LETTERS TO THE EDITOR
Significant Tacrolimus and Dronedarone Interaction in a Kidney Transplant Recipient ronedarone is a recently available derivate of amiodarone indicated for the treatment of atrial fibrillation (1). Dronedarone seems to have improved tolerability, taking out the noncardiovascular adverse effects of amiodarone (2) and lack of interaction with oral anticoagulants (3). Dronedarone may have the ability to increase the concentration of CYP3A4 substrates, such as tacrolimus. Besides, dronedarone is an inhibitor of the P-glycoprotein efflux pump in the gastrointestinal tract, enhancing absorption of some drugs. Theoretically, dronedarone may increase tacrolimus levels, promoting tacrolimus toxicity and potentially extending QT interval in the electrocardiogram (4, 5). There are no reports that identify and describe management of the interaction between tacrolimus and dronedarone and its impact in clinical practice.
D
CASE REPORT A 63-year-old man with diabetic nephropathy received a kidney transplant. The patient had known hypertension, revascularized ischemic heart disease, and paroxysmal atrial fibrillation treated with dronedarone 400 mg two times per day months ago while being treated with hemodialysis. Amiodarone was the initial agent considered by his cardiologist. However, because of the presumed better adverse event profile reported, dronedarone was the final choice. Dronedarone was continued within the second day after kidney transplantation to maintain sinus rhythm. Immunosuppresion consisted of basiliximab induction, tacrolimus retard (Advagraf) 12 mg (0.15 mg/kg) orally per day since postoperative day 1, combined with corticosteroids and mycophenolate acid (Myfortic) 720 mg two times per day. After 3 days of tacrolimus, blood levels were 22.2 ng/mL and continued increasing (930 ng/mL) despite of decreasing tacrolimus dose (Fig. 1). Consequently, tacrolimus therapy was discontinued for 3 days. His treatment during the hospitalization also included enoxaparin, furosemide, insulin, pantoprazole, Transplantation
oxybutynin, nystatin, amlodipine, doxazosin, lorazepam, and metoclopramide, none of them with a tacrolimus interaction. He developed hyperkalemia (6.8 mEq/L), hyponatremia (129 mEq/L), nausea, hyperglycemia (254 mg/dL), and tremor in upper extremities, but his renal function evolution was favorable: serum creatinine, 1.73 mg/dL; estimated glomerular filtration rate 43 mL/min per 1.73 m2 at discharge on postoperative day 11. At this time, tacrolimus levels had decreased to 13.3 ng/mL taking 6 mg/day (50% reduction). His electrocardiogram revealed normal sinus rhythm and QTc interval was 416 ms, despite treatment with both dronedarone and tacrolimus. Three weeks later, the patient was readmitted to the hospital for a urinary tract infection and treated with ciprofloxacin. No other drug with tacrolimus interaction was administered. Nevertheless, during this second inpatient stay, dronedarone was interrupted. The patient was discharged after 4 days with a tacrolimus dose of 2.5 mg/day (80% reduction), and dronedarone was restarted (Fig. 1). Three months after transplantation, graft function was favorable (serum creatinine, 1.37 mg/dL; GFR, 56 mL/min/1.73 m2), tacrolimus dose 1/0.5 mg alternate-days (90% reduction) and significant improvement of his tremor.
DISCUSSION We describe a case of a kidney transplant patient with a drug-drug interaction between dronedarone and tacrolimus,
resulting in tacrolimus toxicity and requiring an important reduction of initial dose. Tacrolimus is extensively metabolized by cytochrome CYP3A4 in both the liver and small intestine (6, 7). Tacrolimus is also a substrate of P-glycoprotein, a drug transporter that decreases the absorption and increases excretion of substrates (8). Dronedarone, like amiodarone, inhibits P-glycoprotein and hepatic metabolism by CYP3A4 and CYP2D6, and therefore may have many drug-drug interactions (9). Amiodarone and tacrolimus interactions have been previously described (10, 11). Dronedarone has the same potential. Nevertheless, there are only a few cases that described interactions between dronedarone and other drugs (9, 12). The only reported interaction between dronedarone and an immunosuppressive drug was an increase by more than threefold of sirolimus concentration (12). To our knowledge, this is the first report showing significant tacrolimusdronedarone interaction. Initially, the interaction was underestimated, and we did not reduce tacrolimus dose because of the less potential interaction between both drugs. However, our expectations failed, the interaction happened and was strong. Because of high tacrolimus levels, the patient showed suboptimal
FIGURE 1. Time of course of dronedarone and tacrolimus doses and levels.
& Volume 98, Number 4, August 27, 2014
www.transplantjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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kidney function, elevated serum potassium, hyperglycemia, nausea, and tremors. Finally, the patient improved when tacrolimus dose was reduced 90%. Although both tacrolimus and dronedarone may prolong the QT interval (4, 5, 11), there was no evidence of QT prolongation in our patient. The patient did not receive any other drugs known to affect tacrolimus levels. Liver function tests were always normal. The Horn Drug Interaction Probability Scale indicates that this case estimates a ‘‘probable’’ (total score 7) interaction between tacrolimus and dronedarone (13). Tacrolimus levels eventually decreased during the second admission after dronedarone removal, but after the reintroduction of dronedarone, tacrolimus levels quickly increased once again. For patients on treatment with dronedarone who need concomitant tacrolimus, electrocardiograms and blood levels are recommended to be closely monitored, and tacrolimus dose reduction should be considered to prevent toxicity.
Transplantation
1 Pharmacy Department Hospital del Mar Barcelona, Spain 2 Nephrology Department Hospital del Mar Barcelona, Spain
The authors declare no funding or conflicts of interest. Address correspondence to: Julio Pascual, M.D., Nephrology Department, Hospital del Mar, Paseo Marı´timo, 25, 08003 Barcelona, Spain. E-mail: [email protected] M.M.-C. designed study, performed study, collected data, analyzed data, and wrote the article. M.J.P.-S. designed study, performed study, collected data, analyzed data, and wrote the article. M.C. collected data and analyzed data. D.E. collected data, analyzed data, and wrote the article. M.M. collected data and analyzed data. J.P. designed study, performed study, collected data, analyzed data, and wrote the article. Received 3 April 2014. Accepted 2 May 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9804-e33 DOI: 10.1097/TP.0000000000000280
4.
5.
6.
7.
8.
9. 10.
REFERENCES 1.
Mo´nica Marin-Casino1 Maria J. Pe´rez-Sa´ez2 Marta Crespo2 Daniel Echeverrı´a1 Marisa Mir2 Julio Pascual2
& Volume 98, Number 4, August 27, 2014
2. 3.
Pamukcu B, Lip GY. Dronedarone as a new treatment option for atrial fibrillation patients: pharmacokinetics, pharmacodynamics and clinical practice. Expert Opin Pharmacother 2011; 12: 131. Adlan AM, Lip GY. Benefit-risk assessment of dronedarone in the treatment of atrial fibrillation. Drug Saf. 2013; 36: 93. Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind,
11.
12.
13.
parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010; 21: 597. Ozkanlar Y, Nishijima Y, da Cunha D, et al. Acute effects of tacrolimus (FK506) on left ventricular mechanics. Pharmacol Res 2005; 52: 307. Gonzalez JE, Sauer WH, Krantz MJ. Ventricular ectopy and QTc-interval prolongation associated with dronedarone therapy. Pharmacotherapy 2013; 33: e179. Scott LJ, McKeage K, Keam SJ, et al. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003; 63: 1247. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 2004; 43: 623. Hebert MF. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev 1997; 27: 201. Schafer JA, Kjesbo NK, Gleason PP. Dronedarone: current evidence and future questions. Cardiovasc Ther 2010; 28: 38. Kisters K, Cziborra M, Funke C, et al. Amiodarone-tacrolimus interaction in kidney transplantation. Clin Nephrol 2008; 70: 563. Burger CI, Clase CM, Gangji AS. Case report: drug interaction between tacrolimus and amiodarone with QT prolongation. Transplantation 2010; 89: 1166. Tichy EM, Medwid AJ, Mills EA, et al. Significant sirolimus and dronedarone interaction in a kidney transplant recipient. Ann Pharmacother 2010; 44: 1338. Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007; 41: 674.
Belatacept-Based Immunosuppression in a Chagasic Adult Recipient of En Bloc Pediatric Kidneys t has been demonstrated that pediatric en bloc kidney (EBK) grafts can extend the limited donor pool with good long-term graft survival and function. However, the higher rate of initial graft loss during the first postoperative year, technical difficulties, the risk of hypertension, and increased protein wasting limit the widespread transplantation of EBKs into adults (1Y4). Especially early after transplantation, small grafts are sensitive to calcineurin inhibitors (CNI) toxicity (5). Belatacept provides effective immunosuppression without the toxicities associated with CNI (6). Moreover, the recipient was seropositive for Trypanosoma cruzi (T. cruzi), the protozoan that causes Chagas disease. We describe the use of
I
belatacept-based immunosuppression in a chagasic adult patient who received small EBK grafts. A 68-year-old white man received an EBK transplant after 35 months of hemodialysis treatment. The donor was a 2-year-old, 12 kg, 87 cm tall female patient, died from a hemorrhagic cerebrovascular accident, had negative serology for Chagas disease, hepatitis B surface antigen, toxoplasmosis, and cytomegalo virus, but was positive for Epstein-Barr virus. The recipient was a chronic untreated T. cruzi carrier, positive for EpsteinBarr virus, had three human leukocyte antigen mismatches, and a panel-reactive antibody of 0%. The 6-cm-long kidneys were retrieved en bloc and preserved in
cold-storage for 22 hr. Induction therapy consisted of antithymocyte globulinFresenius (five doses at 2Y5 mg/kg) and metilprednisolone (three doses at 500 mg, 250 mg, and 125 mg each). Prophylactic therapy consisted of sulfamethoxazoletrimethoprim for Pneumocystis jirovecii pneumonia, ganciclovir for cytomegalovirus, and cefazolin. Maintenance immunosuppression consisted of belatacept 10 mg/kg on postoperative day (POD) 1, 5, 15, 28, 56, and 78 (5 mg/kg every 28 days, thereafter), micophenolate at 1440 mg per day and meprednisone 20 mg per day for the first 6 months and 4 mg per day thereafter. On POD 2, serum creatinine was 2.50 mg/dL, hematocrit 28.8%, leukocytes 10.960/mm3, platelet count 180,000/mm3,
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Significant Tacrolimus and Dronedarone Interaction in a Kidney Transplant Recipient ronedarone is a recently available derivate of amiodarone indicated for the treatment of atrial fibrillation (1). Dronedarone seems to have improved tolerability, taking out the noncardiovascular adverse effects of amiodarone (2) and lack of interaction with oral anticoagulants (3). Dronedarone may have the ability to increase the concentration of CYP3A4 substrates, such as tacrolimus. Besides, dronedarone is an inhibitor of the P-glycoprotein efflux pump in the gastrointestinal tract, enhancing absorption of some drugs. Theoretically, dronedarone may increase tacrolimus levels, promoting tacrolimus toxicity and potentially extending QT interval in the electrocardiogram (4, 5). There are no reports that identify and describe management of the interaction between tacrolimus and dronedarone and its impact in clinical practice.
D
CASE REPORT A 63-year-old man with diabetic nephropathy received a kidney transplant. The patient had known hypertension, revascularized ischemic heart disease, and paroxysmal atrial fibrillation treated with dronedarone 400 mg two times per day months ago while being treated with hemodialysis. Amiodarone was the initial agent considered by his cardiologist. However, because of the presumed better adverse event profile reported, dronedarone was the final choice. Dronedarone was continued within the second day after kidney transplantation to maintain sinus rhythm. Immunosuppresion consisted of basiliximab induction, tacrolimus retard (Advagraf) 12 mg (0.15 mg/kg) orally per day since postoperative day 1, combined with corticosteroids and mycophenolate acid (Myfortic) 720 mg two times per day. After 3 days of tacrolimus, blood levels were 22.2 ng/mL and continued increasing (930 ng/mL) despite of decreasing tacrolimus dose (Fig. 1). Consequently, tacrolimus therapy was discontinued for 3 days. His treatment during the hospitalization also included enoxaparin, furosemide, insulin, pantoprazole, Transplantation
oxybutynin, nystatin, amlodipine, doxazosin, lorazepam, and metoclopramide, none of them with a tacrolimus interaction. He developed hyperkalemia (6.8 mEq/L), hyponatremia (129 mEq/L), nausea, hyperglycemia (254 mg/dL), and tremor in upper extremities, but his renal function evolution was favorable: serum creatinine, 1.73 mg/dL; estimated glomerular filtration rate 43 mL/min per 1.73 m2 at discharge on postoperative day 11. At this time, tacrolimus levels had decreased to 13.3 ng/mL taking 6 mg/day (50% reduction). His electrocardiogram revealed normal sinus rhythm and QTc interval was 416 ms, despite treatment with both dronedarone and tacrolimus. Three weeks later, the patient was readmitted to the hospital for a urinary tract infection and treated with ciprofloxacin. No other drug with tacrolimus interaction was administered. Nevertheless, during this second inpatient stay, dronedarone was interrupted. The patient was discharged after 4 days with a tacrolimus dose of 2.5 mg/day (80% reduction), and dronedarone was restarted (Fig. 1). Three months after transplantation, graft function was favorable (serum creatinine, 1.37 mg/dL; GFR, 56 mL/min/1.73 m2), tacrolimus dose 1/0.5 mg alternate-days (90% reduction) and significant improvement of his tremor.
DISCUSSION We describe a case of a kidney transplant patient with a drug-drug interaction between dronedarone and tacrolimus,
resulting in tacrolimus toxicity and requiring an important reduction of initial dose. Tacrolimus is extensively metabolized by cytochrome CYP3A4 in both the liver and small intestine (6, 7). Tacrolimus is also a substrate of P-glycoprotein, a drug transporter that decreases the absorption and increases excretion of substrates (8). Dronedarone, like amiodarone, inhibits P-glycoprotein and hepatic metabolism by CYP3A4 and CYP2D6, and therefore may have many drug-drug interactions (9). Amiodarone and tacrolimus interactions have been previously described (10, 11). Dronedarone has the same potential. Nevertheless, there are only a few cases that described interactions between dronedarone and other drugs (9, 12). The only reported interaction between dronedarone and an immunosuppressive drug was an increase by more than threefold of sirolimus concentration (12). To our knowledge, this is the first report showing significant tacrolimusdronedarone interaction. Initially, the interaction was underestimated, and we did not reduce tacrolimus dose because of the less potential interaction between both drugs. However, our expectations failed, the interaction happened and was strong. Because of high tacrolimus levels, the patient showed suboptimal
FIGURE 1. Time of course of dronedarone and tacrolimus doses and levels.
& Volume 98, Number 4, August 27, 2014
www.transplantjournal.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e33
e34
www.transplantjournal.com
kidney function, elevated serum potassium, hyperglycemia, nausea, and tremors. Finally, the patient improved when tacrolimus dose was reduced 90%. Although both tacrolimus and dronedarone may prolong the QT interval (4, 5, 11), there was no evidence of QT prolongation in our patient. The patient did not receive any other drugs known to affect tacrolimus levels. Liver function tests were always normal. The Horn Drug Interaction Probability Scale indicates that this case estimates a ‘‘probable’’ (total score 7) interaction between tacrolimus and dronedarone (13). Tacrolimus levels eventually decreased during the second admission after dronedarone removal, but after the reintroduction of dronedarone, tacrolimus levels quickly increased once again. For patients on treatment with dronedarone who need concomitant tacrolimus, electrocardiograms and blood levels are recommended to be closely monitored, and tacrolimus dose reduction should be considered to prevent toxicity.
Transplantation
1 Pharmacy Department Hospital del Mar Barcelona, Spain 2 Nephrology Department Hospital del Mar Barcelona, Spain
The authors declare no funding or conflicts of interest. Address correspondence to: Julio Pascual, M.D., Nephrology Department, Hospital del Mar, Paseo Marı´timo, 25, 08003 Barcelona, Spain. E-mail: [email protected] M.M.-C. designed study, performed study, collected data, analyzed data, and wrote the article. M.J.P.-S. designed study, performed study, collected data, analyzed data, and wrote the article. M.C. collected data and analyzed data. D.E. collected data, analyzed data, and wrote the article. M.M. collected data and analyzed data. J.P. designed study, performed study, collected data, analyzed data, and wrote the article. Received 3 April 2014. Accepted 2 May 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9804-e33 DOI: 10.1097/TP.0000000000000280
4.
5.
6.
7.
8.
9. 10.
REFERENCES 1.
Mo´nica Marin-Casino1 Maria J. Pe´rez-Sa´ez2 Marta Crespo2 Daniel Echeverrı´a1 Marisa Mir2 Julio Pascual2
& Volume 98, Number 4, August 27, 2014
2. 3.
Pamukcu B, Lip GY. Dronedarone as a new treatment option for atrial fibrillation patients: pharmacokinetics, pharmacodynamics and clinical practice. Expert Opin Pharmacother 2011; 12: 131. Adlan AM, Lip GY. Benefit-risk assessment of dronedarone in the treatment of atrial fibrillation. Drug Saf. 2013; 36: 93. Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind,
11.
12.
13.
parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010; 21: 597. Ozkanlar Y, Nishijima Y, da Cunha D, et al. Acute effects of tacrolimus (FK506) on left ventricular mechanics. Pharmacol Res 2005; 52: 307. Gonzalez JE, Sauer WH, Krantz MJ. Ventricular ectopy and QTc-interval prolongation associated with dronedarone therapy. Pharmacotherapy 2013; 33: e179. Scott LJ, McKeage K, Keam SJ, et al. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003; 63: 1247. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 2004; 43: 623. Hebert MF. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev 1997; 27: 201. Schafer JA, Kjesbo NK, Gleason PP. Dronedarone: current evidence and future questions. Cardiovasc Ther 2010; 28: 38. Kisters K, Cziborra M, Funke C, et al. Amiodarone-tacrolimus interaction in kidney transplantation. Clin Nephrol 2008; 70: 563. Burger CI, Clase CM, Gangji AS. Case report: drug interaction between tacrolimus and amiodarone with QT prolongation. Transplantation 2010; 89: 1166. Tichy EM, Medwid AJ, Mills EA, et al. Significant sirolimus and dronedarone interaction in a kidney transplant recipient. Ann Pharmacother 2010; 44: 1338. Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007; 41: 674.
Belatacept-Based Immunosuppression in a Chagasic Adult Recipient of En Bloc Pediatric Kidneys t has been demonstrated that pediatric en bloc kidney (EBK) grafts can extend the limited donor pool with good long-term graft survival and function. However, the higher rate of initial graft loss during the first postoperative year, technical difficulties, the risk of hypertension, and increased protein wasting limit the widespread transplantation of EBKs into adults (1Y4). Especially early after transplantation, small grafts are sensitive to calcineurin inhibitors (CNI) toxicity (5). Belatacept provides effective immunosuppression without the toxicities associated with CNI (6). Moreover, the recipient was seropositive for Trypanosoma cruzi (T. cruzi), the protozoan that causes Chagas disease. We describe the use of
I
belatacept-based immunosuppression in a chagasic adult patient who received small EBK grafts. A 68-year-old white man received an EBK transplant after 35 months of hemodialysis treatment. The donor was a 2-year-old, 12 kg, 87 cm tall female patient, died from a hemorrhagic cerebrovascular accident, had negative serology for Chagas disease, hepatitis B surface antigen, toxoplasmosis, and cytomegalo virus, but was positive for Epstein-Barr virus. The recipient was a chronic untreated T. cruzi carrier, positive for EpsteinBarr virus, had three human leukocyte antigen mismatches, and a panel-reactive antibody of 0%. The 6-cm-long kidneys were retrieved en bloc and preserved in
cold-storage for 22 hr. Induction therapy consisted of antithymocyte globulinFresenius (five doses at 2Y5 mg/kg) and metilprednisolone (three doses at 500 mg, 250 mg, and 125 mg each). Prophylactic therapy consisted of sulfamethoxazoletrimethoprim for Pneumocystis jirovecii pneumonia, ganciclovir for cytomegalovirus, and cefazolin. Maintenance immunosuppression consisted of belatacept 10 mg/kg on postoperative day (POD) 1, 5, 15, 28, 56, and 78 (5 mg/kg every 28 days, thereafter), micophenolate at 1440 mg per day and meprednisone 20 mg per day for the first 6 months and 4 mg per day thereafter. On POD 2, serum creatinine was 2.50 mg/dL, hematocrit 28.8%, leukocytes 10.960/mm3, platelet count 180,000/mm3,
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
