Road to individualising tacrolimus therapy in solid organ transplant recipients

Road to individualising tacrolimus therapy in solid organ transplant recipients Christine E. Staatz1 1University of Queensland, School of Pharmacy, Brisbane, QLD, Australia.

Aims: Tacrolimus is a pivotal immunosuppressant used to prevent and treat rejection in solid organ transplant recipients. Sub-optimal dosing of tacrolimus causes significant morbidity and mortality. Drug-induced toxicity (including hypertension, hyperglycaemia, nephrotoxicity and neurotoxicity), excessive immunosuppression (causing infections and malignancy) and rejection are frequent problems transplant recipients face. In the last decade several advances have been made to improve tacrolimus dosing. The aim of this talk is to highlight recent progress in this field.

Methods: A literature search was conduct and key study findings have been summarized.

Results: Tacrolimus has a narrow therapeutic index and displays large between subject pharmacokinetic variability. Several studies have demonstrated a relationship between drug exposure and patient outcomes (1). Currently 56 population models have been developed to describe the pharmacokinetics of tacrolimus in transplant recipients (2). Variability in tacrolimus pharmacokinetics amongst transplant recipients has most commonly been related to cytochrome P450 3A5 genotype; patient weight, haematocrit and hepatic function; and time post-transplant (2). The predictive performance of Bayesian forecasting methods to predict tacrolimus area under the concentration-time curve (AUC) based on a limited number of concentration-time measurements has been examined in 14 studies (2). Bias in prediction ranged from -15 to 10%, while imprecision is generally poorer overall, ranging from 0.8 to 40%. In a single-centre, prospective study involving 80 renal transplant recipients, subjects were randomised to receive either computerised or conventional manual dosage adjustment based on trough concentrations (3). Computerised dosing was associated with a significantly higher proportion of trough concentrations within the target range and significantly lower plasma glucose levels at 8 weeks after transplantation (3). Further work is required to promote the uptake of population pharmacokinetic models and Bayesian forecasting into the clinical setting (2). Programs are needed with comprehensive clinical capabilities which are flexible and user friendly. More research is also required to establish optimal tacrolimus exposure in transplant recipients. Since the SYMPHONY study (4) which demonstrated lower rates of acute rejection and improved graft function with low-dose tacrolimus in combination with mycophenolate mofetil and corticosteroids, many transplant centres are using tacrolimus minimisation protocols and lower target tacrolimus trough concentrations (3-7ng/mL). Further prospective studies are required, covering a range of post-transplant times to determine optimal AUC targets. In terms of its mechanism of action, tacrolimus blocks the calcineurin enzyme leading to inhibition of transcription of interleukin-2 and other cytokines normally generated during the late phase of T-cell activation (5). An increasing number of studies are starting to examine the biological efficacy of tacrolimus through immune parameters such as calcineurin enzyme activity, interleukin-2 mRNA expression and interleukin-2 production (5). Pharmacokinetic-pharmacodynamic models based on measurement of an appropriate biomarker may be helpful in adjusting the tacrolimus dose more precise to individual immunopharmacological profiles in the future.

Conclusion: Patient outcomes in solid organ transplant recipients are likely to be improved if dosing of tacrolimus is individualised, with concentration targeting based on rigorous pharmacokinetic and pharmacodynamics analyses.

References: 1. Staatz CE, Tett SE. Pharmacokinetic and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 2004;43(10):623-53. 2. Brooks E, Tett SE, Isbel NM, Staatz CE. Population pharmacokinetic modelling and bayesian estimation of tacrolimus exposure. Clin Pharmacokinet. 2016 [in press]. 3. Storset E, Asberg A, Skauby M, Neely M, Gergan S, Bremer S, et al. Improved tacrolimus target concentration achievement using computerized dosing in renal transplant recipients. Transplantation 2015; 99(10): 2158-66. 4. Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N. Engl. J. Med. 2007;357:2562–2575. 5. Barraclough KA, Staatz CE, Isbel NM, McTaggart SJ. Pharmacodynamic monitoring of immunosuppression in kidney transplantation. Nephrology 2010;15(5):522-32.