Clinical Pharmacokinetics and Impact of Hematocrit on Monitoring and Dosing of Tacrolimus Early After Heart and Lung Transplantation

Abstract

The calcineurin inhibitor tacrolimus is an effective immunosuppressant and is extensively used in solid organ transplantation. In the first week after heart and lung transplantation, tacrolimus dosing is difficult due to considerable physiological changes because of clinical instability, and toxicity often occurs, even when tacrolimus concentrations are within the therapeutic range. The physiological and pharmacokinetic changes are outlined. Excessive variability in bioavailability may lead to higher interoccasion (dose-to-dose) variability than interindividual variability of pharmacokinetic parameters. Intravenous tacrolimus dosing may circumvent this high variability in bioavailability. Moreover, the interpretation of whole-blood concentrations is discussed. The unbound concentration is related to hematocrit, and changes in hematocrit may increase toxicity, even within the therapeutic range of whole-blood concentrations. Therefore, in clinically unstable patients with varying hematocrit, aiming at the lower therapeutic level is recommended and tacrolimus personalized dosing based on hematocrit-corrected whole-blood concentrations may be used to control the unbound tacrolimus plasma concentrations and subsequently reduce toxicity. Invited proposal CPKA-D-18-00212.

Factors Affecting Time-Varying Clearance of Cyclosporine in Adult Renal Transplant Recipients: A Population Pharmacokinetic Perspective

“…This relationship is consistent with known physiological properties [48]. Moreover, increases in the HCT led to the elevation of CsA binding to erythrocytes, which could partly prevent CsA extraction via the liver and distribution into peripheral tissues, resulting in elevated concentrations and decreased CL/F [21][22][23].…”

Prediction of tacrolimus and Wuzhi tablet pharmacokinetic interaction magnitude in renal transplant recipients

“…Taking collinearity into consideration, body weight was not included in the subsequent analysis because its correlation coefficient with sex was .7. Although the CYP3A5 genotype, PPI and Hct did not show significant correlations with ΔC 0 /D, they were still included in the following multivariate models due to previous reports of their potential clinical significance in DDI 20–23 …”

Variability of Tacrolimus Trough Concentration in Liver Transplant Patients: Which Role of Inflammation?

“…The association between ALAT and tacrolimus C/D was expected, given that tacrolimus is highly metabolized by cytochrome P4503A4/3A5; decreased hepatic clearance could require reducing the daily dose to maintain the tacrolimus Cmin within the target therapeutic window, consequently leading to an increase in the tacrolimus C/D. In addition, tacrolimus is taken up by and binds to erythrocytes, resulting in a proportion of its related bound form increasing, along with an increase in hematocrit [23,24], which would explain the positive association between hematocrit and tacrolimus Cmin. In addition, acute inflammation episodes are characterized by the increased synthesis of acute-phase proteins, including alpha1-acid glycoprotein, for which tacrolimus shows high affinity and saturable binding capability [25].…”