Pharmacokinetics of Tacrolimus in Egyptian Liver Transplant Recipients: Role of the Classic Co-variables

Abstract

Objectives: This work was performed to study the pharmacokinetics of tacrolimus in adult liver transplant recipients after optimization of all the known classic factors contributing to inter-patient variability in whole blood tacrolimus levels. Also, to detect if any variability in whole blood tacrolimus levels still exists or this variability is only a function of the classic co-variables so that their optimization will diminish or eliminate it. Methods: Twenty-Six male patients with end-stage liver disease undergoing living donor liver transplantation were selected from the Gastroenterology Department of the International Medical Center, Cairo, Egypt, were enrolled in the study. A patient is initially considered to be a candidate for this study when tacrolimus was indicated as a part of a triple immune suppressive regimen with mycophenolate mofetil and prednisolone. Patients were selected to have non-significant variations in their demographics and pretreatment clinical data. Blood samples were drawn from each patient before the morning dose at specified intervals and the whole blood was assayed for tacrolimus, using Chemiluminescent Microparticle Immunoassay method (CMIA). Six months after liver transplantation, patients were classified into 3 groups based on their tacrolimus trough levels; normalized by its daily dose (C/D ratio), into fast, intermediate and slow metabolizers. Results: The results revealed unpredictable variability in whole blood tacrolimus levels among patients at each sampling time and a marked inter-patient variability in mean whole blood tacrolimus levels among individuals throughout the six months post transplantation period, (P value: <0.0001). Considerable inter-patient variability was also evident in tacrolimus pharmacokinetics. During 1 st month post-transplant, tacrolimus C/D ratio varied from 0.53 to 12.2 (ng/ml*1/mg) and tacrolimus oral clearance (CL/F) varied from 3.4 to 79.4 L/hr. At 3 rd month post-transplant, tacrolimus C/D ratio varied from 0.78 to 8.50 (ng/ml*1/mg) and tacrolimus CL/F varied from 4.9 to 53.2 L/hr. At 6 th month post-transplant, tacrolimus C/D ratio varied from 0.73 to 7.10 (ng/ml*1/mg) and tacrolimus CL/F varied from 5.9 to 56.8 L/hr. The overall mean C/D ratio and oral clearance also showed a great variability among patients with a mean of 2.80±1.89 (CV: 67.5%) and 21.3±12.9 (CV:60.7%), respectively. Conclusion: The variability in whole blood tacrolimus concentrations and tacrolimus pharmacokinetics existed in spite of careful patient selection and optimization of all the classic co-variables known to affect tacrolimus concentrations, suggesting the presence of other unstudied factors; the recently evolving genetic factors might contribute to this variability. It is recommended to still considering therapeutic drug monitoring as an integral part of tacrolimus therapy to control variations in response until the discovery of a model that considers all the expected covariates to predict the response.

Using Prior Knowledge on Systems Through PBPK to Gain Further Insight into Routine Clinical Data on Trough Concentrations: The Case of Tacrolimus in Chronic Kidney Disease

“…If the top-down approach was attempted without information from the bottom-up approach, the model would not have been identifiable to the level of unbound metabolic CL int, and the effect would have been masked by the high level of uncertainty and interpatient variability, as reported by other top-down-only studies. 4 , 43 Adopting this approach enables the incorporation of available or known covariate effects as strong fixed priors based on clinical and biochemical data. Subsequently, other undefined covariate effects of interest on the pharmacokinetic parameters were investigated (Fig.…”

Impacts of High Intra- and Inter-Individual Variability in Tacrolimus Pharmacokinetics and Fast Tacrolimus Metabolism on Outcomes of Solid Organ Transplant Recipients

“…Therapeutic drug monitoring (TDM) is essential for achieving therapeutic trough concentrations. Despite the fact that monitoring blood trough concentrations is an effective method for adjusting tacrolimus oral doses, clinical studies have reported that it may not be valuable for future dosage estimation and may also not be an accurate assessment of overall drug exposure among various individuals [ 17 , 23 , 24 , 25 , 26 ]. It is sometimes challenging to achieve and maintain target tacrolimus trough concentrations despite periodic tacrolimus TDM [ 3 ].…”

“…The narrow therapeutic index of tacrolimus necessitates the frequent monitoring of the whole-blood concentration to achieve optimal therapeutic levels while drug toxicity [ 17 , 23 , 24 , 25 , 26 ]. Even a small variance in the dose or concentration can lead to therapeutic failure.…”

Tacrolimus’s Time Below Therapeutic Range Is Associated With Acute Pancreatic Graft Rejection and the Development of De Novo Donor-specific Antibodies

“…It presents a narrow therapeutic window, requiring strict monitoring and constant dosing modification [ 5 ]. Differences in tacrolimus absorption [ 6 , 7 ], metabolism [ 8 , 9 ], and drug interactions [ 6 , 10 , 11 ] often lead to either sub- or supratherapeutic trough levels [ 12 , 13 ]. Above-target trough levels are associated with adverse effects, whereas those below target are associated with an increased risk of rejection and development of de novo donor-specific antibody (dnDSA) [ 14 , 15 ].…”

“…Given the pharmacokinetics and pharmacodynamics of tacrolimus [6,[8][9][10][11], several formulas have been developed to explore the correlation of tacrolimus trough levels with graft outcomes. Intrapatient variability (IPV) calculates the variability coefficient by dividing the standard deviation of tacrolimus samples by their mean [16,17].…”