1: Clin Pharmacokinet  2001;40(4):283-95

Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult
patients.

Wallemacq PE, Verbeeck RK.

Department of Clinical Chemistry, University Hospital St Luc, Catholic
University of Louvain, Brussels, Belgium. wallemacq@lbcm.ucl.ac.be

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 (t1/2beta) 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, t1/2beta 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.

Publication Types:
Review
Review, Tutorial

PMID: 11368293 [PubMed - indexed for MEDLINE]