Comparative Clinical Pharmacokinetics of Tacrolimus in Paediatric and Adult Patients


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Abstract

Tacrolimus is a potent immunosuppressive agent used to prevent allograft rejection. The pharmacokinetics of tacrolimus have been studied in healthy volunteers and transplant recipients, mostly by using immunoassays to measure tacrolimus in plasma or blood. However, because of the cross-reactivity for certain tacrolimus metabolites of the antibodies used, these methods often lack specificity. This should be carefully taken into account when interpreting pharmacokinetic results for tacrolimus.In adult patients, tacrolimus is generally rapidly absorbed following oral administration (the time to reach maximum concentration is 1 to 2 hours), but in some patients absorption is slow or even delayed. Because of presystemic elimination, the oral bioavailability is low (around 20%) but may vary between 4 and 89%. Tacrolimus is highly bound to erythrocytes. Its binding to plasma proteins varies between 72 and 98% depending on the methodology used. Because of the extensive partitioning of tacrolimus into erythrocytes, its apparent volume of distribution (Vd) based on blood concentrations is much lower (1.0 to 1.5 L/kg) compared with values based on plasma concentrations (about 30 L/kg). Tacrolimus is metabolised by cytochrome P450 (CYP) 3A4 to at least 10 metabolites, some of which retain significant activity. Biliary excretion is the route of elimination of the tacrolimus metabolites. Systemic plasma clearance of tacrolimus is very high (0.6 to 5.4 L/h/kg), whereas blood clearance is much lower (0.03 to 0.09 L/h/kg). The terminal elimination half-life (t½β) of tacrolimus is approximately 12 hours (with a range of 3.5 to 40.5 hours).Only limited information is available on the pharmacokinetics of tacrolimus in paediatric patients. The rate and extent of tacrolimus absorption after oral administration do not seem to be altered in paediatric patients. The Vd of tacrolimus based on blood concentrations in paediatric patients (2.6 L/kg) is approximately twice the adult value. Blood clearance of tacrolimus is also approximately twice as high in paediatric (0.14 L/h/kg) compared with adult (0.06 L/h/kg) patients. Consequently, t½β does not appear modified in children, but oral doses need to be generally 2-fold higher than corresponding adult doses to reach similar tacrolimus blood concentrations. More pharmacokinetic studies in paediatric patients are, however, needed to rationalise the use of therapeutic drug monitoring for optimisation of tacrolimus therapy in this patient population.

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