Tacrolimus—why pharmacokinetics matter in the clinic

Abstract

The calcineurin inhibitor (CNI) Tacrolimus (Tac) is the most prescribed immunosuppressant drug after solid organ transplantation. After renal transplantation (RTx) approximately 95% of recipients are discharged with a Tac-based immunosuppressive regime. Despite the high immunosuppressive efficacy, its adverse effects, narrow therapeutic window and high intra- and interpatient variability (IPV) in pharmacokinetics require therapeutic drug monitoring (TDM), which makes treatment with Tac a major challenge for physicians. The C/D ratio (full blood trough level normalized by daily dose) is able to classify patients receiving Tac into two major metabolism groups, which were significantly associated with the clinical outcomes of patients after renal or liver transplantation. Therefore, the C/D ratio is a simple but effective tool to identify patients at risk of an unfavorable outcome. This review highlights the challenges of Tac-based immunosuppressive therapy faced by transplant physicians in their daily routine, the underlying causes and pharmacokinetics (including genetics, interactions, and differences between available Tac formulations), and the latest data on potential solutions to optimize treatment of high-risk patients.

Exploring the Knowledge, Attitude, and Practice of Sudanese Medical Doctors Towards Tacrolimus, at Ahmed Gasim Hospital, Kidney Transplant Center Unit, Khartoum, Sudan (2022 – 2023)

“…The dose adjustment not occur by just calculated the dose base on the BMI only, but the plasma level plays an important role. Machine-learning based approaches, statistic modelling, and genetic analyses, which have been proven to be effective in dose calculation recently in clinical practice (6,12,22). In the present study the medical doctors kept attention for the tacrolimus trough concentration level more than other parameters.…”

“…One brand of tacrolimus available in Sudan (Prograf® by Astellas), instead of that the patients who did the transplant operation out of Sudan came with different brands and therefore some of the physicians record abnormal trough plasma concentrations when they were shifted to the local available brand, which was a reasonable response among the pharmaceutical products as that differences on the impact of different pharmaceutical products observed also among the extended-release (ER-Tac) and immediate release (IR-Tac) (9,27). Bioequivalence between the generic or branded drugs and the original Prograf® has been shown in at least 10 publications, recently reviewed by Kocur et al with the exception of the granular formulation (Modigraf®), which showed a 23% and 18% higher mean for Cmax and AUC, respectively (12,(28)(29)(30). In the present study use of one brand exclude the impact of the drug formulation in the tacrolimus trough concentration among the population under study.…”

“…CYP3A43 is less well studied, and so little is known about its functions (10,11). besides P-glycoprotein, plasma protein concentrations, hematocrit, age, sex, ethnicity, time post-transplantation, type of transplanted organ, hepatic dysfunction, diurnal variations, food, and drug-drug interactions (10,12). Dosing recommendations are based on patient age, transplanted organ, time post-transplant, and concurrent immunosuppressive therapy, dosing suggestions are also provided based on race, with black patients requiring higher doses than white patients to achieve similar concentrations (10,13).…”