Physiologically Based Population Pharmacokinetic Modeling Approach for Ciprofloxacin in Bone of Patients Undergoing Orthopedic Surgery.

Abstract

Ciprofloxacin is highly active against bacteria that commonly cause bone infections. However, the time-course of ciprofloxacin in bone has not been characterized using population pharmacokinetic modeling. Thirty-nine patients received a 1-h infusion of 400 mg of ciprofloxacin before orthopedic surgery. Blood and bone samples were collected at 0.5 to 20 h following the start of the infusion. Bone samples were separated into cortical and cancellous bone and pulverized under liquid nitrogen using a cryogenic mill. Ciprofloxacin in plasma, and cortical and cancellous bone was quantified by liquid chromatography-tandem mass spectrometry. A physiologically based pharmacokinetic modeling approach was utilized to describe the concentration-time profiles in plasma and bone. Ciprofloxacin concentrations ranged from 0.176 to 5.98 mg/L (median, 1.67; density, 1.99 g/cm3) in cortical, and 0.224 to 14.6 mg/L (median, 1.22; 1.92 g/cm3) in cancellous bone. The average observed cortical bone/plasma concentration ratio was 0.67 at 0.5 to 2 h (n = 7) and 5.1 at 13 to 20 h (n = 9). For cancellous bone the respective average ratios were 0.77 and 4.4. The population PK model included a central (blood) compartment, two peripheral tissue compartments, and compartments for the organic and inorganic (hydroxyapatite) matrix in cortical and cancellous bone. The population mean ciprofloxacin clearance was 20.7 L/h. The estimated partition coefficients of the organic bone matrix were 3.39 for cortical and 5.11 for cancellous bone. Ciprofloxacin achieved higher concentrations in bone than plasma. Slow redistribution from bone to plasma may have been due to binding to the inorganic bone matrix. The developed model presents a step toward optimized antibiotic dosing in osteomyelitis.