Abstract

Aim: To develop a population pharmacokinetic model of adefovir dipivoxil in healthy volunteers and evaluate the effect of individual factors on the pharmacokinetics of adefovir dipivoxil. Methods: Plasma concentration data collected from 32 healthy Chinese subjects in a Phase I clinical study was pooled. Subjects received a single oral dose of 10 mg, 20 mg, or 30 mg adefovir dipivoxil, or multiple doses of 10 mg once a day for 9 days. Plasma concentrations of adefovir dipivoxil were measured using a validated liquid chromatography-mass spectrometric method. A nonlinear mixed-effect model was used to analyze the plasma concentration data of adefovir dipivoxil in healthy volunteers and to calculate the relevant parameters as well as inter- and intra-individual variability. Results: The time course of adefovir dipivoxil concentration is best described by a firstorder absorption and first-order elimination two-compartment model with lag time. The final estimate of total body clearance (CL) is 56.9 L/h and 78.7 L/h for single and multiple dosing regimen, respectively; the volume distribution of the central compartment (V₂) is 106 L; inter-compartmental clearance (Q) is 220 L/h; volume distribution of the peripheral compartment (V₃) is 498 L and 800 L for single and multiple dosing regimen, respectively; absorption rate is 0.509 h^–1; and lag time is 0.315 hours. The inter-individual variabilities of CL and V₂ were 22.4% and 58.9%, respectively. The proportional error of residual variability is 14.1% and the additive error is 0.30 ng/L. The final pharmacokinetic model was evaluated using a bootstrap method. Conclusions: A nonlinear mixed effect model for oral adefovir dipivoxil formulations was developed in healthy Chinese subjects. A multiple dosing regimen may significantly increase the body clearance and volume distribution of the peripheral compartment compared to a single dosing regimen.

*These authors contribute equally to this work.

Author Details

Authors

• Jihan Huang¹*
• Yaping Zhang²*
• Xiaohui Huang³
• Lujin Li¹
• Yunfei Li¹
• Kun Wang¹,²
• Juan Yang¹
• Yingchun He¹
• Yinghua Lv¹
• Qingshan Zheng¹

Departments

• ¹ Department of Pharmacometrics, Center for Drug Clinical Research, Shanghai University of Chinese Medicine, Shanghai, China,
• ² Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA, and
• ³ Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China

Address

Dr. Kun Wang
Department of pharmacometrics
Center for Drug Clinical Research
Shanghai University of Chinese Medicine
Shanghai 20123, China
Email: [email protected]

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