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Predicting behavior of immunosuppressants in liver transplantation
LIVER TRANSPLANTATION WORLDWIDE Predicting Behavior of Immunosuppressants in Liver Transplantation Clinical Utility of Monitoring Tacrolimus Blood Concentrations in Liver Transplant Recipients. Venkataramanan R, Shaw LM, Sarkozi L, et al. J Clin Pharmacol 2001;41:542-551. (Reprinted by Permission of Sage Publications Inc.) Abstract
Abstract Unavailable. Please See Print Journal.
Comments Legend has it that if you ask an Irishman for directions, he will suggest a landmark a mile beyond the destination. In a not too dissimilar fashion, Dr. Tom Starzl, whose mother was Irish, recommended dosing cyclosporine to nephrotoxicity and then reducing the dose. This was before therapeutic monitoring (TDM) was
848
introduced for cyclosporine. It was an inspired observation because it was also before the drug’s mechanism of action was known. Subsequent studies showed that both the desired and undesired effects of cyclosporine were related to its inhibition of calcineurin phosphatase and thus nephrotoxicity was an external marker of the level of immunosuppression. With the advent of assays for cyclosporine, its pharmacokinetic profile was found to be extremely variable and TDM was recommend.1 Unfortunately drug trough levels, which were used to guide treatment for almost 2 decades, were found not to correlate with either total drug exposure or clinical outcomes.2 Tacrolimus shares with cyclosporine the pharmacodynamic linkage between desired and undesired effects, but its pharmacokinetic profile is different. Pharmacokinetic study of a subset of patients who took part in the registration trials of tacrolimus showed that the drug trough level correlated with total exposure as measured by the area under the curve (I. Bekersky, Fujisawa, USA, personal communication, February 2002). The so-called good behavior of tacrolimus has been confirmed in later studies.3 The current study looks at the relationship of trough tacrolimus blood level and acute rejection, nephrotoxicity, and other toxicities after liver transplantation. The primary goal of this multicenter prospective study was to validate an enzyme-linked immunosorbent assay of tacrolimus, which was dosed according to local practice. Presumably this allowed for a wide variation in drug exposure and the discrimination of its association with the clinical endpoints. Data were collected prospectively, and associations were tested using logistic regression analysis, Cox proportional hazards regression model, and receiver operator characteristic (ROC) curve analysis. One hundred and eleven adult liver transplant recipients were followed up for 3 months after transplantation. Thirty-six patients experienced acute rejection. Thirty-eight experienced nephrotoxicity (doubling of serum creatinine), and 10 patients experienced other toxicities thought to be related to tacrolimus. Trough levels for tacrolimus varied between 0 and 50 ng/mL. The event rate and range of drug exposure were sufficient to allow for detection of relationships. Logistic regression analysis showed a significant correlation between the trough level and a decreasing risk of acute rejection, an increasing risk of nephrotoxicity, and an increasing risk of other toxicities. This information is most clinically accessible in a probability plot, which is
Liver Transplantation, Vol 8, No 9 (September), 2002: pp 848-850
849
Liver Transplantation Worldwide
Figure 1. Effect of whole blood levels of tacrolimus on the probability of rejection, nephrotoxicity, or other toxicity in liver transplant recipients. (Reprinted by Permission of Sage Publications Inc.)
reproduced here (Fig. 1). This shows that at a tacrolimus trough level of 10 ng/mL there is a 20% probability of acute rejection and nephrotoxicity. If the exposure to tacrolimus increases to 15 ng/mL, the probability of acute rejection decreases to 10% but the probability of nephrotoxicity increases to above 50%. On the other hand, ROC curves show that tacrolimus blood concentrations alone cannot differentiate between acute rejection and a nonevent with good sensitivity. Discrimination for toxicity is greatest at trough concentrations of approximately 12 ng/mL for nonrenal toxicity and at a range from 12 to 15 ng/mL for nephrotoxicity. An interesting associated finding is that ROC analysis for alanine aminotransferase values over 200 IU/L distinguishes acute rejection with sensitivity and specificity of 88% and 75%, respectively. This study is important because it suggests that the pharmacokinetic–pharmacodynamic– clinical outcome relationship is stable and predictable in liver transplant recipients receiving tacrolimus. It shows that there is no therapeutic window for a protocol based on full-dose tacrolimus therapy. Some patients will experience rejection or toxicity. Currently the nephrotoxicity associated with calcineurin inhibition is considered clinically acceptable, but a doubling of the serum creatinine level in these patients represents a significant impairment in renal function and a major risk to longterm function. A predictable relationship between drug exposure and clinical events, seen in this study with tacrolimus, cannot be present in immunosuppressants currently administered in fixed doses, such as prednisone, azathioprine, and mycophenolate mofetil, because these
Image Unavailable. Please See Print Journal.
drugs have large interpatient variability in bioavailability and TDM is not used. Newer assays for mycophenolic acid are unlikely to improve the relationship for mycophenolate mofetil unless area under the curve measurement is used.4 On the other hand, sirolimus, a molecule with a very similar structure to that of tacrolimus, seems to behave predictably and a correlation between trough levels and clinical outcome has been derived for renal transplant patients receiving that drug in combination with cyclosporine.5 When given together, tacrolimus and sirolimus continue to behave predictably in liver transplant recipients.3 The study by Venkataramanan et al, reviewed here, is an elegant analysis of the clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. It deserves close review, and it should help inform us regarding our use of that drug in liver transplantation. Although not specifically analyzed, it implies that there is a relationship between nephrotoxicity and freedom from rejection in tacrolimus-treated patients. This likely also applies to cyclosporine because the correlation depends on the pharmacodynamic rather than the pharmacokinetic characteristics of the calcineurin inhibitor. This implies that Dr. Starzl’s advice, before the development of therapeutic drug monitoring, was sound. Vivian McAlister, FRCSI Department of Surgery University Of Western Ontario London, Ontario, Canada doi: 10.1056/jlts.2002.34967
850
Liver Transplantation Worldwide
References 1. Burckart GJ, Venkataramanan R, Ptachcinski RJ, Starzl TE, Gartner JC Jr, Zitelli BJ, et al. Cyclosporine absorption following orthotopic liver transplantation. J Clin Pharmacol 1986;26:647651. 2. Grant D, Kneteman N, Tchervenkov J, Roy A, Murphy G, Tan A, et al. Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: Results of a prospective, randomized comparison of neoral and sandimmune for liver transplantation (NOF-8). Transplantation 1999;67:1133-1137.
3. McAlister VC, Peltekian KM, Malatjalian DA, Colohan S, MacDonald S, Bitter-Suermann H, MacDonald AS. Orthotopic liver transplantation using low-dose tacrolimus and sirolimus. Liver Transpl 2001;7:701-708. 4. Pillans PI, Rigby RJ, Kubler P, Willis C, Salm P, Tett SE, Taylor PJ. A retrospective analysis of mycophenolic acid and cyclosporin concentrations with acute rejection in renal transplant recipients. Clin Biochem 2001;34:77-81. 5. MacDonald A, Scarola J, Burke JT, Zimmerman JJ. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther 2000;22(suppl B):B101-121.
Abstract Unavailable. Please See Print Journal.
Comments Legend has it that if you ask an Irishman for directions, he will suggest a landmark a mile beyond the destination. In a not too dissimilar fashion, Dr. Tom Starzl, whose mother was Irish, recommended dosing cyclosporine to nephrotoxicity and then reducing the dose. This was before therapeutic monitoring (TDM) was
848
introduced for cyclosporine. It was an inspired observation because it was also before the drug’s mechanism of action was known. Subsequent studies showed that both the desired and undesired effects of cyclosporine were related to its inhibition of calcineurin phosphatase and thus nephrotoxicity was an external marker of the level of immunosuppression. With the advent of assays for cyclosporine, its pharmacokinetic profile was found to be extremely variable and TDM was recommend.1 Unfortunately drug trough levels, which were used to guide treatment for almost 2 decades, were found not to correlate with either total drug exposure or clinical outcomes.2 Tacrolimus shares with cyclosporine the pharmacodynamic linkage between desired and undesired effects, but its pharmacokinetic profile is different. Pharmacokinetic study of a subset of patients who took part in the registration trials of tacrolimus showed that the drug trough level correlated with total exposure as measured by the area under the curve (I. Bekersky, Fujisawa, USA, personal communication, February 2002). The so-called good behavior of tacrolimus has been confirmed in later studies.3 The current study looks at the relationship of trough tacrolimus blood level and acute rejection, nephrotoxicity, and other toxicities after liver transplantation. The primary goal of this multicenter prospective study was to validate an enzyme-linked immunosorbent assay of tacrolimus, which was dosed according to local practice. Presumably this allowed for a wide variation in drug exposure and the discrimination of its association with the clinical endpoints. Data were collected prospectively, and associations were tested using logistic regression analysis, Cox proportional hazards regression model, and receiver operator characteristic (ROC) curve analysis. One hundred and eleven adult liver transplant recipients were followed up for 3 months after transplantation. Thirty-six patients experienced acute rejection. Thirty-eight experienced nephrotoxicity (doubling of serum creatinine), and 10 patients experienced other toxicities thought to be related to tacrolimus. Trough levels for tacrolimus varied between 0 and 50 ng/mL. The event rate and range of drug exposure were sufficient to allow for detection of relationships. Logistic regression analysis showed a significant correlation between the trough level and a decreasing risk of acute rejection, an increasing risk of nephrotoxicity, and an increasing risk of other toxicities. This information is most clinically accessible in a probability plot, which is
Liver Transplantation, Vol 8, No 9 (September), 2002: pp 848-850
849
Liver Transplantation Worldwide
Figure 1. Effect of whole blood levels of tacrolimus on the probability of rejection, nephrotoxicity, or other toxicity in liver transplant recipients. (Reprinted by Permission of Sage Publications Inc.)
reproduced here (Fig. 1). This shows that at a tacrolimus trough level of 10 ng/mL there is a 20% probability of acute rejection and nephrotoxicity. If the exposure to tacrolimus increases to 15 ng/mL, the probability of acute rejection decreases to 10% but the probability of nephrotoxicity increases to above 50%. On the other hand, ROC curves show that tacrolimus blood concentrations alone cannot differentiate between acute rejection and a nonevent with good sensitivity. Discrimination for toxicity is greatest at trough concentrations of approximately 12 ng/mL for nonrenal toxicity and at a range from 12 to 15 ng/mL for nephrotoxicity. An interesting associated finding is that ROC analysis for alanine aminotransferase values over 200 IU/L distinguishes acute rejection with sensitivity and specificity of 88% and 75%, respectively. This study is important because it suggests that the pharmacokinetic–pharmacodynamic– clinical outcome relationship is stable and predictable in liver transplant recipients receiving tacrolimus. It shows that there is no therapeutic window for a protocol based on full-dose tacrolimus therapy. Some patients will experience rejection or toxicity. Currently the nephrotoxicity associated with calcineurin inhibition is considered clinically acceptable, but a doubling of the serum creatinine level in these patients represents a significant impairment in renal function and a major risk to longterm function. A predictable relationship between drug exposure and clinical events, seen in this study with tacrolimus, cannot be present in immunosuppressants currently administered in fixed doses, such as prednisone, azathioprine, and mycophenolate mofetil, because these
Image Unavailable. Please See Print Journal.
drugs have large interpatient variability in bioavailability and TDM is not used. Newer assays for mycophenolic acid are unlikely to improve the relationship for mycophenolate mofetil unless area under the curve measurement is used.4 On the other hand, sirolimus, a molecule with a very similar structure to that of tacrolimus, seems to behave predictably and a correlation between trough levels and clinical outcome has been derived for renal transplant patients receiving that drug in combination with cyclosporine.5 When given together, tacrolimus and sirolimus continue to behave predictably in liver transplant recipients.3 The study by Venkataramanan et al, reviewed here, is an elegant analysis of the clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. It deserves close review, and it should help inform us regarding our use of that drug in liver transplantation. Although not specifically analyzed, it implies that there is a relationship between nephrotoxicity and freedom from rejection in tacrolimus-treated patients. This likely also applies to cyclosporine because the correlation depends on the pharmacodynamic rather than the pharmacokinetic characteristics of the calcineurin inhibitor. This implies that Dr. Starzl’s advice, before the development of therapeutic drug monitoring, was sound. Vivian McAlister, FRCSI Department of Surgery University Of Western Ontario London, Ontario, Canada doi: 10.1056/jlts.2002.34967
850
Liver Transplantation Worldwide
References 1. Burckart GJ, Venkataramanan R, Ptachcinski RJ, Starzl TE, Gartner JC Jr, Zitelli BJ, et al. Cyclosporine absorption following orthotopic liver transplantation. J Clin Pharmacol 1986;26:647651. 2. Grant D, Kneteman N, Tchervenkov J, Roy A, Murphy G, Tan A, et al. Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: Results of a prospective, randomized comparison of neoral and sandimmune for liver transplantation (NOF-8). Transplantation 1999;67:1133-1137.
3. McAlister VC, Peltekian KM, Malatjalian DA, Colohan S, MacDonald S, Bitter-Suermann H, MacDonald AS. Orthotopic liver transplantation using low-dose tacrolimus and sirolimus. Liver Transpl 2001;7:701-708. 4. Pillans PI, Rigby RJ, Kubler P, Willis C, Salm P, Tett SE, Taylor PJ. A retrospective analysis of mycophenolic acid and cyclosporin concentrations with acute rejection in renal transplant recipients. Clin Biochem 2001;34:77-81. 5. MacDonald A, Scarola J, Burke JT, Zimmerman JJ. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther 2000;22(suppl B):B101-121.