Tacrolimus is used initially as an immunosuppressant drug in solid organ transplant population. This
calcineurin inhibitor has also been recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis
for the treatment of nephrotic syndrome in children and adults. Tacrolimus is characterized by a narrow therapeutic
index and large pharmacokinetic (PK) variations. Therefore, routine Therapeutic Drug Monitoring (TDM) is
critical to keep tacrolimus blood levels within the therapeutic range. Tacrolimus is mainly metabolized by cytochrome
P450 (CYP) enzymes 3A5 and 3A4. Actually, for pediatric patients, they are totally different to adults.
Profound changes in CYP3A expression and activity occur throughout fetal life and in the neonatal and childhood
periods thereby influencing their catalytic function. CYP3A7, CYP3A5, and CYP3A4 display an age-dependent
maturation pattern. Notably, the CYP3A7-CYP3A4 switch taking place during the very early life will affect tacrolimus
metabolism. Meanwhile, CYP3A isoforms are polymorphic enzymes, especially for CYP3A5. The
guideline has recommended that the tacrolimus dosage should be adjusted according to the CYP3A5 genotype.
Additionally, genetic CYP3A4 variation (e.g., CYP3A4*22) is also associated with interindividual variability of
exposure level to tacrolimus. However, age (ontogeny) sometimes trumps genetics (genotype) in determining the
enzymatic functions (phenotype) in pediatric patients. It’s important to discriminate at what age the ontogeny
plays key roles and at what age genetic variation become a major determinant. Thus, we need to better understand
the mechanisms driving the CYP3A maturation and integrate ontogeny and genetics into the tacrolimus
disposition, thereby tailoring the dosage individually for pediatric NS patients at different developmental stages.