Dosing strategies for de novo once-daily extended release tacrolimus in kidney transplant recipients based on CYP3A5 genotype  

作　　者：Adam Diamond Sunil Karhadkar Kenneth Chavin Serban Constantinescu Kwan N.Lau Oscar Perez-Leal Kerry Mohrien Nicole Sifontis Antonio Di Carlo 

机构地区：[1]Department of Pharmacy,Temple University Hospital,Philadelphia,PA 19140,United States [2]Department of Surgery,Temple University Hospital,Philadelphia,PA 19140,United States [3]Department of Medicine,Temple University School of Medicine,Philadelphia,PA 19140,United States [4]Department of Pharmaceutical Sciences,Jayne Haines Center for Pharmacogenomics and Drug Safety,Temple University School of Pharmacy,Philadelphia,PA 19140,United States [5]Department of Pharmacy Practice,Temple University School of Pharmacy,Philadelphia,PA 19140,United States

出　　处：《World Journal of Transplantation》2023年第6期368-378,共11页世界移植杂志

基　　金：Supported by Veloxis Pharmaceuticals,Inc.1001 Winstead Drive Suite 310,Cary,NC 27513.

摘　　要：BACKGROUND Tacrolimus extended-release tablets have been Food and Drug Administrationapproved for use in the de novo kidney transplant population.Dosing requirements often vary for tacrolimus based on several factors including variation in metabolism based on CYP3A5 expression.Patients who express CYP3A5 often require higher dosing of immediate-release tacrolimus,but this has not been established for tacrolimus extended-release tablets in the de novo setting.AIM To obtain target trough concentrations of extended-release tacrolimus in de novo kidney transplant recipients according to CYP3A5 genotype.METHODS Single-arm,prospective,single-center,open-label,observational study(ClinicalTrials.gov:NCT037-13645).Life cycle pharma tacrolimus(LCPT)orally once daily at a starting dose of 0.13 mg/kg/day based on actual body weight.If weight is more than 120%of ideal body weight,an adjusted body weight was used.LCPT dose was adjusted to maintain tacrolimus trough concentrations of 8-10 ng/mL.Pharmacogenetic analysis of CYP3A5 genotype was performed at study conclusion.RESULTS Mean time to therapeutic tacrolimus trough concentration was longer in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers(6 d vs 13.5 d vs 4.5 d;P=0.025).Mean tacrolimus doses and weight-based doses to achieve therapeutic concentration were higher in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers(16 mg vs 16 mg vs 12 mg;P=0.010)(0.20 mg/kg vs 0.19 mg/kg vs 0.13 mg/kg;P=0.018).CYP3A5 extensive metabolizers experienced lower mean tacrolimus trough concentrations throughout the study period compared to CYP3A5 intermediate metabolizers and non-expressers(7.98 ng/mL vs 9.18 ng/mL vs 10.78 ng/mL;P=00.008).No differences were identified with regards to kidney graft function at 30-d post-transplant.Serious adverse events were reported for 13(36%)patients.CONCLUSION Expression of CYP3A5 leads to higher starting doses and incremental dosage titration of extended-release tacrolimus to achieve target trough concentratio

关 键 词：IMMUNOSUPPRESSION Kidney transplant DOSING TACROLIMUS Therapeutic drug monitoring GENOTYPE 

分 类 号：R69[医药卫生—泌尿科学]