Therapeutic Monitoring of Calcineurin Inhibitors for the Nephrologist

Abstract

The calcineurin inhibitors (CNI) cyclosporine and tacrolimus remain the backbone of immunosuppression for most kidney transplant recipients. Despite many years of experience, protocols that optimize efficacy with minimal toxicity remain a subject of debate. Nevertheless, studies of the pharmacokinetic properties of the CNI, particularly cyclosporine, have led to improved dosing strategies. The purpose of this article is to review the current understanding of CNI pharmacokinetics and its relevance to proper dosing and monitoring of these medications. This article also reviews the trials that have helped to define the optimal dosages and discusses the effect of adjunctive immunosuppressive agents on CNI pharmacokinetics and dosing.

Safety and Tolerability of Cyclosporin A in Severe Traumatic Brain Injury Patients: Results from a Prospective Randomized Trial

“…With the increased clinical use of CsA in transplantation medicine and to treat autoimmune disease, significant CsArelated side effects have become apparent in the organ transplant population, and the regulation of immunosuppression remains a challenge in the care of these transplant patients (Shaw et al, 1996). Furthermore, CsA is a drug with a narrow therapeutic index, and is characterized by significant pharmacokinetic inter-and intra-individual variability and unpredictability in its pharmacodynamic effects, mandating strict blood level monitoring and careful titration (Danovitch, 2005;Kapturczak et al, 2004, Paul andde Fijter, 2004;Ptachcinski et al, 1986;Schiff et al, 2007).…”

ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome

“…1,5 To minimize side effects without increasing the risk of rejection, treatment is titrated to target CsA blood levels according to well established guidelines. 6 However, the therapeutic index remains narrow, whereas the frequency and severity of CsA-related adverse effects are considerably variable among patients, even at comparable CsA levels. 1,6 This suggests the possibility that a heterogeneous individual susceptibility may result in increased risk in some patients despite exposure to CsA levels that in the majority of cases are devoid of significant toxicity.…”

“…6 However, the therapeutic index remains narrow, whereas the frequency and severity of CsA-related adverse effects are considerably variable among patients, even at comparable CsA levels. 1,6 This suggests the possibility that a heterogeneous individual susceptibility may result in increased risk in some patients despite exposure to CsA levels that in the majority of cases are devoid of significant toxicity. 6 Thus, identifying markers or predictors of individual response to CsA therapy might help to tailor CsA therapy and optimize the risk/benefit profile of CsA-based immunosuppression.…”

Association of CYP3A variants with kidney transplant outcomes

“…2 However, the clinical use of cyclosporine has been limited by its narrow therapeutic index and its variable interindividual pharmacokinetics. 3 Therapeutic drug monitoring of cyclosporine is routinely performed, with the drug dosage adjusted according to wholeblood drug concentrations and patient clinical response. 3 An understanding of the influence of genetic factors on the pharmacokinetics of calcineurin inhibitors could allow identification of the optimal immunosuppressant drug combination, starting dose, and maintenance regimen for a particular individual, and help to identify patients with an increased risk of adverse effects.…”