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/cm 3 ) in cortical, and 0.224 to 14.6 mg/L (median, 1.22; 1.92 g/cm 3 ) 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.

Model-Informed Precision Dosing of Antibiotics in Osteoarticular Infections

“…With a PB of about 25% and a T 1/2 of 4 h, 34 FDA recommends 400 mg, iv,q8 h or q12 h, with a duration of 4 to 8 weeks for OAI patients. In 2020, Landersdorfer et al 49 developed a PB/ PK model consisting of 39 patients with a single dose of 400 mg, iv, at 0.5-20 h before orthopedic surgery to study the complete time-course of ciprofloxacin in bone. It included a central (blood) compartment, two peripheral tissue compartments, and compartments for the organic and inorganic (hydroxyapatite) matrix in cortical and cancellous bone.…”

Penetration of Vancomycin into Noninfected Bone in Patients Undergoing Total Joint Arthroplasty Evaluated by a Minimal Physiologically Based Population Pharmacokinetic Modeling Approach

“…However, the ratio of tissue concentrations to serum concentrations of a drug can change with time if there is relatively slow equilibration between the two regions, a phenomenon known as system hysteresis. Depending on the physicochemical characteristics of a drug, the bone to serum drug concentration ratio may depend on the sampling time in relation to the time of the dose of the drug. , Also, as is the case in the present study, antibiotic bone penetration is most often studied in patients undergoing TJA, where only one bone sample can be obtained per subject. , Population pharmacokinetic (PK) modeling approaches are the method of choice in this scenario. Modeling of antibiotic concentrations in serum and bone over a time-course enables the appropriate evaluation of the extent of antibiotic penetration into bone based on the areas under the curve (AUC) in bone and serum, instead of the concentration ratio at a single time point .…”

Spatial quantitation of antibiotics in bone tissue compartments by laser-capture microdissection coupled with UHPLC-tandem mass spectrometry

“…Techniques to separate the different anatomical compartments of bone and measure concentrations in each are lacking [4]. Microdialysis has been used to determine unbound drug concentrations within interstitial bone fluid [6,7], but it is not known whether the concentration measured represents the concentration that may occur at the site of infection [8]. 18F-Radiolabelled drug molecules have been used to determine concentrations of fluoroquinolones by positron emission tomography (PET) in bone from healthy volunteers.…”