CYP3A4*22 as Pharmacogenomic Predictor of Tacrolimus Pharmacokinetics in Renal Transplant Recipients

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 a widely used immunosuppressive drug in organ transplantation. The oral bioavailability of tacrolimus varies greatly between individuals and depends largely on the activity of the CYP3A subfamily. CYP3A4 is the main CYP isoform in human liver and intestine involved in the metabolism of many drugs. The CYP3A4*22 variant has been associated with significantly increased oral bioavailability of tacrolimus (Elens et al., 2013). In this study we aimed to determine the relationship between the CYP3A4*22 polymorphism in combination with CYP3A5 genotype and tacrolimus disposition in stable renal transplant recipients on different tacrolimus formulations.

Methods: A total of 43 stable kidney transplant recipients were included. Genetic polymorphisms in CYP3A4*22 and CYP3A5 genes were determined. The mean tacrolimus dose, Cmax, AUC0-24 and trough tacrolimus concentrations were compared between the genotypes and between the immediate (Prograf®) and prolonged release (Advagraf®) tacrolimus preparations. Tacrolimus whole blood concentrations were determined by liquid chromatography-tandem mass spectrometry and data were analysed using analysis of variance (ANOVA).

Results: When patients were grouped according to CYP3A4*22 genotype, there was a significant decrease in tacrolimus dose-normalized C0, Cmax and AUC0-24 in CYP3A4*22 CC in comparison with the CYP3A4*22 CT variant. The mean tacrolimus dose-normalized C0 (µg/L/mg/Kg) fell from 14.3 SD 10.1 to 7.5 SD 5.7 with a 44% reduction (90% CI 15 to 64%; P <0.01). The decrease in the dose-normalized Cmax was 50% (P <0.05) and dose-normalized AUC0-24 was 40% (P <0.01) for carriers of the CYP3A4*22 CC allele. When patients were grouped according to CYP3A5 and CYP3A4*22 genotypes, we did not observe any significant differences in tacrolimus pharmacokinetics between the CYP3A4*22 CC homozygote (n=20) and CYP3A4*22 CT allele (n=4) in CYP3A5 non-expressers, the combination that was only found in the investigated population. No difference was found between Prograf® and Advagraf® in mean weight-adjusted dose, dose-normalized C0, Cmax and AUC0-24 between CYP3A4*22 C carriers (p >0.05).

Conclusion: The CYP3A4*22 CT genotype presented a significantly higher level of tacrolimus exposure (AUC, Cmax) compared with the CYP3A4*22 CC genotype. We concluded that CYP3A4*22 may be an important determinant of the tacrolimus dose-adjusted blood concentration in renal transplanted patients.