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.

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

“…As allografts are nowadays rarely lost as a consequence of acute rejection, adverse events associated with long-term immunosuppression have become increasingly evident [19]. Reducing the toxic effects of immunosuppression has become a major goal in the treatment of transplant recipients [20]. The most frequently used means of Tac monitoring is the measurement of the predose concentration (C 0 ) in whole blood.…”

High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury

“…Furthermore, tacrolimus metabolism may change with drug-drug interactions by inhibiting or competing with the transporter P-glycoprotein (Pgp) and the enzymes cytochrome P450 (CYP) 3A4/5 [13, 14]. These variations in pharmacokinetics in the early phase may result in high fluctuations in the whole-blood tacrolimus concentrations, increasing tacrolimus toxicity and decreasing tacrolimus efficacy [15, 16]. …”

The Individual Tailoring of Immunosuppressive Therapy After Heart Transplantation

“…В крови препарат на 85-95% связан с эритроцитами, 0,5% -с лимфоцитами; в плазме крови на 60% такролимус связан с альбумином, 30% -с липопротеидами высокой плотности, 8% -липопротеидами низкой плотности, 2% -с липопротеидами очень низкой плотности. В крови происходит непрерывный обмен такролимуса между плазменными компонентами и форменными элементами крови, поэтому для определения концентрации предпочтительно использовать цельную кровь [54].…”