title: Pharmacokinetics and Toxicity of Tacrolimus Early After Heart and Lung Transplantation.
abstract: Annually, about 8000 heart and lung transplantations are successfully performed worldwide. However, morbidity and mortality still pose a major concern. Renal failure in heart and lung transplant recipients is an essential adverse cause of morbidity and mortality, often originating in the early postoperative phase. At this time of clinical instability, the kidneys are exposed to numerous nephrotoxic stimuli. Among these, tacrolimus toxicity plays an important role, and its pharmacokinetics may be significantly altered in this critical phase by fluctuating drug absorption, changed protein metabolism, anemia and (multi-) organ failure. Limited understanding of tacrolimus pharmacokinetics in these circumstances is hampering daily practice. Tacrolimus dose adjustments are generally based on whole blood trough levels, which widely vary early after transplantation. Moreover, whole blood trough levels are difficult to predict and are poorly related to the area under the concentration-time curve. Even within the therapeutic range, toxicity may occur. These shortcomings of tacrolimus monitoring may not hold for the unbound tacrolimus plasma concentrations, which may better reflect tacrolimus toxicity. This review focuses on posttransplant tacrolimus pharmacokinetics, discusses relevant factors influencing the unbound tacrolimus concentrations and tacrolimus (nephro-) toxicity in heart and lung transplantation patients.
authors.affiliation: Department of Intensive Care Medicine and National Poisons Information Center, University Medical Center of Utrecht, the Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Sikma
authors.affiliation: Department of Clinical Pharmacy, University Medical Center of Utrecht, the Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: van Maarseveen
authors.affiliation: Department of Lung Transplantation, University Medical Center of Utrecht, the Netherlands.
authors.forename: E A
authors.initials: EA
authors.lastname: van de Graaf
authors.affiliation: Department of Heart Transplantation, University Medical Center of Utrecht, the Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Kirkels
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center of Utrecht, the Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: Verhaar
authors.affiliation: Department of Intensive Care Medicine, University Medical Center of Utrecht, the Netherlands.
authors.forename: D W
authors.initials: DW
authors.lastname: Donker
authors.affiliation: Department of Intensive Care Medicine, University Medical Center of Utrecht, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kesecioglu
authors.affiliation: Department of Intensive Care Medicine, National Poisons Information Center, Institute for Risk Assessment Sciences, University of Utrecht, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Meulenbelt
mesh_terms: D016903:Drug Monitoring; D006084:Graft Rejection / Q000378:metabolism* / Q000517:prevention & control; D016041:Heart-Lung Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D011183:Postoperative Complications; D011379:Prognosis; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000633:toxicity*; D014018:Tissue Distribution
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: calcineurin inhibitor: tacrolimus; critical care/intensive care management; drug toxicity; immunosuppressant; patient safety; pharmacokinetics/pharmacodynamics