Moes D.J.A.R, Swen J.J., den Hartigh J, van der Straaten T., Homan van der Heide J.J. Bemelman F., de Fijter J.W., Guchelaar H.J.
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
Objectives: 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 [1]. The aim of this study was to investigate the effect of the CYP3A4*22 and CYP3A5 polymorphisms on tacrolimus, everolimus and cyclosporine pharmacokinetics after kidney transplantation using population pharmacokinetic methodology.
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 as part of routine patient care and recorded in the electronic patient record. Available data on cyclosporine (6800), everolimus (1807) and tacrolimus (921) blood concentrations were extracted. Population pharmacokinetics analysis was performed for each immunosuppressive drug using NONMEM (non-linear mixed effects modeling) and demographic factors, CYP3A4*22 (rs35599367) and CYP3A5 (rs776746) genetic polymorphisms were included as covariates. The final models were validated by using a bootstrap and visual predictive check.
Results: The pharmacokinetics of cyclosporine were best described by two compartment model disposition model with delayed absorption. The pharmacokinetics of tacrolimus and everolimus were best described by a two-compartment model with lag-time. Bodyweight, prednisolone dosage (cyclosporine), Ideal weight (everolimus), hematocrit (tacrolimus) were identified as demographic covariates. The effect of CYP3A4*22 on the pharmacokinetics of cyclosporine, everolimus and tacrolimus was less than 17%. Carriers of the CYP3A5*1/*3 had 1.5 fold higher tacrolimus clearance than CYP3A5*1/*3 carriers. CYP3A5 had no significant influence on everolimus and ciclosporin pharmacokinetics.
Conclusions: Our data suggests that CYP3A4*22 is not likely to be suitable as a clinically relevant predictive marker for cyclosporine, tacrolimus or everolimus pharmacokinetics during maintenance therapy in renal transplantation patients. Therefore dose adjustments based on CYP3A4*22 genotype does not appear to be indicated. CYP3A5 is only suitable as a clinically relevant predictive marker for tacrolimus pharmacokinetics.
References:
[1] A new Functional CYP3A4 Intron 6 Polymorphism Significantly Affects Tacrolimus Pharmacokinetics in Kidney Transplant Recipients, Elens et al, Clinical Chemistry 57:11 1574-1583 (2011)
Reference: PAGE 22 () Abstr 2781 [www.page-meeting.org/?abstract=2781]
Poster: Covariate/Variability Model Building