Ferraresso M et al. (2007) Influence of the Cyp3a5 genotype on tacrolimus pharmacokinetics and pharmacodynamics in young kidney transplant recipients. Pediatr Transplant 11: 296–300

As tacrolimus has a narrow therapeutic index and variable pharmacokinetics, it is difficult to achieve effective blood concentrations in all patients. Variability could be due, in part, to the existence of different forms of the CYP3A5 enzyme, which is involved in tacrolimus metabolism. Patients homozygous for the CYP3A5*3 allele (a single nucleotide A>G polymorphism in intron 3 of CYP3A5) lack CYP3A5 activity. Such activity requires the presence of at least one CYP3A5*1 allele.

Researchers investigated how CYP3A5 polymorphism affected tacrolimus dosing and outcomes in 30 adolescent renal transplant recipients (mean age 15.8 ± 7 years) in whom the drug was the primary immunosuppressant. Twenty-one patients (70%) were CYP3A5*3/*3 homozygotes, eight (27%) were CYP3A5*1/*3 heterozygotes and one (3%) was a CYP3A5*1/*1 homozygote (who was included in the heterozygote group).

One-year graft and patient survival rates were 100% in each group. One-year mean serum creatinine levels and incidences of delayed graft function were similar in both groups, but acute rejection occurred more frequently in heterozygotes than in CYP3A5*3/*3 homozygotes (62.5% vs 21.7%; P = 0.04). Mean tacrolimus blood concentrations were significantly lower in heterozygotes than homozygotes; tacrolimus doses needed to achieve the desired therapeutic level were, therefore, about twice as high in heterozygotes as they were in homozygotes. In addition, drug distribution was greater and mean arterial blood pressure was consistently higher in heterozygotes than in homozygotes, confirming the previous finding that hypertension is a common adverse effect of tacrolimus use.

These results indicate that CYP3A5 genotyping might allow tacrolimus doses to be tailored to individual patients.