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Erschienen in:
01.07.2011 | Short Communication
Influence of Cytochrome P450 3A5 (CYP3A5) Genetic Polymorphism on the Pharmacokinetics of the Prolonged-Release, Once-Daily Formulation of Tacrolimus in Stable Renal Transplant Recipients
Erschienen in: Clinical Pharmacokinetics | Ausgabe 7/2011
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Background and Objective: Tacrolimus is metabolized by cytochrome P450 (CYP) 3A5. The objective of this study was to investigate the influence of the genetic polymorphism of CYP3A5 on the pharmacokinetics of a new modified-release, once-daily formulation of tacrolimus (Advagraf®) after a switch from the immediate-release formulation (Prograf®)
Patients and Methods: This was a prospective, single-centre, open-label study in stable kidney transplant recipients. Seventeen ‘expressor’ patients (CYP3A5*1/*3 or *1/*1) were matched to 15 ‘non-expressor’ patients (CYP3A5*3/*3). Exposure variables (concentrations and area under the blood concentration-time curve from 0 to 24 hours [AUC24]) were obtained before and 15 days after the switch. Delay since grafting was similar for both groups of patients (expressors: 49±24 months; non-expressors: 45±22 months).
Results: During administration of tacrolimus as Prograf® or Advagraf®, the mean tacrolimus daily dose was significantly higher and the dose-adjusted AUC24 was significantly lower in the expressor group. Following the switch to Advagraf®, there was a significant decrease in the dose-adjusted AUC24 for both non-expressor (5910 ± 3019 vs 5334 ± 2668 ng · h/mL per mg/kg/day; p = 0.041) and expressor patients (3701 ± 1409 vs 3273 ± 1372 ng · h/mL per mg/kg/day; p = 0.03). In the non-expressor group, mean blood trough concentration (C0) was comparable for both formulations while it decreased significantly in the expressor group after the switch (8.2 ± 2.2 vs 6.3 ± 2.5ng/mL; p = 0.02). However, a good correlation between AUC24 and C0 was observed for both Advagraf® and Prograf® regardless of CYP3A5 genotype.
Conclusion: Tacrolimus exposure significantly decreases after a switch from Prograf® to Advagraf®, on a milligram-for-milligram basis, in CYP3A5 expressor recipients. Consequently, these patients should be carefully monitored.