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; Weituo Zhang; Zhihai Peng

doi:10.1016/j.eclinm.2022.101752

Genotype-guided model significantly improves accuracy of tacrolimus initial dosing after liver transplantation

EClinicalMedicine. 2022 Nov 24:55:101752. doi: 10.1016/j.eclinm.2022.101752. eCollection 2023 Jan.

Authors

Baojie Shi^{1

2}, Yuan Liu³, Dehua Liu^{1

2}, Liyun Yuan⁴, Wenzhi Guo⁵, Peihao Wen⁵, Zhaojie Su^{1

2}, Jie Wang^{1

2}, Shiquan Xu^{1

2}, Junjie Xia², Wenbin An^{1

2}, Rui Wang^{1

2}, Peizhen Wen^{1

2}, Tonghai Xing³, Jinyan Zhang³, Haitao Gu³, Zhaowen Wang³, Lin Zhong³, Junwei Fan³, Hao Li^{1

2}, Weituo Zhang⁶, Zhihai Peng^{1

2}

Affiliations

¹ Organ Transplantation Clinical Medical Center of Xiamen University, Department of Organ Transplantation, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China.
² Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China.
³ Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, 200080, Shanghai, China.
⁴ Bio-Med Big Data Center, Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
⁵ Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, China.
⁶ Hongqiao International Institute of Medicine, Shanghai Tong Ren Hospital and Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, 200050, Shanghai, China.

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.

Keywords: Liver transplantation; Pharmacogenomics; Precision medicine; Tacrolimus.