2262 PERSONALIZED INITIAL DOSE OF TACROLIMUS BASED ON THE CYP3A5 POLYMORPHISM AND ITS IMPACT ON THE 1-MONTH GRAFT FUNCTION: A PRELIMINARY EXPERIENCE

Abstract

INTRODUCTION AND OBJECTIVES: Patients with CYP3A5*1 allele (CYP3A5 expressers) require a higher daily tacrolimus dose than those with CYP3A5*3/*3 genotype (non-expressers) in order to maintain target trough levels (C0) (Tsuchiya, Transplantation, 2004). Recently, we reported that renal cortical interstitial fibrosis (IF) from 0-hour to 1-year post-transplantation increased in non-expressers than CYP3A5 expressers. Unexpected highly tacrolimus levels in non-expressers might influence the development of IF, despite therapeutic drug monitoring (Miura, Transplantation 2011). Therefore, since January 2011, we have started to a personalized initial dosing regimen of controlled-release tacrolimus based on the CYP3A5 polymorphism. The present study investigated the impact of personalized regimen of tacrolimus on the pharmacokinetics and 1-month graft function comparing to the non-personalized regimen. METHODS: Initial oral doses of tacrolimus were 0.20mg/kg for CYP3A5 expressers and 0.10mg/kg for non-expressers. In the nonpersonalized regimen, all patients received 0.20mg/kg of tacrolimus. The target trough levels of tacrolimus were same between the two regimes. RESULTS: Twenty patients were involved in the personalized regimen; CYP3A5 expressers in 6 and non-expressers in 14 cases. Twenty-five patients were in involved in the non-personalized regimen; CYP3A5 expressers in 10 and non-expressers in 15 cases. In the non-personalized regimen, C0 and area under the blood concentrationtime curve (AUC) of tacrolimus and estimated glomerular filtration rate (eGFR) in CYP3A5 expressers and non-expressers were: C0 (4.8 vs. 8.5 ng/ml, p 0.001) and AUC (218 vs. 373 nghr/ml, p 0.001) at day 1 after first administration of tacrolimus, C0 (5.4 vs 7.8 ng/ml, p 0.004) and AUC (218 vs 287 nghr/ml, p 0.013) and eGFR (59.2 vs 42.4 ml/min/1.73m2, p 0.028) at day 28 post-transplantation. In the personalized regimen, C0 and AUC of tacrolimus and eGFR in CYP3A5 expressers and non-expressers were; C0 (6.9 vs 2.7 ng/ml, p 0.279) and AUC (377 vs 136 nghr/ml, p 0.268) at day 1, C0 (8.9 vs 5.2 ng/mL, p 0.0270) and AUC (332 vs 226 nghr/mL, p 0.073) and eGFR (47.7 vs 64.6 ml/min/1.73m2, p 0.202) at day 28. CONCLUSIONS: The personalized medicine of tacrolimus based on the CYP3A5 polymorphism may decrease the pharmacokinetic difference between CYP3A5 expressers and non-expressers, and it may contribute better graft function in non-expressers in the early post-transplantation.