Genotype-guided model significantly improves accuracy of tacrolimus initial dosing after liver transplantation
Baojie Shi, Yuan Liu, Dehua Liu, Liyun Yuan, Wenzhi Guo, Peihao Wen, Zhaojie Su, Jie Wang, Shiquan Xu, Junjie Xia, Wenbin An, Rui Wang, Peizhen Wen, Tonghai Xing, Jinyan Zhang, Haitao Gu, Zhaowen Wang, Lin Zhong, Junwei Fan, Hao Li, Wei-Tuo Zhang, Zhihai Peng
Abstract
Background The initial dose of tacrolimus after liver transplantation (LT) is critical for rapidly achieving the steady state of the drug concentration, minimizing the potential adverse reactions and warranting long-term patient prognosis. We aimed to develop and validate a genotype-guided model for determining personalized initial dose of tacrolimus. Methods By combining pharmacokinetic modeling, pharmacogenomic analysis and multiple statistical methods, we developed a genotype-guided model to predict individualized tacrolimus initial dose after LT in the discovery (n = 150) and validation cohorts (n = 97) respectively. This model was further validated in a prospective, randomized and single-blind clinical trial from August, 2021 to February, 2022 (n = 40, ChiCTR2100050288). Findings Our model included donor's and recipient's genotypes, recipient's weight and total bilirubin, which achieved an area under the curve of receiver operating characteristic curve (AUC of ROC) of 0.88 and 0.79 in the discovery and validation cohorts, respectively. We found that patients who were given tacrolimus within the recommended concentration range (RCR) (4–10 ng/mL), the new-onset metabolic syndromes are lower, especially for new-onset diabetes (p = 0.043). In the clinical trial, compared to those in experience-based (EB) group, patients in the model-based (MB) group were more likely to achieving the RCR (75% vs 40%, p = 0.025) with a more variable individualized dose (0.023–0.096 mg/kg/day vs 0.045–0.057 mg/kg/day). Moreover, significantly fewer medication adjustments were required for the MB group than the EB group (2.75 ± 2.01 vs 6.05 ± 3.35, p = 0.001). Interpretation Our genotype-based model significantly improved the initial dosing accuracy of tacrolimus and reduced the number of medication adjustments, which are critical for improving the prognosis of LT patients. Funding National Natural Science Foundation of China, Shanghai three-year action plan, National Science and Technology Major Project of China.