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The Impact of Sulfonylureas on Tacrolimus Apparent Clearance Revealed by a Population Pharmacokinetics Analysis in Chinese Adult Liver-Transplant Patients

Zhang, Xiao-qing PhD*; Wang, Zhao-wen MD, PhD; Fan, Jun-wei MD, PhD; Li, Yu-ping MD*; Jiao, Zheng PhD; Gao, Jun-wei PhD§; Peng, Zhi-hai MD, PhD; Liu, Gao-Lin PhD

doi: 10.1097/FTD.0b013e31824a67eb
Original Article

Aims The aims of this study were to determine the population pharmacokinetics of tacrolimus in Chinese adult liver-transplant recipients and to identify factors that may account for this variability.

Methods Tacrolimus dose and blood concentrations, along with clinical data, were collected retrospectively from 262 liver-transplant recipients. Data were analyzed using a nonlinear mixed-effects modeling method. A 1-compartment model with first-order absorption and elimination was selected as the base model. The influence of the following parameters were explored: (1) demographic characteristics, (2) biochemical and hematological laboratory test results, (3) surgery parameters, and (4) commonly used comedications.

Results The typical values (interindividual variability percent coefficient of variation) for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 20.9 L h−1 (23.8%) and 808 l (70.4%), respectively. The residual variability was 33.6%. Finally, the 4 covariates that showed a strong correlation with CL/F in this study were daily dose, hematocrit, total plasma protein, and the coadministration of sulfonylureas. CL/F was reduced significantly with sulfonylureas cotherapy, higher hematocrit levels, and elevated total protein. Moreover, CL/F increased nonlinearly with larger daily doses of tacrolimus.

Conclusions Concurrent therapy with sulfonylureas influenced tacrolimus CL/F in liver transplantation patients. These results and model will help clinicians to optimize tacrolimus regimens in Chinese liver transplantation patients.

*Department of Pharmacy, Shanghai pulmonary Hospital, Tongji University School of Medicine

Department of Hepatobiliary Pancreatic Surgery, Shanghai First People's Hospital, Shanghai Jiaotong University

Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University

§Department of Pharmacy, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.

Supported by the Natural Science Foundation of the People's Republic of China (81170446); Leading Project of Science and Technology Commission of Shanghai Municipality (074119605); and National Key Technology R&D Program in the 11th Five year Plan of China (2008BAI60B03).

The authors declare no conflict of interest.

X. Zhang and Z. Wang contributed equally to this work.

Correspondence: Gao-Lin Liu, PhD, Department of Pharmacology, First People's Hospital, Shanghai Jiao Tong University, No 100 Haining Road, Shanghai, China (e-mail: drliugl@yahoo.cn).

Received August 8, 2011

Accepted January 10, 2012

© 2012 Lippincott Williams & Wilkins, Inc.