Future of the Pharmacogenomics of Calcineurin Inhibitors in Renal Transplant Patients

Abstract

Since the introduction of calcineurin inhibitors (CNIs), cyclosporine A (CsA) in the early 1980s, and tacrolimus (Tac) in the 1990s, the short-term and long-term survival of kidney grafts have been significantly improved [1]. Nowadays, either CsA or Tac is one of the most commonly used immunosuppressant in renal transplant patients. However, both of them have a narrow therapeutic window and large interindividual variability, resulting in therapeutic drug monitoring (TDM), necessary for adjusting the dose in order to reduce the toxicity and improve the efficacy. Although TDM is widely recommended in clinical practice and has been conducted for approximately 30 years, this strategy for CNI therapy is controversial according to recent reports [2]. First, the determination of area under the concentration–time curve (AUC) is hard to perform in clinical practice and the evidence for the use of limited sampling strategies is weak [3]. Second, given the drug interactions, diet and poly morphisms potentially attribute to the variability in the pharmacokinetics of CNIs, the start and optimal titration dose for individual patients is difficult to determine based solely on the empirical dose adjustment based on TDM [2]. Third, TDM only provides pharmacokinetic information, and the correlation between pharmacokinetics and pharmacodynamics remains controversial [2]. Thus, more methods should be established to assist TDM and efforts should now be focused on explaining the interindividual variations in the pharmacokinetics and p harmacodynamics of CNIs.