Bootcongres

Background Cyclosporine, everolimus and tacrolimus form the cornerstone of maintenance immunosuppressive therapy in renal transplantation. These drugs have a small therapeutic windows and highly variable pharmacokinetics which make it difficult to maintain adequate exposure and prevent serious adverse effects. Cyclosporine, everolimus and tacrolimus are metabolized by enzymes of the CYP3A subfamily. A small part of the variability in pharmacokinetics can be explained by genetic variation in CYP3A5. Recently CYP3A4*22 was identified as a possible predictive marker for tacrolimus pharmacokinetics. The aim of this study was to investigate the effect of CYP3A4*22, CYP3A5*3 and CYP3A combined genotypes on tacrolimus, everolimus and cyclosporine pharmacokinetics after kidney transplantation. Methods Renal transplant patients on maintenance cyclosporine (298), everolimus (97) and tacrolimus therapy (101) were included. Blood concentrations were determined with fluorescence polarization immunoassay or liquid chromatography-tandem mass spectrometry. Available data on cyclosporine (6800), everolimus (1807) and tacrolimus (921) blood concentrations were used. Population pharmacokinetics analysis was performed for each immunosuppressive drug using non-linear mixed effects modeling and demographic factors, CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) genetic polymorphisms were included as covariates. The final models were validated by using a bootstrap and visual predictive check.

Results CYP3A4*22 carriers showed a significant lower clearance for cyclosporine (-15%) and a trend was observed for everolimus (-7%) and tacrolimus (-16%). Patients carrying at least one CYP3A5*1 allelehad 1.5 fold higher tacrolimus clearance compared to non-carriers, however CYP3A5*3 appeared not predictive for everolimus and cyclosporine. CYP3A combined genotype did not significantly improve prediction of clearance compared to CYP3A5*3 or CYP3A4*22 alone. Conclusion These data suggest that CYP3A4*22 does not influence cyclosporine, everolimus or tacrolimus pharmacokinetics to a clinically relevant extend. This study confirmed that CYP3A5*3 is only suitable as a predictive marker for tacrolimus clearance but close TDM remains essential due to the remaining variability between patients with the same genotype. The CYP3A4 and CYP3A5 combined genotypes do not further improve the predictive performance compared to the predictive performance of the polymorphisms alone.