Clinical Pharmacokinetics and Pharmacodynamics of Tacrolimus in Solid Organ Transplantation

Abstract

The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients. Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates. Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 'acceptable' ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immunosuppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.

Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice

“…However, while we observed that a single injection with FK506 improved fear conditioned memory function in Tg2576 mice, prolonged treatment of humans with FK506 has been reported to be associated with significant side effects, most notably nephrotoxicity (Olyaei et al, 2001;Baran et al, 2004;Staatz and Tett, 2004). Therefore, before considering clinically attractive the idea of CaN inhibitors for treating AD, future studies will have to determine whether lower, less nephrotoxic doses of FK506 administered for longer periods of time still provide behavioral benefits or whether novel behaviorally-active drugs that selectively target only CaN in the CNS could eventually be designed.…”

Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients

“…The reason for the lower exposure for MR tacrolimus on d 84 is still unclear. It is well known that many factors infl uence the PK profiles of tacrolimus [1] . In this study, the patients were all in stable condition, and any drug known to alter the CYP450 enzyme system was prohibited before and during the study period to avoid drug-drug interaction.…”

“…It has been marketed mainly for preventing or treating graft rejection in solid organ transplantation [1,2] . Tacrolimus has a narrow therapeutic window, and its bioavailability shows high interand intra-individual variability [1,3,4] . The systemic exposure AUC is a significant efficacy variable; therefore, therapy is optimized on an individual patient basis by monitoring trough levels as surrogate markers of exposure.…”

Effects of bile duct stricture on the pharmacokinetics of the immunosuppressant tacrolimus in rats

“…TAC is the drug of choice for living donor liver transplant recipients in our university hospital, Kyoto Prefectural University of Medicine. The pharmacokinetics (PK) of TAC are characterized by a marked and unexplained variability, particularly in the early period after transplantation [5,6]. TAC is highly lipophilic and insoluble in water, and is a substrate for the drug efflux pump, P-glycoprotein (Pgp), and the metabolizing enzyme, cytochrome P450 (CYP) 3A.…”