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Population Pharmacokinetic Analysis of Linezolid in Patients With Infectious Disease: Application to Lower Body Weight and Elderly Patients

From Clinical Pharmacology, Global Research & Development, Tokyo Laboratories, Pfizer, Tokyo, Japan (S. Abe); Department of Drug Development Science & Clinical Evaluation Faculty of Pharmacy, Keio University, Tokyo, Japan (S. Abe, K. Chiba, T. Suwa); Amylin Pharmaceuticals, Inc, San Diego, California (B. Cirincione); Cognigen Corporation, Buffalo, New York (T. H. Grasela); and Pharmacometrics, Global Research & Development, Pfizer, New London, Connecticut (K. Ito).

Linezolid (Zyvox), belonging to oxazolidinone antibiotics, is commonly used for the treatment of patients infected with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Although linezolid has been approved worldwide, the Japanese pharmacokinetic (PK) profile has not been characterized in detail. The objective of this study is to develop a population PK model for linezolid that can be applied to a Japanese population. This population PK model was established based on the 1 Japanese phase III and 4 Caucasian phase II/III studies. A total of 2539 linezolid plasma concentration measurements from 455 patients, aged 18 to 98 years and body weight 30 to 190.5 kg, were used for the analysis. The data were analyzed using nonlinear mixed effects modeling. Body weight (BW), age, ethnicity, and gender were investigated as covariates. The final model was validated by the bootstrap technique. The PK profiles of linezolid were described with a 1-compartment PK model with first-order absorption and first-order elimination. In the final population PK model, BW and age were influential covariates on clearance, and the distribution volume was affected by BW. The present population PK model of linezolid described well the PK profiles in Japanese patients who have lower BW and are relatively older compared with those in the United States/European Union.

Key Words: Population pharmacokinetics • linezolid • NONMEM • antibacterial agents • Japanese patients

Address for reprints: Sadahiro Abe, Pfizer Japan, Inc, Shinjuku Bunka Quint Building, 3-22-7, Yoyogi, Shibuya-ku, Tokyo, Japan 151-8589; e-mail: Sadahiro.abe{at}pfizer.com.

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