The Influence of P450 Oxidoreductase*28 Polymorphism on the Pharmacokinetics of Tacrolimus in Stable Renal Transplant Patients.

T Elnahhas1,2, M Moreton2, T Lee2, D McKeown2, J Popoola3, R Ramkhelawon3, I MacPhee3, A Johnston1,2. 1Clinical Pharmacology, William Harvey Research Institute, Barts and The London, Queen Mary University of London, London, UK, 2Analytical Services International, St. George’s, University of London, London, UK, 3Division of Clinical Sciences-Renal Medicine, St. George’s, University of London, London, UK

Tacrolimus is mainly metabolized by cytochrome P450 3A isoenzymes. P450 oxidoreductase (POR) is essential for cytochrome P450 (CYP) activity in humans. The POR*28 polymorphism was associated with the increased CYP3A5 activity using midazolam as a probe drug (de Jonge et al., 2011). The goal of this study was to investigate the association between tacrolimus pharmacokinetic variability and POR*28 and CYP3A5 genotype in adult renal transplantation recipients on different tacrolimus preparations.

Method: Forty-three renal transplant recipients enrolled in the study after providing written informed consent. Patients were genotyped for POR*28 and CYP3A5*3. Tacrolimus daily dose, Cmax, AUC0-24 and trough tacrolimus concentrations were compared between the genotypes immediate (Prograf®) and prolonged release (Advagraf®) tacrolimus preparation. Data were analysed using analysis of variance (ANOVA).

Results: Our findings showed that, on analysis of the whole group, there were no significant differences in dose-adjusted Cmax, AUC0-24, C0 and the daily dose (mg/kg) in POR*28 CT/TT in comparison with POR*28 CC variant. In patients expressing CYP3A5, POR*28 alleles had no significant differences in tacrolimus pharmacokinetics. While in CYP3A5 non-expressers, there was a significant difference in tacrolimus pharmacokinetics between the POR*28 CC genotype (n=9) and the POR*28 CT/TT genotype (n=15) with respect to dose-normalized Cmax (27.23 ± 10.6 vs. 21.07 ± 9.9µg/L/mg/Kg; p < 0.05), dose-normalized AUC0 – 24 (413.1 ± 183.4 vs. 268.3 ± 133.8 ng*hour/mL/mg/Kg; p < 0.001), dose-normalized C0 (14.5 ± 4.3 vs. 8.4 ± 2.7 mg/kg; p < 0.001) and the daily dose ( 0.04 ± 0.02 vs. 0.06 ± 0.03 µg/L/mg/Kg; p < 0.001). No difference was found between Prograf® and Advagraf® in tacrolimus exposure between those with and without the POR*28 polymorphism.

Conclusion: The POR*28 CT/TT genotype was associated with a significantly lower tacrolimus exposure (AUC0-24, Cmax) compared with the POR*28 CC genotype in CYP3A5 non-expressing subjects. This differs to previously published data where this association was only found in CYP3A5 expressers.