Background. Tacrolimus is available in two formulations, immediate-release, (Prograf®) and prolonged -release formulation of tacrolimus (Advagraf®). Tacrolimus has a narrow therapeutic index with wide variation between- and within individuals. It is mainly metabolized by CYP3A4/5 and is transported by P-glycoprotein (P-gp). Expression of CYP3A decreases and expression of P-gp increases along the length of the gut.

Objective. We aimed to determine whether the CYP3A5*3 and ABCB1 genotypes influence the pharmacokinetics of prolonged-release tacrolimus in the same way as is well established for the immediate release preparation, in stable renal transplant recipients.

Methods. A total of sixty-four stable renal transplant recipients treated with twice daily tacrolimus (Prograf®) were switched to the same total daily dose of Advagraf® with 24 hour pharmacokinetic profiles before and two weeks after the change. Patients were divided into 4 genotype categories based on expression of CYP3A5 (*1/*1 or *1/*3), CYP3A5 non-expressers (*3/*3), high expressers of P-gp (ABCB1; CC) or low expressers of P-gp (ABCB1; CT or TT).

Results. ABCB1 polymorphisms contributed to significant changes in tacrolimus pharmacokinetic parameters and dose requirements only in CYP3A5*1 allele carriers. Dose-normalized pharmacokinetic parameters were significantly lower in CYP3A5 expressers than in CYP3A5 non-expressers for both preparations (Table). The influence of the CYP3A5 and ABCB1 genotype on tacrolimus exposure was the same for the prolonged release preparation Advagraf® as for the immediate release preparation, Prograf®.

Conclusion. Pharmacogenetic dosing strategies based on these genotypes are likely to be equally applicable to prescribing the once daily tacrolimus formulation, Advagraf®, as to twice daily formulations.

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