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PharmGKB summary: cyclosporine and tacrolimus pathways

Tacrolimus (FK506) and cyclosporine (cyclosporin A, CsA) are cornerstone immunosuppressive agents administered to solid organ transplant recipients to prevent and treat allograft rejection. The discovery of cyclosporine in the 1970s, and its entry into the collection of immunosuppressants in the early 1980s, was a major breakthrough in medicine. Cyclosporine was the most successful antirejection drug to date, and it radically improved the chance of survival for transplant recipients. In 1994, the Food and Drug Administration (FDA) approved tacrolimus, an effective alternative to cyclosporine [1]. Since then, tacrolimus and cyclosporine have become the principal immunosuppressive drugs for solid organ transplantation. The United States Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients showed that in 2011, 86% of the 16 055 patients who received a kidney transplant were prescribed tacrolimus upon discharge, and 2.4% were prescribed cyclosporine. One year after transplant, 84 and 4% of patients received tacrolimus and cyclosporine therapy, respectively [2]. Global differences exist in the usage of tacrolimus and cyclosporine: 2008 figures from the Australia and New Zealand Dialysis and Transplant Registry show that 61% of the 391 Australian patients who received a deceased kidney donor graft were prescribed tacrolimus, and 35% were prescribed cyclosporine. At 1-year post-transplant, these numbers changed to 55 and 33% for tacrolimus and cyclosporine, respectively [3]. Both drugs are also prescribed for liver, intestinal, lung, and heart transplant recipients [2], and can be used to manage severe autoimmune conditions, such as atopic dermatitis [4,5] and rheumatoid arthritis [6,7]. 
 
Tacrolimus and cyclosporine differ in their chemical structure: cyclosporine is a cyclic endecapeptide [8], whereas tacrolimus is a macrocyclic lactone [9]. However, they act in a similar manner. Both are calcineurin inhibitors; their main mechanism of action involves inhibition of this important phosphatase [1]. Tacrolimus exhibits similar effects to cyclosporine, but at concentrations 100 times lower [10]. Despite these differences in potency, tacrolimus and cyclosporine both show excellent survival rates for grafts across many comparative studies (summarized in Maes and Vanrenterghem [11]). However, several studies have shown that use of tacrolimus is associated with a lower allograft rejection rate compared with cyclosporine [12-14]. 
 
The principal adverse effects associated with tacrolimus and cyclosporine treatment are neurotoxicity, nephrotoxicity, hypertension, hyperglycemia, gastrointestinal disturbances, infections, and malignancy [15]. Although the two drugs have similar side-effect profiles, they may differ in the frequency of effects. For example, tacrolimus is more likely to cause alopecia [16], tremors [17], and new-onset diabetes mellitus [12], whereas cyclosporine is associated with hyperlipidemia [18], hypertrichosis, and gingival hyperplasia [19]. The idea that tacrolimus is less nephrotoxic than cyclosporine remains controversial [20], particularly as most studies of renal injury are based on evaluations in renal transplant patients, making it difficult to discriminate between drug-induced organ damage and other causes of organ dysfunction [21]. A recent study in pancreatic transplant recipients examined baseline kidney biopsies and 5-year post-transplant biopsies, and reported that the chronic nephrotoxic effects of tacrolimus and cyclosporine were similar [20]. 
 
Despite the success of both drugs, treatment is complicated by narrow therapeutic indices and large intrapatient and interpatient pharmacokinetic variability [22,23]. Although adequate exposure is essential to prevent rejection, overexposure can lead to toxicities that reduce tolerability and affect long-term allograft and patient survival [24]. Therapeutic drug monitoring (TDM), therefore, is mandatory for both drugs. However, because individual transplant recipients respond differently to similar immunosuppressant concentrations, achieving the recommended therapeutic target range does not guarantee absence of drug toxicity or complete immunosuppressant efficacy. A mechanistic understanding of the underlying factors affecting the pharmacokinetics and pharmacodynamics of calcinuerin inhibitors may prove useful in being able to further personalize these therapies. 
 
This review aims to provide a broad overview of recently published literature on the pharmacokinetics, pharmacodynamics, and pharmacogenetics of tacrolimus and cyclosporine in transplant patients, with the goals of clarifying current understanding and identifying areas of future research. In doing so, this review builds on the work of others in this field [1,8,24-27]. A particular emphasis is given to pharmacogenetics, as developments in this area may provide a way to optimize treatment with these drugs, potentially avoiding negative side effects while still maintaining efficacy.