de SQTL hereditárias e adquiridas19.

Estudos in vitro sugeriram que a maioria dos medicamentos que prolongam o intervalo QT bloqueia o componente IKr que é codificado pelo hERG (gene humano relacionado com o éter-a-go-go) em seres humanos. Embora a corrente funcional IKr tenha sido identificada em várias espécies animais, como cães, cobaias e coelhos, existe muito pouca, se é que há alguma, corrente funcional IKr ou do tipo hERG no ventrículo do rato20. Estudos com antibióticos macrolídeos em ratos mostraram boa concordância entre as avaliações de prolongamento do intervalo QT com base em dados de ECG em ratos e os achados clínicos em seres humanos; no entanto, tais resultados devem ser cuidadosamente avaliados, considerando-se a existência de diferenças entre ratos e seres humanos21.

Pacientes com câncer podem ser particularmente suscetíveis ao prolongamento do intervalo QT, pois muitos deles (16% a 36%) apresentam alterações no ECG basal e usam medicamentos concomitantes, tais como antieméticos, antimicóticos ou antibióticos, que podem prolongar o intervalo QT7,9. Além disso, pacientes com câncer frequentemente apresentam sintomas, tais como náusea, vômito, diarreia e redução da ingestão oral, que podem levar a distúrbios eletrolíticos, que representam risco de prolongamento do intervalo QT7,22.

Os TKIs tiveram importante papel no tratamento de várias malignidades nos últimos anos, trazendo uma significativa melhora na evolução dos pacientes1. O uso de pequenas moléculas de inibidores da tirosina quinase-receptores do fator de crescimento vascular endotelial (VEGFr-TKIs) mostrou aumento do risco e da incidência de eventos adversos fatais (EAFs) em pacientes tratados para câncer. Comparada a 0,7% para os controles, a incidência de EAFs associada ao uso de VEGFr-TKIs foi de 1,5%. Toxicidade cardíaca é a segunda causa mais comum de EAFs1. O uso de TKIs na última década revelou um novo espectro de efeitos adversos pró-arritmogênicos, sendo o prolongamento do intervalo QT um dos mais importantes7,9. O prolongamento do intervalo QT foi relatado em vários estudos utilizando terapia molecular alvo-dirigida, tendo o prolongamento do intervalo QT chamado atenção devido ao risco de arritmia cardíaca maligna e morte súbita cardíaca23.

Prolongamento do intervalo QT foi associado com vários TKIs dirigidos a múltiplos alvos, tais como sunitinibe, vandetanibe e nilotinibe7,9,10,24. Alguns estudos clínicos relatam que 2% (11/558) dos pacientes que receberam pazopanibe apresentaram prolongamento do intervalo QT. Torsade de pointes foi relatada em menos de 1% (2/977) daqueles recebendo pazopanibe em estudos com monoterapia. Em um ensaio clínico randomizado, 3 de 290 pacientes em uso de pazopanibe apresentaram valores pós-basais de QTc entre 500 e 549 ms. Nenhum dos pacientes recebendo placebo apresentou valores pós-basais de QTc maiores do que ou iguais a 500 msec25. A despeito desses achados, French e cols.26 conduziram uma série de experimentos detalhados examinando a potencial cardiotoxicidade de sunitinibe, sorafenibe e pazopanibe em roedores sob efeito de estresse com dobutamina, e não encontraram qualquer alteração em bioquímica, mitocôndrias, frequência cardíaca, ECG ou ecocardiografia com strain radial e circunferencial em monitoramento de 12 horas. Entretanto, em um recente estudo clínico avaliando o efeito de doses orais repetidas de pazopanibe na condução cardíaca de pacientes com tumores sólidos, obtiveram-se concentrações supraterapêuticas com a administração de pazopanibe por 8 dias, o que produziu uma redução dependente da concentração na frequência cardíaca e um prolongamento do intervalo QTc independente da concentração27.

Os betabloqueadores são considerados terapia profilática de primeira linha na SQTL. Conforme as diretrizes atuais, há indicação classe I para o tratamento com betabloqueadores para pacientes com diagnóstico clínico de SQTL28,29. Diferentes betabloqueadores têm eficácia semelhante na prevenção de eventos cardíacos em pacientes com SQTL30. Um outro estudo mostrou que o pré-tratamento com diltiazem e propranolol reduz o prolongamento do intervalo QTc induzido por epinefrina31. Um estudo em animais abordou os efeitos benéficos dos bloqueadores de canais de cálcio em insuficiência cardíaca e SQTL30. Além disso, pró-arritmia e prolongamento do intervalo QT foram demonstrados predominantemente com agentes antiarrítmicos classes Ia, Ic e III32,33. Portanto, metoprolol e diltiazem foram selecionados para avaliação no presente estudo34.

O presente estudo avaliou o prolongamento do intervalo QT induzido por pazopanibe em um modelo experimental com ratos. Primeiramente, demonstrou-se prolongamento do intervalo QTc nos ratos tratados apenas com pazopanibe. Três horas após a administração do medicamento, os ratos do grupo controle, que receberam pazopanibe e injeção intraperitoneal de solução salina, apresentaram prolongamento do intervalo QTc, corroborando assim os estudos prévios que mostraram associação entre TKIs e alterações do ECG7,9. Em segundo lugar, este estudo mostrou que o efeito de prolongamento do intervalo QT do pazopanibe pode ser revertido por alguns medicamentos. Os grupos PZP+metoprolol e PZP+diltiazem não apresentaram prolongamento do intervalo QTc quando comparados ao grupo controle-PZP+SP. No entanto, os intervalos QTc dos grupos PZP+metoprolol e PZP+diltiazem foram semelhantes entre si e significativamente mais curtos do que aqueles do grupo controle. Com base nos resultados do estudo, tanto metoprolol quanto diltiazem foram considerados eficientes para prevenir o efeito de prolongamento do intervalo QT induzido por pazopanibe.

Com frequência, pacientes com câncer necessitam de tratamento com TKIs que prolongam o intervalo QT. Os riscos e os benefícios dessa terapia precisam ser pesados. O tratamento deve ser iniciado com a suspensão do medicamento que precipita a alteração. Fatores de risco subjacentes devem ser avaliados, a administração do medicamento possivelmente precipitante deve ser interrompida, e condições reversíveis, como distúrbios metabólicos, devem ser corrigidos antes do início do medicamento34. O uso concomitante de vários medicamentos que prolongam o intervalo QT deve ser evitado. Os pacientes devem ser orientados quanto ao risco pró-arrítmico. Monitorização periódica com ECG e acompanhamento rigoroso são essenciais para a detecção precoce e tratamento de pacientes de alto risco e com história de prolongamento do intervalo QT, para pacientes em uso de antiarrítmicos, e para indivíduos com doença preexistente relevante, como bradicardia e desequilíbrio eletrolítico35.

Este estudo apresenta limitações. A primeira decorre do fato de se tratar de estudo experimental em ratos. Permanecem à espera de investigação adicional questões como a relevância desses resultados experimentais para seres humanos no contexto clínico e suas implicações terapêuticas. Em segundo lugar, no nosso estudo não se realizou teste de estabilidade ventricular. Devido a essa limitação, os possíveis efeitos profiláticos dos medicamentos com relação à pró-arritmia não podem ser avaliados com base em nossos resultados. Consequentemente, diferentes estudos com modelos específicos de estabilidade ventricular são necessários para que o uso profilático de tais medicamentos seja recomendado.

A redução da toxicidade cardíaca de tais agentes requer melhor conhecimento dos possíveis efeitos colaterais cardíacos do pazopanibe e identificação dos pacientes que correm maior risco. Este estudo avaliou os efeitos do metoprolol e do diltiazem na prevenção do prolongamento do intervalo QT induzido por pazopanibe.

Concluindo, metoprolol e diltiazem encurtaram significativamente o prolongamento do intervalo QT induzido por pazopanibe. Embora metoprolol e diltiazem tenham evitado o prolongamento do intervalo QT, estudos de longo prazo que incluam teste de estabilidade ventricular em diferentes modelos podem fornecer evidência para o uso profilático de tais medicamentos em pacientes de alto risco tratados com pazopanibe.

Contribuição dos autores

Concepção e desenho da pesquisa e Obtenção de financiamento: Akman T, Erbas O, Akman L, Yilmaz AU; Obtenção de dados, Análise e interpretação dos dados e Análise estatística: Akman T, Erbas O, Akman L; Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante Akman T, Yilmaz AU.

Potencial conflito de interesse

Declaro não haver conflito de interesses pertinentes.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.