Dosing Regimen Recommendations for Sirolimus in Adult Liver Transplant Recipients: Insights from a Population Pharmacokinetic Model

Juehui Mao,1– 3 Yunshan Cheng,4 Dong Liu,1 Bo Zhang,5 Xiping Li1 1Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 3Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4College of Biology and Pharmacy, China Three Gorges University, Yichang, People’s Republic of China; 5Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences, Wuhan, People’s Republic of ChinaCorrespondence: Xiping Li, Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China, Email [email protected] Bo Zhang, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences, Wuhan, 430030, People’s Republic of China, Email [email protected]: Sirolimus is a commonly used immunosuppressant administered after solid organ transplantation. It is characterized by a narrow therapeutic window and highly variable exposure, necessitating the identification of the sources of variability and design of individualized drug therapies.Aim: This study aimed to perform a population pharmacokinetic (PK) analysis of sirolimus in adult liver transplant recipients and develop dosing regimen recommendations according to patient characteristics.Methodology: A total of 216 measurements of whole blood sirolimus concentrations in 103 adult patients were obtained for analysis. Covariates influencing the PKs of sirolimus were investigated using a stepwise procedure. Monte Carlo simulations were conducted to recommend dosing regimens for patients with different levels of covariates.Results: A one-compartment model with first-order elimination provided the best fit of the data. Hematocrit (HCT) significantly influenced the apparent clearance of sirolimus. Monte Carlo simulations showed that for patients with a low HCT level of 28%, dosing regimens of 1.5 mg qd or 1 mg qd alternating with 1.5 mg qd should be recommended. For patients with a normal HCT level, the recommended dosing regimens were 1 mg qd, 2 mg qod, or 0.5 mg qd alternating with 1 mg qd.Conclusion: Based on our population PK model of sirolimus in adult liver transplant recipients, which has the largest sample size to date, we recommend to tailor dosing regimens to various HCT levels in such patients.Keywords: sirolimus, population pharmacokinetic analysis, dosing regimen, liver transplant, hematocrit