Unbound Plasma, Total Plasma, and Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

Abstract

Background and Objective Abstract Therapeutic drug monitoring of tacrolimus whole-blood concentrations is standard care in thoracic organ transplantation. Nevertheless, toxicity may appear with alleged therapeutic concentrations possibly related to variability in unbound concentrations. However, pharmacokinetic data on unbound concentrations are not available. The objective of this study was to quantify the pharmacokinetics of whole-blood, total, and unbound plasma tacrolimus in patients early after heart and lung transplantation. Methods Twelve-hour tacrolimus whole-blood, total, and unbound plasma concentrations of 30 thoracic organ recipients were analyzed with high-performance liquid chromatography-tandem mass spectrometry directly after transplantation. Pharmacokinetic modeling was performed using non-linear mixed-effects modeling. Results Plasma concentration was < 1% of the whole-blood concentration. Maximum binding capacity of erythrocytes was directly proportional to hematocrit and estimated at 2700 pg/mL (95% confidence interval 1750-3835) with a dissociation constant of 0.142 pg/mL (95% confidence interval 0.087-0.195). The inter-individual variability in the binding constants was considerable (27% maximum binding capacity, and 29% for the linear binding constant of plasma). Conclusions Tacrolimus association with erythrocytes was high and suggested a non-linear distribution at high concentrations. Monitoring hematocrit-corrected whole-blood tacrolimus concentrations might improve clinical outcomes in clinically unstable thoracic organ transplants. Clinical Trial Registration NTR 3912/EudraCT 2012-001909-24.

Tacrolimus dose, blood concentrations and acute nephrotoxicity, but not CYP3A5/ABCB1 genetics, are associated with allograft tacrolimus concentrations in renal transplant recipients

“…There appeared to be a stronger direct correlation between dose and C Graft than between dose and C 0Blood . An important source of variability in the relationship between dose and C 0Blood is likely to be the significant binding of tacrolimus to red blood cells and plasma proteins 40 . Since only unbound tacrolimus is available to be taken up (either passively or actively) from plasma into the allograft kidney, the stronger correlation may be due to C Graft better reflecting unbound plasma tacrolimus concentrations and hence dose.…”

Model-Informed Precision Dosing of Everolimus: External Validation in Adult Renal Transplant Recipients

“…For tacrolimus, which displays similar erythrocyte partitioning as everolimus, various authors have advocated for the implementation of TDM based on haematocrit-normalised whole-blood concentrations across different fields of transplantation [39][40][41][42][43]. Additionally, a recent consensus paper on tacrolimus TDM included recommendations for further investigation of alternative TDM strategies, including haematocrit normalisation, to explain and resolve the highly variable tacrolimus efficacy in patient subpopulations [37].…”

Synthèse des recommandations de l’International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) sur le suivi thérapeutique pharmacologique du tacrolimus

“…Les données en transplantation thoracique (cardiaque, pulmonaire et cardio-pulmonaire) sont anciennes et les recommandations datant de 20 ans font état d'une cible de 15 à 20 ng/mL qui n'est plus d'actualité [12]. Deux études récentes, l'une en transplantation cardiaque et l'autre en transplantation pulmonaire, suggèrent que des concentrations résiduelles au-delà de 15 ng/mL au cours des 2 premières semaines post-transplantation sont péjoratives au plan rénal pour les patients [13,14]. Les données disponibles à ce jour ne permettent pas de recommander une minimisation plus importante de l'exposition au tacrolimus dans ces indications.…”