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.

Figure 1

Ciprofloxacin concentrations in plasma, cortical bone and cancellous bone on log-scale (upper panel) and over the first 6 h on linear scale (lower panel). Ciprofloxacin concentrations in bone are expressed as mg/L, using a density of 1.99 g/cm³ for cortical and 1.92 g/cm³ for cancellous bone.

Figure 2

Final structural PK model.

Figure 3

Visual predictive checks for ciprofloxacin in (a) plasma, (b) cortical bone, and (c) cancellous bone. The plots present the observed concentrations, the 90% prediction interval (10th percentile [P10] to 90th percentile [P90]), and the predicted interquartile range (25th percentile [P25] to 75th percentile [P75]).

Figure 4

Probabilities of target attainment for plasma, cortical bone, and cancellous bone after 1-h infusions of 400 mg of ciprofloxacin q8h (top) and q12h (bottom) at steady state. The fAUC/MIC target for plasma was 40, and the AUC/MIC targets for cortical and cancellous bone were 86 and 135, respectively.