From the Guidelines
Tacrolimus is the preferred choice over cyclosporine for immunosuppression in liver transplant patients due to its association with reduced mortality, graft loss, and rejection rates, as evidenced by a meta-analysis including 3813 patients 1. The differences between tacrolimus and cyclosporine are significant, with tacrolimus being generally more potent and requiring lower doses to achieve immunosuppression.
- Typical oral doses of tacrolimus are 0.1-0.3 mg/kg/day, compared to 3-10 mg/kg/day for cyclosporine.
- Tacrolimus is often preferred in liver transplantation as it is associated with better patient and graft survival, and lower rejection rates 1.
- Tacrolimus also causes less hypertension, hyperlipidemia, and gingival hyperplasia than cyclosporine, but more commonly causes neurotoxicity, diabetes mellitus, and gastrointestinal disturbances.
- Both medications require therapeutic drug monitoring due to narrow therapeutic windows and significant drug interactions.
- The choice between these medications depends on transplant type, patient-specific factors, and institutional protocols, with tacrolimus being used in almost 90% of liver transplanted patients 1. A prolonged-release formulation of tacrolimus has been developed to provide once-daily dosing, with similar efficacy and safety to the twice-daily formulation 1. In contrast, cyclosporine is more commonly associated with dyslipidemia and gingival hyperplasia, and is available in original (Sandimmune) and microemulsion (Neoral) formulations with different bioavailability profiles 1. Overall, the evidence suggests that tacrolimus is the preferred choice for immunosuppression in liver transplant patients due to its association with improved patient and graft outcomes, and its more favorable side effect profile compared to cyclosporine 1.
From the FDA Drug Label
In a randomized, open-label, multicenter trial (Study 1), 1,589 kidney transplant patients received tacrolimus (Group C, n=401), sirolimus (Group D, n=399), or one of two cyclosporine (CsA) regimens (Group A, n=390 and Group B, n=399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab Patients in the tacrolimus group exhibited higher estimated creatinine clearance rates (eCLcr) using the Cockcroft-Gault formula (Table 20) and experienced fewer efficacy failures, defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or loss to follow-up (Table 21) in comparison to each of the other three groups Table 20. Estimated Creatinine Clearance at 12 Months (Study 1) Group eCLcr [mL/min] at Month 121 N MEAN SD MEDIAN (A) CsA/MMF/CS 390 56.5 25.8 56.9 -8.6 (-13.7, -3.7) (B) CsA/MMF/CS/Daclizumab 399 58.9 25.6 60.9 -6.2 (-11.2, -1.2) (C) Tac/MMF/CS/Daclizumab 401 65.1 27.4 66.2 - (D) Siro/MMF/CS/Daclizumab 399 56.2 27.4 57.3 -8.9 (-14.1, -3. 9) Table 21 Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1) Group A N = 390 Group B N = 399 Group C N = 401 Group D N = 399 Overall Failure 141 (36.2%) 126 (31.6%) 82 (20.4%) 185 (46.4%) Components of efficacy failure BPAR 113 (29.0%) 106 (26.6%) 60 (15.0%) 152 (38.1%) Graft loss excluding death 28 (7.2%) 20 (5.0%) 12 (3.0%) 30 (7.5%) Mortality 13 (3.3%) 7 (1.8%) 11 (2. 7%) 12 (3.0%) Lost to follow-up 5 (1.3%) 7 (1.8%) 5 (1.3%) 6 (1.5%)
Comparison of Tacrolimus and Cyclosporine:
- Efficacy: Tacrolimus exhibited higher estimated creatinine clearance rates and fewer efficacy failures compared to cyclosporine.
- Safety: Patients in the tacrolimus group were more likely to develop diarrhea and diabetes after transplantation, but experienced similar rates of infections compared to patients in the cyclosporine group.
- Dosing: The protocol-specified target tacrolimus trough concentrations were 3 to 7 ng/mL, while the observed median trough concentrations approximated 7 ng/mL throughout the 12-month trial.
- MMF Dose Reduction: The MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12, compared to 49% and 45% in the two cyclosporine arms. 2 2
From the Research
Comparison of Tacrolimus and Cyclosporine
- Tacrolimus and cyclosporine are both effective immunosuppressants used in solid organ transplantation, with similar short- and medium-term outcome variables, including 1-year serum creatinine, graft and patient survival 3.
- Initial randomized clinical trials showed a lower incidence of acute rejection in tacrolimus than in cyclosporine-treated patients, in combination with steroids and azathioprine 3.
- However, when used in conjunction with mycophenolate mofetil, the difference in the incidence of acute rejection episodes is less clear 3.
- Tacrolimus has been shown to be superior to cyclosporin in improving graft survival and preventing acute rejection after kidney transplantation, but increases post-transplant diabetes, neurological and gastrointestinal side effects 4.
Side Effects and Risk Factors
- Cyclosporine and tacrolimus have a different impact on cardiovascular risk factors, with tacrolimus having a better profile on arterial tension and lipid metabolism, and cyclosporine on glucose metabolism 3.
- Tacrolimus may be preferred over cyclosporine due to its fewer negative effects on kidney functions in the early postoperative period 5.
- Everolimus exposure is 2.5-fold higher with cyclosporine relative to tacrolimus, suggesting that the dose of everolimus when combined with tacrolimus needs to be higher than when combined with cyclosporine to reach a given everolimus blood level 6.
Efficacy and Safety
- Both tacrolimus and cyclosporine inhibit calcineurin and effectively down-regulate cytokines, with tacrolimus potentially being more advantageous due to its ability to lower the likelihood of acute rejection and reverse allograft rejection following cyclosporine treatment 7.
- Graft survival rates seem to be comparable for the two calcineurin inhibitors, with further research required to mitigate their side effects and improve long-term prognosis 7.