Tacrolimus starting dose prediction based on genetic polymorphisms and clinical factors in chinese renal transplant recipients

Abstract

Aims: Tacrolimus has extensive pharmacokinetic variability among patients and a narrow therapeutic window. The U.S. Clinical Pharmacogenetics Implementation Consortium recommends a starting dose for tacrolimus of 0.15-0.3 mg/kg/day, which is much higher compared with 0.05-0.15 mg/kg/day used in China. The purpose of this study was to investigate the influence of clinical factors and single nucleotide polymorphisms (SNPs) on tacrolimus concentrations in Chinese renal transplant recipients. Methods: This study enrolled 406 tacrolimus-treated patients. After renal transplantation, the first tacrolimus trough concentration and corresponding clinical information were collected from all patients. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to genotype 15 SNPs. The relationship between the genetic and clinical factors and dose-adjusted tacrolimus trough concentration was examined. The tacrolimus starting dose was predicted using a classification and regression tree analysis. Results: Examination of the 15 SNPs and several clinical factors identified the CYP3A5 genotype ( p = 5.6 × 10-11) and hemoglobin ( p = 8.4 × 10-10) as the most significant determinants of tacrolimus C0/D. Accordingly, a concise tacrolimus recommendation dosage model, a classification scheme, and a regression tree were developed. Conclusion: A new classification and regression tree model was developed for establishing the starting dose of tacrolimus based on the CYP3A5 genotype and hemoglobin values. This result may help clinicians prescribe an appropriate initial tacrolimus dose.