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Cyclosporine and Sirolimus Interaction in a Kidney Transplant Patient
Cyclosporine and Sirolimus Interaction in a Kidney Transplant Patient E. Da¸browska-Zamojcin, A. Pawlik, L. Doman´ski, J. Róz˙an´ski, and M. Droz´dzik ABSTRACT Cyclosporin A and sirolimus are becoming commonly used in immunosuppressive treatment in organ transplant patients. The drugs are both metabolized by cytochrome P450 3A4 and are substrates of P-glycoprotein. Thus, interaction between these drugs is possible. The case reported here illustrated that clinicians should be aware of this important drug– drug interaction.
T
HE DEVELOPMENT of new agents over the past decade has improved graft survival rates. Immunosuppressants available at present include calcineurin inhibitors (cyclosporine [CsA], tacrolimus), antimetabolites (azathioprine, leflunomide, methotrexate, mycophenolate mofetil), antiproliferatives (sirolimus [SRL]), monoclonal antibodies to T lymphocytes, (basiliximab, daclizumab, murononabCD3), and anticytokines (anakinra, infliximab). Immunotherapy in transplantation and autoimmune diseases is tending toward the use of multidrug regimens matched for individual patients.1 However, concomitant administration of several drugs raise the possibility of drug– drug interactions. A synergistic effect of the SRL and CsA combination allows for decreased CsA doses with subsequent reduction in CsA side effects. Bai et al show the effects of this drug combination.2 However, these two drugs are both metabolized by cytochrome P450 CYP3A4 and are substrates for drug transporter glycoprotein p170 (P-glycoprotein, P-gp), which may involve a drug– drug interaction.3 CASE REPORT A 34-year-old woman was admitted to hospital with symptoms of diarrhea and fever. She had been transplanted with an allogenic kidney 5 months before hospital admission due to renal failure of unknown origin (probably toxic). The posttransplant period was complicated by two episodes of acute graft rejection, in the first and fourth month after the surgery, confirmed by graft biopsy. They were treated with methylprednisolone pulses. Maintenance therapy before hospital admission constituted of mycophenolate mofetil (CellCept, Roche; 2 ⫻ 0.75 g/d), CsA (Neoral, Novartis; 2 ⫻ 0.175 g/d), and prednisone (Encorton, Polfa; 1 ⫻ 0.25 g/d). Admission laboratory values included leukocyte count of 3000/mL, erythrocyte count of 2.57 ⫻ 106 mL and platelet count 110,000/mL. Serum urea nitrogen was 200 mg/dL; serum creatinine level was 3.34 mg/dL. Liver function tests (bilirubin, aspartate, and alanine aminotransferases activities) were within normal range.
In the hospital immunosuppressive therapy was continued. The mycophenolate mofetil on admission was not reduced. It was even slightly increased from 2 ⫻ 0.75 g to 1.0 g and 0.75 g/daily in view of the elevated creatinine and urea nitrogen levels since an infectious origin of the diarrhea was suspected. Daily CsA (175 mg and 200 mg) as well as prednisone 40 mg doses, were maintained. Additional therapy with lansoprazol, acyclovir, furosemide, atorvastatin, nystatin, cefuroxim, loperamide, and metronidazole was introduced. These drugs did not influence CsA levels. After physical examination and laboratory tests performed, no site of infection was found, leading to mycophenolate mofetil discontinuation as a potential cause of diarrhea, and its replacement with SRL (Rapamune, Wyeth) on day 7 of hospitalization. CsA and SRL were administered together at the same time of the day. Five days after SRL introduction improvement of clinical symptoms and blood morphology was observed: WBC 3.62 G/L, RBC 2.75 T/L, PLT 138 G/L. The serum levels of creatinine and urea nitrogen were 2.54 mg/dL and 136.9 mg/dL, respectively. The clinical symptoms disappeared, and the patient was discharged after 22 days of therapy on SRL (2 mg/d), prednisone (30 mg), CsA (400 mg), and lansoprazol as maintenance therapy. Two weeks later, she was readmitted to hospital because of an elevated serum creatinine (4.22 mg/dL), urea (198.3 mg/dL), increased blood pressure (180/120 mm Hg), and high of CsA (536 ng/mL measured 2 hours postdose by immunofluorescence polarization assay). Due to clinical evidence of CsA effects, elevated creatinine and urea levels as well as increased blood pressure, its dose was reduced to 300 mg, which led to normalization of drug concentrations to 276 ng/mL. Reduced CsA doses were followed by therapeutic serum concentrations of the drug irrespectively of SRL administration. During the same period SRL concentrations were From the Departments of Pharmacology (E.D.-Z˙, A.P., M.D.) and Nephrology (L.D., J.R.), Transplantation and Internal Medicine Pomeranian Medical University, Szczecin, Poland. Address reprint requests to Andrzej Pawlik, MD, PhD, Department of Pharmacology, Pomeranian Academy of Medicine, Powstancow Wlkp. 72, 70-111 Szczecin, Poland. E-mail: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.03.094
Transplantation Proceedings, 37, 2317–2319 (2005)
2317
DA¸BROWSK˙A-ZAMOJCIN, PAWLIK, DOMAN´SKI ET AL
2318
Fig 1.
Doses and concentrations of sirolimus, cyclosporine, and mycophenolate mofetil.
almost within the recommended values 5.2 to 10.6 ng/mL (recommended values 4 to 8 ng/mL; Fig 1). The patient was genotyped for the common polymorphism in MDR1 (C3435T) gene encoding P-glycoprotein and was found to be CT heterozygote. CYP3A4 was evaluated to determine the CYP3A4*1B allele, but a wild-type homozygous was observed.
DISCUSSION
In the reported patient an interaction between CsA and SRL was described. As a result of this interaction there was a significant rise, far above therapeutic concentrations of CsA in blood. The increased concentration of the drug was accompanied by typical CsA toxic side effects; rise in serum creatinine and urea level as well as hypertension,4 which appeared a few days after SRL introduction. Reduction of CsA doses caused normalization of the drug level in blood. The hepatic microsomal cytochrome P450 superfamily (P450) includes the mixed-function oxidase system, which catalyzes the metabolism of numerous lipophilic endogenous and exogenous compounds. The human cytochrome enzyme CYP3A4, comprising approximately 30% of the total hepatic P450 system, metabolizes many structurally diverse compounds, including CsA and SRL.5,6 At therapeutic concentrations, each drug is typically metabolized primarily by this single isoenzyme of the P450 system. The rate and pathway of metabolism is determined by an
individual’s phenotype, concomitant drug therapy, and disease state. Drug– drug interactions at the level of P450 3A4 may influence rate of SRL and CsA drug biotransformation, with a resultant increase in blood CsA and/or SRL concentrations. Our patient showed an increase in CsA concentrations, an observation consistent with suggestions to use SRL to reduce CsA dosages.7 Another contribution for observed interaction can be competition of CsA and SRL for P-gp drug transporter (multidrug resistance-1 gene product), which exports a wide variety of xenobiotics from the cytoplasm outside the cell. The immunosuppressive agents CsA, SRL, and corticosteroids act as substrates and inhibitors of P-gp. They are not the only substrates for transport by P-gp. Thus they compete for transport among themselves and with a large number of other drugs and endogenous compounds handled by this transporter,8 but additionally as available data suggest SRL may function as an MDR-reversing agent, thereby influencing the pharmacokinetics of other drugs.9 The study in rats confirmed that concomitant administration of SRL and CsA produced an increase in CsA blood and tissue concentrations.10 However, Kaplan et al11 reported that administration of CsA and SRL in renal transplant patients resulted in elevated SRL blood concentrations but had no effects on CsA pharmacokinetics. The
CYCLOSPORINE AND SIROLIMUS INTERACTION
authors postulated a 4-hour interval in dosing the two drugs to avoid the drug interaction. An increased level of CsA observed after SRL introduction into the therapeutic regimen of a kidney transplant patient may be explained by a drug– drug interaction at the level of both CYP3A4 and P-glycoprotein. Myelosuppression observed in our patient was probably a side effect of mycophenolate mofetil, since blood morphology parameters normalized shortly after withdrawal of the drug, an observation consistent with the report of Engelen et al.12 REFERENCES 1. Kovarik JM, Burtin P: Immunosuppressants in advanced clinical development for organ transplantation and selected autoimmunediseases. Expert Opin Emerg Drugs 8:47, 2003 2. Bai S, Stepkowski SM, Kahan BD, et al: Metabolic interaction between cyclosporine and sirolimus. Transplantation 77:1507, 2004 3. Kelly P, Kahan BD: Review: metabolism of immunosuppressant drugs. Curr Drug Metab 3:275, 2002 4. Lo A, Burckart GJ: P-glycoprotein and drug therapy in organ transplantation. J Clin Pharmacol 39:995, 1999 5. Kronbach T, Fischer V, Meyer UA: Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family
2319 as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs. Clin Pharmacol Ther 43:630, 1988 6. Sattler M, Guengerich FP, Yun CH, et al: Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab Dispos 20:753, 1992 7. Mahalati K, Kahan BD: Clinical pharmacokinetics of sirolimus. Clin Pharmacokin 40:573, 2001 8. Miller DS, Fricker G, Dreve J: P-glycoprotein-mediated transport of a fluorescent rapamycin derivate in renal proximal tubule. J Pharmacol Exp Ther 282:449, 1997 9. Arceci R, Stieglitz, Bierer B: Immunosuppressants FK 506 and Rapamycin function as reversal agents of the multidrug resistance phenotype. Blood 80:1528, 1992 10. Napoli KL, Wang ME, Stepkowski SM, et al: Relative tissue distributions of cyclosporine and sirolimus after concomitant peroral administration to the rat: evidence for pharmacokinetic. Ther Drug Monit 20:123, 1998 11. Kaplan B, Meier-Kriesche HU, Napoli KL, et al: The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther 63:48, 1998 12. Engelen W, Verpooten GA, Van der Planken M, et al: Four cases of red blood cell aplasia in association with the use of mycophenolate mofetil in renal transplant patients. Clin Nephrol 60:119, 2003
T
HE DEVELOPMENT of new agents over the past decade has improved graft survival rates. Immunosuppressants available at present include calcineurin inhibitors (cyclosporine [CsA], tacrolimus), antimetabolites (azathioprine, leflunomide, methotrexate, mycophenolate mofetil), antiproliferatives (sirolimus [SRL]), monoclonal antibodies to T lymphocytes, (basiliximab, daclizumab, murononabCD3), and anticytokines (anakinra, infliximab). Immunotherapy in transplantation and autoimmune diseases is tending toward the use of multidrug regimens matched for individual patients.1 However, concomitant administration of several drugs raise the possibility of drug– drug interactions. A synergistic effect of the SRL and CsA combination allows for decreased CsA doses with subsequent reduction in CsA side effects. Bai et al show the effects of this drug combination.2 However, these two drugs are both metabolized by cytochrome P450 CYP3A4 and are substrates for drug transporter glycoprotein p170 (P-glycoprotein, P-gp), which may involve a drug– drug interaction.3 CASE REPORT A 34-year-old woman was admitted to hospital with symptoms of diarrhea and fever. She had been transplanted with an allogenic kidney 5 months before hospital admission due to renal failure of unknown origin (probably toxic). The posttransplant period was complicated by two episodes of acute graft rejection, in the first and fourth month after the surgery, confirmed by graft biopsy. They were treated with methylprednisolone pulses. Maintenance therapy before hospital admission constituted of mycophenolate mofetil (CellCept, Roche; 2 ⫻ 0.75 g/d), CsA (Neoral, Novartis; 2 ⫻ 0.175 g/d), and prednisone (Encorton, Polfa; 1 ⫻ 0.25 g/d). Admission laboratory values included leukocyte count of 3000/mL, erythrocyte count of 2.57 ⫻ 106 mL and platelet count 110,000/mL. Serum urea nitrogen was 200 mg/dL; serum creatinine level was 3.34 mg/dL. Liver function tests (bilirubin, aspartate, and alanine aminotransferases activities) were within normal range.
In the hospital immunosuppressive therapy was continued. The mycophenolate mofetil on admission was not reduced. It was even slightly increased from 2 ⫻ 0.75 g to 1.0 g and 0.75 g/daily in view of the elevated creatinine and urea nitrogen levels since an infectious origin of the diarrhea was suspected. Daily CsA (175 mg and 200 mg) as well as prednisone 40 mg doses, were maintained. Additional therapy with lansoprazol, acyclovir, furosemide, atorvastatin, nystatin, cefuroxim, loperamide, and metronidazole was introduced. These drugs did not influence CsA levels. After physical examination and laboratory tests performed, no site of infection was found, leading to mycophenolate mofetil discontinuation as a potential cause of diarrhea, and its replacement with SRL (Rapamune, Wyeth) on day 7 of hospitalization. CsA and SRL were administered together at the same time of the day. Five days after SRL introduction improvement of clinical symptoms and blood morphology was observed: WBC 3.62 G/L, RBC 2.75 T/L, PLT 138 G/L. The serum levels of creatinine and urea nitrogen were 2.54 mg/dL and 136.9 mg/dL, respectively. The clinical symptoms disappeared, and the patient was discharged after 22 days of therapy on SRL (2 mg/d), prednisone (30 mg), CsA (400 mg), and lansoprazol as maintenance therapy. Two weeks later, she was readmitted to hospital because of an elevated serum creatinine (4.22 mg/dL), urea (198.3 mg/dL), increased blood pressure (180/120 mm Hg), and high of CsA (536 ng/mL measured 2 hours postdose by immunofluorescence polarization assay). Due to clinical evidence of CsA effects, elevated creatinine and urea levels as well as increased blood pressure, its dose was reduced to 300 mg, which led to normalization of drug concentrations to 276 ng/mL. Reduced CsA doses were followed by therapeutic serum concentrations of the drug irrespectively of SRL administration. During the same period SRL concentrations were From the Departments of Pharmacology (E.D.-Z˙, A.P., M.D.) and Nephrology (L.D., J.R.), Transplantation and Internal Medicine Pomeranian Medical University, Szczecin, Poland. Address reprint requests to Andrzej Pawlik, MD, PhD, Department of Pharmacology, Pomeranian Academy of Medicine, Powstancow Wlkp. 72, 70-111 Szczecin, Poland. E-mail: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.03.094
Transplantation Proceedings, 37, 2317–2319 (2005)
2317
DA¸BROWSK˙A-ZAMOJCIN, PAWLIK, DOMAN´SKI ET AL
2318
Fig 1.
Doses and concentrations of sirolimus, cyclosporine, and mycophenolate mofetil.
almost within the recommended values 5.2 to 10.6 ng/mL (recommended values 4 to 8 ng/mL; Fig 1). The patient was genotyped for the common polymorphism in MDR1 (C3435T) gene encoding P-glycoprotein and was found to be CT heterozygote. CYP3A4 was evaluated to determine the CYP3A4*1B allele, but a wild-type homozygous was observed.
DISCUSSION
In the reported patient an interaction between CsA and SRL was described. As a result of this interaction there was a significant rise, far above therapeutic concentrations of CsA in blood. The increased concentration of the drug was accompanied by typical CsA toxic side effects; rise in serum creatinine and urea level as well as hypertension,4 which appeared a few days after SRL introduction. Reduction of CsA doses caused normalization of the drug level in blood. The hepatic microsomal cytochrome P450 superfamily (P450) includes the mixed-function oxidase system, which catalyzes the metabolism of numerous lipophilic endogenous and exogenous compounds. The human cytochrome enzyme CYP3A4, comprising approximately 30% of the total hepatic P450 system, metabolizes many structurally diverse compounds, including CsA and SRL.5,6 At therapeutic concentrations, each drug is typically metabolized primarily by this single isoenzyme of the P450 system. The rate and pathway of metabolism is determined by an
individual’s phenotype, concomitant drug therapy, and disease state. Drug– drug interactions at the level of P450 3A4 may influence rate of SRL and CsA drug biotransformation, with a resultant increase in blood CsA and/or SRL concentrations. Our patient showed an increase in CsA concentrations, an observation consistent with suggestions to use SRL to reduce CsA dosages.7 Another contribution for observed interaction can be competition of CsA and SRL for P-gp drug transporter (multidrug resistance-1 gene product), which exports a wide variety of xenobiotics from the cytoplasm outside the cell. The immunosuppressive agents CsA, SRL, and corticosteroids act as substrates and inhibitors of P-gp. They are not the only substrates for transport by P-gp. Thus they compete for transport among themselves and with a large number of other drugs and endogenous compounds handled by this transporter,8 but additionally as available data suggest SRL may function as an MDR-reversing agent, thereby influencing the pharmacokinetics of other drugs.9 The study in rats confirmed that concomitant administration of SRL and CsA produced an increase in CsA blood and tissue concentrations.10 However, Kaplan et al11 reported that administration of CsA and SRL in renal transplant patients resulted in elevated SRL blood concentrations but had no effects on CsA pharmacokinetics. The
CYCLOSPORINE AND SIROLIMUS INTERACTION
authors postulated a 4-hour interval in dosing the two drugs to avoid the drug interaction. An increased level of CsA observed after SRL introduction into the therapeutic regimen of a kidney transplant patient may be explained by a drug– drug interaction at the level of both CYP3A4 and P-glycoprotein. Myelosuppression observed in our patient was probably a side effect of mycophenolate mofetil, since blood morphology parameters normalized shortly after withdrawal of the drug, an observation consistent with the report of Engelen et al.12 REFERENCES 1. Kovarik JM, Burtin P: Immunosuppressants in advanced clinical development for organ transplantation and selected autoimmunediseases. Expert Opin Emerg Drugs 8:47, 2003 2. Bai S, Stepkowski SM, Kahan BD, et al: Metabolic interaction between cyclosporine and sirolimus. Transplantation 77:1507, 2004 3. Kelly P, Kahan BD: Review: metabolism of immunosuppressant drugs. Curr Drug Metab 3:275, 2002 4. Lo A, Burckart GJ: P-glycoprotein and drug therapy in organ transplantation. J Clin Pharmacol 39:995, 1999 5. Kronbach T, Fischer V, Meyer UA: Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family
2319 as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs. Clin Pharmacol Ther 43:630, 1988 6. Sattler M, Guengerich FP, Yun CH, et al: Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab Dispos 20:753, 1992 7. Mahalati K, Kahan BD: Clinical pharmacokinetics of sirolimus. Clin Pharmacokin 40:573, 2001 8. Miller DS, Fricker G, Dreve J: P-glycoprotein-mediated transport of a fluorescent rapamycin derivate in renal proximal tubule. J Pharmacol Exp Ther 282:449, 1997 9. Arceci R, Stieglitz, Bierer B: Immunosuppressants FK 506 and Rapamycin function as reversal agents of the multidrug resistance phenotype. Blood 80:1528, 1992 10. Napoli KL, Wang ME, Stepkowski SM, et al: Relative tissue distributions of cyclosporine and sirolimus after concomitant peroral administration to the rat: evidence for pharmacokinetic. Ther Drug Monit 20:123, 1998 11. Kaplan B, Meier-Kriesche HU, Napoli KL, et al: The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther 63:48, 1998 12. Engelen W, Verpooten GA, Van der Planken M, et al: Four cases of red blood cell aplasia in association with the use of mycophenolate mofetil in renal transplant patients. Clin Nephrol 60:119, 2003