What is it about?
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.
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Why is it important?
In the first week after thoracic organ transplantation, extreme interoccasion (dose-to-dose) variability in pharmacokinetic parameters is shown to be higher than interindividual variability and is mainly due to excessive variability in bioavailability. The whole-blood to unbound plasma concentration ratios differ with changes in hematocrit, and show saturation in the higher range of whole-blood tacrolimus concentrations, which may increase toxicity in these higher concentration ranges. Due to the complicated bioanalytical challenges, hematocrit- corrected whole-blood concentrations may be the most feasible and suitable surrogate for the prediction of clinical outcomes.
Perspectives
Tacrolimus pharmacokinetics differ between clinically stable and clinically unstable patients, such as thoracic organ recipients. This results in higher rates of tacrolimus nephrotoxicity in these latter patients. In unstable thoracic organ recipients, a large interoccasion variability in relative bioavailability makes pharmacokinetic-guided dosing of orally administered tacrolimus of limited added value. Within the blood compartment, erythrocyte concentrations appear to be an important factor to consider as tacrolimus is mainly associated with these cells. In clinically unstable thoracic organ transplant patients, erythrocyte concentrations are highly variable, subsequently changing the unbound tacrolimus concentrations. To improve tacrolimus personalized dosing in the future, we recommend administering tacrolimus intravenously and aiming at the lower therapeutic range value in the first days after transplantation. Monitoring hematocrit-corrected whole-blood concentrations may further improve tacrolimus dosing.
Ms Maaike A. Sikma
Universitair Medisch Centrum Utrecht
Read the Original
This page is a summary of: Clinical Pharmacokinetics and Impact of Hematocrit on Monitoring and Dosing of Tacrolimus Early After Heart and Lung Transplantation, Clinical Pharmacokinetics, December 2019, Springer Science + Business Media,
DOI: 10.1007/s40262-019-00846-1.
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