Pharmacokinetic Analysis of Gatilfoxacin in Plasma and Sinus Aspirate Drug Treatment of Maxiliary Sinusitis
Purpose. A novel approach to collect sinus exudate was utilized and the time course of gatifloxacin (GAT) in the blood and at the primary infection site were assessed during treatment for acute maxillary sinusitis (AMS).
Methods. Twelve patients with AMS received 400 mg of GAT daily for 5 days. The maxillary antrum was punctured and a sinus catheter was inserted into the nasal cavity prior to dosing. Blood and sinus samples were collected after 4 days of therapy pre-dose and at 0.5, 1, 2, 4 and 6 hr. Sinus exudate was loosened using approximately 2 mL of saline and immediately aspirated. HPLC was used to determine GAT concentrations in sinus fluid (LLOQ=0.03 mg/L) and plasma (LLOQ=0.05 mg/L). Endogenous urea concentrations were measured to correct for saline dilution; GAT sinus concentrations were determined as the assayed concentration times the ratio of urea in plasma/sinus. GAT concentrations in plasma and sinus were modeled simultaneously for each subject using NONMEM®.
Results. Seven subjects were available for pharmacokinetic evaluation. A onecompartment model with first-order absorption and elimination adequately described GAT concentrations in plasma. A variation of the biophase model was used to describe sinus GAT concentrations. The transfer rate constant from the plasma to sinus (k1S) and the apparent elimination rate constant from the sinus (kS0) were modeled independently and did not assume steady-state conditions. The median k1s and ks0 were 0.34 and 0.17 hr-1, respectively. The model enabled determination of steady-state measures of GAT exposure; the median of the individual ratios of AUC and Cmax between the sinus and plasma were 1.51 and 0.90, respectively.
Conclusions. Techniques to measure drug exposure at the primary infection site may contribute to more accurate assessment of the time course of antimicrobial effect than traditional models that rely upon plasma drug concentrations or hypothetical drug concentrations at the primary infection site.
By Joel S Owen