Pharmacokinetics and Toxicity of Tacrolimus Early After Heart and Lung Transplantation

• Published in: American journal of transplantation Vol. 15; no. 9; pp. 2301 - 2313
• Main Authors: Sikma, M. A., van Maarseveen, E. M., van de Graaf, E. A., Kirkels, J. H., Verhaar, M. C., Donker, D. W., Kesecioglu, J., Meulenbelt, J.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2015
• Subjects: calcineurin inhibitor: tacrolimus; critical care/intensive care management; Drug Monitoring; drug toxicity; Graft Rejection - metabolism; Graft Rejection - prevention & control; Heart; Heart-Lung Transplantation; Humans; immunosuppressant; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - toxicity; Morbidity; patient safety; pharmacokinetics/pharmacodynamics; Postoperative Complications; Prognosis; Tacrolimus - pharmacokinetics; Tacrolimus - toxicity; Tissue Distribution; Toxicity; Transplants & implants; patient safety; immunosuppressant; calcineurin inhibitor: tacrolimus; drug toxicity; pharmacokinetics/pharmacodynamics; critical care/intensive care management
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.13309

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. Clinical instability early after heart and lung transplantation significantly changes tacrolimus pharmacokinetics, complicates dosing, and may increase unbound plasma concentration, potentiating nephrotoxicity and morbidity.