Update on the Use of Tacrolimus in Pediatrics

Kristi Higgins, PharmD

Disclosures

Pediatr Pharm. 2018;24(12) 

In This Article

Pharmacokinetics

It is critical for patients to achieve optimal immunosuppression in the first days following solid organ transplantation to avoid rejection. Tacrolimus has a narrow therapeutic index, making it challenging for patients to achieve therapeutic dosing while avoiding adverse effects. Measurement of the area under the curve (AUC) would be the most effective way of measuring tacrolimus concentrations, however, this is not always feasible for patients or institutions. Whole blood trough levels correlate with the AUC and are more commonly used to monitor tacrolimus.[4]

Tacrolimus absorption occurs primarily in the small intestine. The differences in intestinal Pglycoprotein (PGP) and intestinal motility in children can account for some of the variability in absorption. Tacrolimus distributes widely throughout the body to the lungs, spleen, liver, kidney, brain and muscle. It is highly protein bound to alpha 1-acid-gycoprotein and, to a lesser extent, albumin. Pediatric patients have a reduced drug binding affinity of plasma proteins, leading to an increased fraction of unbound drug. This can cause an increased distribution and elimination of free drug, and higher doses of tacrolimus may be needed to achieve the same concentration range.

Tacrolimus is metabolized primarily via cytochrome P450 3A5 (CYP3A5). Activity of this hepatic enzyme is age-dependent and may not be fully developed in younger children. Tacrolimus is also a substrate of PGP, an efflux pump encoded by multidrug resistance 1 gene (MDR1 or ABCB1). This gene contributes to tacrolimus metabolism, producing inactive metabolites, but to a lesser extent.[5] These two modes of metabolism may account for the pharmacokinetic variation in tacrolimus seen between adults and children.[6]

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