Unbound Plasma, Total Plasma, and Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation
Por:
Sikma MA, Van Maarseveen EM, Hunault CC, Moreno JM, Van de Graaf EA, Kirkels JH, Verhaar MC, Grutters JC, Kesecioglu J, De Lange DW and Huitema ADR
Publicada:
1 jun 2020
Ahead of Print:
1 dic 2019
Resumen:
Background and Objective 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.
Filiaciones:
Sikma MA:
Dutch Poisons Information Center and Department of Intensive Care, Division of Anesthesiology, Intensive Care and Emergency Medicine, University Medical Center Utrecht and Utrecht University, F06.149, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.
Department of Intensive Care, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.
Van Maarseveen EM:
Department of Clinical Pharmacy, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
Hunault CC:
Dutch Poisons Information Center, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
:
Department of Pharmacy and Pharmaceutical Technology, University of Valencia and University Hospital Dr. Peset, Valencia, Spain
Van de Graaf EA:
Department of Lung Transplantation, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
Kirkels JH:
Department of Heart Transplantation, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
Verhaar MC:
Department of Nephrology and Hypertension, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
Grutters JC:
Department of Lung Transplantation, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
Department of Pulmonology, St. Antonius Hospital, Nieuwegein, The Netherlands
Kesecioglu J:
Department of Intensive Care, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
De Lange DW:
Dutch Poisons Information Center and Department of Intensive Care, Division of Anesthesiology, Intensive Care and Emergency Medicine, University Medical Center Utrecht and Utrecht University, F06.149, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
Department of Intensive Care, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
Huitema ADR:
Department of Clinical Pharmacy, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands
Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Green Published, hybrid
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