American Journal of Therapeutics 23, e614–e616 (2016)
Colchicine-Induced Myopathy in a Tacrolimus-Treated Renal Transplant Recipient: Case Report and Literature Review Zeenat Yousuf Bhat, MD,1* Samitha Reddy, MD,1 Unnikrishnan Pillai, MD,1 Mona Doshi, MD,1 and Elizabeth Wilpula, PharmD2
Renal transplant recipients are prone to develop drug toxicities because of polypharmacy and drug– drug interactions. Colchicine is often used for the treatment of gout in these patients as nonsteroidal medications are contraindicated. In addition, patients are often on corticosteroids and frequent, periodic, dose escalation for gouty flare may lead to side effects. Colchicine-induced myopathy has been very well described in the literature. Several cases of colchicine toxicity have been reported in cyclosporine-treated patients due to a drug–drug interaction. We report a 62-year-old African American renal transplant recipient who had been doing well on tacrolimus-based immunosuppression and was started on colchicine (0.6 mg twice daily) for gouty flare. A few days later, he was found to have a 4-fold increase in aspartate aminotransferase and an elevated creatine phosphokinase. Although this interaction is very well known with cyclosporine, it has not yet been reported in patients on tacrolimus. Keywords: Colchicine toxicity, tacrolimus, renal transplant
INTRODUCTION A 62-year-old African American male who had undergone a deceased donor renal transplant 4 years ago and had been doing well on tacrolimus-based immunosuppression, He presented to the clinic with a red, painful, swollen big toe and was diagnosed with acute gout. He was started on colchicine (0.6 mg twice daily). He returned to the clinic a few days later with malaise, fatigue, diffuse aches, and pains. He was noted to have a 4-fold increase in aspartate aminotransferase (AST) (52–209 U/ L) and an elevated creatine phosphokinase (CPK) (9084 U/L). His previous AST and CPK had been in the normal
1
Division of Nephrology, Department of Internal Medicine, Wayne State University-Detroit Medical Center, Detroit, MI; and 2Pharmacy Department, Harper University Hospital, Detroit, MI. The authors have no conflicts of interest to declare. *Address for correspondence: Division of Nephrology, Department of Internal Medicine, Wayne State University-Detroit Medical Center, 4160 John R suite 908, Detroit, MI 48201. E-mail: [email protected]
range (Figures 1A, B). He had a stable therapeutic concentration of tacrolimus (6.1 ng/mL), serum creatinine (1.2 mg/dL), and white blood cells (6.7 K/cumm). Other liver function tests were found within the normal range. His medications included tacrolimus, mycophenolate mofetil, omeprazole, allopurinol, losartan, atenolol, nifedepine, and vardenafil. No other medications had been recently started. He was not drinking grapefruit juice or taking a statin, and no over-the-counter medications or herbal supplement use was noted. Colchicine toxicity was suspected and the drug was discontinued, his gouty flare was treated with a short tapering course of methylprednisolone. There was a prompt decrease of CPK to 5204 units/L in 3 days. Muscle and liver enzymes (AST) returned to normal in 2 months.
DISCUSSION Colchicine was originally extracted from the plant Colchicum autumnale, also known as meadow saffron or autumn crocus. It is one of the oldest available therapies for acute gout. Some reports suggest that the plant extracts containing colchicine have been used for joint pain for more than 2000 years.1
1075–2765 Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Tacrolimus and Colchicine Myopathy
e615
FIGURE 1. AST (A) and CPK (B) levels of the patient. There was a 4-fold increase in AST (52–209 U/L) and an elevated CPK (9084 U/L).
The absorption of oral colchicine is rapid but variable. The absolute bioavailability is less than 50%, and peak plasma concentrations usually occur 1–2 hours after dosing.2 The formation of colchicine–tubulin complexes in tissue contribute to the large volume of distribution. The exact metabolism of colchicine in humans is unknown, but in vitro studies indicate that it undergo oxidative demethylation by hepatic and enteric cytochrome P450 3A4, resulting in inactive metabolites.3 The elimination of colchicine is by multiple routes. Renal elimination accounts for approximately 10%– 20%, and there is also significant enterohepatic recirculation and biliary excretion.2 Colchicine is a substrate for P-glycoprotein, a transmembrane protein encoded by the MDR1 gene (also known as ABCB1). P-glycoprotein is located throughout the body including in the liver, kidney, and intestine. This transporter is primarily responsible for efflux of colchicine from these cells limiting drug absorption and increasing excretion.4,5 There have been several published reports of solid organ transplant recipients on cyclosporine who have developed colchicine toxicity after the initiation of colchicine.6–8 Cyclosporine is a known inhibitor of P-glycoprotein, and CYP3A4 and coadministration will result in increased colchicine exposure and decreased hepatic and renal elimination.9 This may lead to colchicine toxicity, presenting as gastrointestinal symptoms, liver dysfunction, polyneuropathy, myopathy, rhabdomyolysis, arrythmias, and/or pancytopenia.10 Our patient developed signs and symptoms of myopathy soon after the colchicine initiation, which quickly resolved after discontinuation. The medications he was taking are not known to cause myopathy, and he did not report any over the counter or herbal supplement use. Vardenafil is a substrate of CYP3A4 has recently www.americantherapeutics.com
been reported to be an inhibitor of P-glycoprotein,11 however, no drug–drug interactions related to this mechanism have been published. Although colchicine may cause myopathy independently of a drug–drug interaction, the dose is typically higher than 1.2 mg daily. Most cases of colchicine-induced myopathy at this dose have been reported when a coadministered medication is impairing metabolism and/or transport of colchicine, or in the presence of renal or hepatic insufficiency.8 To the best of our knowledge, there have been no case reports of colchicine toxicity in patients on tacrolimus-based immunosuppression. Tacrolimus, like cyclosporine, is a substrate for P-glycoprotein and CYP3A4 and has been shown in vitro to be a moderate to strong inhibitor of P-glycoprotein.12 Guidelines addressing colchicine dose reduction in the in the presence of P-glycoprotien and CYP3A4 inhibitors have recently been published.12 It is recommended to reduce the dose of colchicine by two-thirds when treating acute gout flares and by three-fourths for prophylaxis in patients who are also taking cyclosporine or tacrolimus to avoid increased susceptibility to colchicine toxicity.12 Close monitoring of patients on this combination is essential.
REFERENCES 1. Hartung EF. History of the use of colchicum and related medicaments in gout. Ann Rheum Dis. 1954;13:190–200. 2. ColcrysTM [package insert]. Philadelphia, PA: Mutual Pharmaceutical Company, Inc; 2009. 3. Tateishi T, Soucek P, Caraco Y, et al. Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation. Biochem Pharmacol. 1997;53:111–116. American Journal of Therapeutics (2016) 23(2)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e616 4. Lin JH, Yamazaki M. Role of P-glycoprotein in pharmacokinetics. Clinical implications. Clin Pharmacokinet. 2003; 42:59–98. 5. Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum. 2008;38:411–419. 6. Gruberg L, Har-Zahav Y, Agranat O, et al. Acute myopathy induced by colchicine in a cyclosporine treated heart transplant recipient: possible role of the multidrug resistance transporter. Transpl Proc. 1999;31:2157–2158. 7. Eleftheriou G, Bacis G, Fiocchi R, et al. Colchicineinduced toxicity in a heart transplant patient with chronic renal failure. Clin Toxicol (Phila). 2008;46:827–830. 8. Wilbur K, Makowsky M. Colchicine myotoxicity: case reports and literature review. Pharmacotherapy. 2004;24: 1784–1792.
American Journal of Therapeutics (2016) 23(2)
Yousuf Bhat et al 9. Wason S, Digiacinto JL, Davis MW. Effect of cyclosporine on the pharmacokinetics of colchicine in healthy subjects. Postgrad Med. 2012;124:189–196. 10. Putterman C, Ben-Chetrit E, Caraco Y, et al. Colchicine intoxication: clinical pharmacology, risk factors, features, and management. Semin Arthritis Rheum. 1991;21:143–155. 11. Ding P, Tiwari AK, Ohnuma S, et al. The phosphodiesterase-5 inhibitor vardenafil is a potent inhibitor of ABCB1/P-glycoprotein transporter. PLoS One. 2011;6:e19629. 12. Terkeltaub RA, Furst DE, Digiacinto JL, et al. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum. 2011;63:2226–2237.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Colchicine-Induced Myopathy in a Tacrolimus-Treated Renal Transplant Recipient: Case Report and Literature Review Zeenat Yousuf Bhat, MD,1* Samitha Reddy, MD,1 Unnikrishnan Pillai, MD,1 Mona Doshi, MD,1 and Elizabeth Wilpula, PharmD2
Renal transplant recipients are prone to develop drug toxicities because of polypharmacy and drug– drug interactions. Colchicine is often used for the treatment of gout in these patients as nonsteroidal medications are contraindicated. In addition, patients are often on corticosteroids and frequent, periodic, dose escalation for gouty flare may lead to side effects. Colchicine-induced myopathy has been very well described in the literature. Several cases of colchicine toxicity have been reported in cyclosporine-treated patients due to a drug–drug interaction. We report a 62-year-old African American renal transplant recipient who had been doing well on tacrolimus-based immunosuppression and was started on colchicine (0.6 mg twice daily) for gouty flare. A few days later, he was found to have a 4-fold increase in aspartate aminotransferase and an elevated creatine phosphokinase. Although this interaction is very well known with cyclosporine, it has not yet been reported in patients on tacrolimus. Keywords: Colchicine toxicity, tacrolimus, renal transplant
INTRODUCTION A 62-year-old African American male who had undergone a deceased donor renal transplant 4 years ago and had been doing well on tacrolimus-based immunosuppression, He presented to the clinic with a red, painful, swollen big toe and was diagnosed with acute gout. He was started on colchicine (0.6 mg twice daily). He returned to the clinic a few days later with malaise, fatigue, diffuse aches, and pains. He was noted to have a 4-fold increase in aspartate aminotransferase (AST) (52–209 U/ L) and an elevated creatine phosphokinase (CPK) (9084 U/L). His previous AST and CPK had been in the normal
1
Division of Nephrology, Department of Internal Medicine, Wayne State University-Detroit Medical Center, Detroit, MI; and 2Pharmacy Department, Harper University Hospital, Detroit, MI. The authors have no conflicts of interest to declare. *Address for correspondence: Division of Nephrology, Department of Internal Medicine, Wayne State University-Detroit Medical Center, 4160 John R suite 908, Detroit, MI 48201. E-mail: [email protected]
range (Figures 1A, B). He had a stable therapeutic concentration of tacrolimus (6.1 ng/mL), serum creatinine (1.2 mg/dL), and white blood cells (6.7 K/cumm). Other liver function tests were found within the normal range. His medications included tacrolimus, mycophenolate mofetil, omeprazole, allopurinol, losartan, atenolol, nifedepine, and vardenafil. No other medications had been recently started. He was not drinking grapefruit juice or taking a statin, and no over-the-counter medications or herbal supplement use was noted. Colchicine toxicity was suspected and the drug was discontinued, his gouty flare was treated with a short tapering course of methylprednisolone. There was a prompt decrease of CPK to 5204 units/L in 3 days. Muscle and liver enzymes (AST) returned to normal in 2 months.
DISCUSSION Colchicine was originally extracted from the plant Colchicum autumnale, also known as meadow saffron or autumn crocus. It is one of the oldest available therapies for acute gout. Some reports suggest that the plant extracts containing colchicine have been used for joint pain for more than 2000 years.1
1075–2765 Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Tacrolimus and Colchicine Myopathy
e615
FIGURE 1. AST (A) and CPK (B) levels of the patient. There was a 4-fold increase in AST (52–209 U/L) and an elevated CPK (9084 U/L).
The absorption of oral colchicine is rapid but variable. The absolute bioavailability is less than 50%, and peak plasma concentrations usually occur 1–2 hours after dosing.2 The formation of colchicine–tubulin complexes in tissue contribute to the large volume of distribution. The exact metabolism of colchicine in humans is unknown, but in vitro studies indicate that it undergo oxidative demethylation by hepatic and enteric cytochrome P450 3A4, resulting in inactive metabolites.3 The elimination of colchicine is by multiple routes. Renal elimination accounts for approximately 10%– 20%, and there is also significant enterohepatic recirculation and biliary excretion.2 Colchicine is a substrate for P-glycoprotein, a transmembrane protein encoded by the MDR1 gene (also known as ABCB1). P-glycoprotein is located throughout the body including in the liver, kidney, and intestine. This transporter is primarily responsible for efflux of colchicine from these cells limiting drug absorption and increasing excretion.4,5 There have been several published reports of solid organ transplant recipients on cyclosporine who have developed colchicine toxicity after the initiation of colchicine.6–8 Cyclosporine is a known inhibitor of P-glycoprotein, and CYP3A4 and coadministration will result in increased colchicine exposure and decreased hepatic and renal elimination.9 This may lead to colchicine toxicity, presenting as gastrointestinal symptoms, liver dysfunction, polyneuropathy, myopathy, rhabdomyolysis, arrythmias, and/or pancytopenia.10 Our patient developed signs and symptoms of myopathy soon after the colchicine initiation, which quickly resolved after discontinuation. The medications he was taking are not known to cause myopathy, and he did not report any over the counter or herbal supplement use. Vardenafil is a substrate of CYP3A4 has recently www.americantherapeutics.com
been reported to be an inhibitor of P-glycoprotein,11 however, no drug–drug interactions related to this mechanism have been published. Although colchicine may cause myopathy independently of a drug–drug interaction, the dose is typically higher than 1.2 mg daily. Most cases of colchicine-induced myopathy at this dose have been reported when a coadministered medication is impairing metabolism and/or transport of colchicine, or in the presence of renal or hepatic insufficiency.8 To the best of our knowledge, there have been no case reports of colchicine toxicity in patients on tacrolimus-based immunosuppression. Tacrolimus, like cyclosporine, is a substrate for P-glycoprotein and CYP3A4 and has been shown in vitro to be a moderate to strong inhibitor of P-glycoprotein.12 Guidelines addressing colchicine dose reduction in the in the presence of P-glycoprotien and CYP3A4 inhibitors have recently been published.12 It is recommended to reduce the dose of colchicine by two-thirds when treating acute gout flares and by three-fourths for prophylaxis in patients who are also taking cyclosporine or tacrolimus to avoid increased susceptibility to colchicine toxicity.12 Close monitoring of patients on this combination is essential.
REFERENCES 1. Hartung EF. History of the use of colchicum and related medicaments in gout. Ann Rheum Dis. 1954;13:190–200. 2. ColcrysTM [package insert]. Philadelphia, PA: Mutual Pharmaceutical Company, Inc; 2009. 3. Tateishi T, Soucek P, Caraco Y, et al. Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation. Biochem Pharmacol. 1997;53:111–116. American Journal of Therapeutics (2016) 23(2)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e616 4. Lin JH, Yamazaki M. Role of P-glycoprotein in pharmacokinetics. Clinical implications. Clin Pharmacokinet. 2003; 42:59–98. 5. Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum. 2008;38:411–419. 6. Gruberg L, Har-Zahav Y, Agranat O, et al. Acute myopathy induced by colchicine in a cyclosporine treated heart transplant recipient: possible role of the multidrug resistance transporter. Transpl Proc. 1999;31:2157–2158. 7. Eleftheriou G, Bacis G, Fiocchi R, et al. Colchicineinduced toxicity in a heart transplant patient with chronic renal failure. Clin Toxicol (Phila). 2008;46:827–830. 8. Wilbur K, Makowsky M. Colchicine myotoxicity: case reports and literature review. Pharmacotherapy. 2004;24: 1784–1792.
American Journal of Therapeutics (2016) 23(2)
Yousuf Bhat et al 9. Wason S, Digiacinto JL, Davis MW. Effect of cyclosporine on the pharmacokinetics of colchicine in healthy subjects. Postgrad Med. 2012;124:189–196. 10. Putterman C, Ben-Chetrit E, Caraco Y, et al. Colchicine intoxication: clinical pharmacology, risk factors, features, and management. Semin Arthritis Rheum. 1991;21:143–155. 11. Ding P, Tiwari AK, Ohnuma S, et al. The phosphodiesterase-5 inhibitor vardenafil is a potent inhibitor of ABCB1/P-glycoprotein transporter. PLoS One. 2011;6:e19629. 12. Terkeltaub RA, Furst DE, Digiacinto JL, et al. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum. 2011;63:2226–2237.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
