A Novel Quinolone Antimicrobial Agent:analysis and pharmacokinetics

Abstract

OPC-17116 (grepafloxacin), a new fluoroquinolone antimicrobial agent, has a broad spectrum of in vitro activity that includes Gram-negative, Gram-positive and anaerobic bacteria. OPC-17116 exhibits improved activity, compared to other fluoroquinolones, against staphylococci, streptococci, Bacteroides fragilis and Chlamydia species. Pharmacokinetics, the study of the time course of drug absorption, distribution, metabolism and excretion, must be determined for a novel antimicrobial. Serum pharmacokinetics cannot accurately predict levels at extravascular sites as most antibiotics are unevenly distributed throughout the body. To be effective in vivo, the concentration of an antimicrobial at the site of infection must be high enough to be active against the causative pathogen. Therefore, it is important to measure drug concentrations in samples taken from potential sites of infection. In order to investigate the pharmacokinetics and extravascular penetration of a new antimicrobial, assays capable of measuring levels in different samples are required. A high performance liquid chromatography and a microbiological assay were, therefore, developed (and validated) for determining OPC-17116 concentrations in different sample types. In the first study, the pharmacokinetics, penetration into inflammatory exudate and excretion of OPC-17116, following a 400 mg oral dose, were investigated in Caucasian subjects. In the second, OPC-17116 concentrations were measured in serum, epithelial lining fluid, alveolar macrophages and bronchial mucosa, collected using bronchoalveolar lavage from adults undergoing diagnostic bronchoscopy. OPC-17116 was rapidly absorbed (mean maximum serum concentration of 1.34 mg/L obtained within 2-3 hours) and penetrated readily into inflammatory exudate (96.2-109.4% penetration). Recovery of unchanged OPC-17116 in urine was low (4-10% of the dose). OPC-17116 penetrated well into the respiratory tree; mean site:serum ratios of 171.4, 14.2 and 3.2 for macrophages, epithelial lining fluid and bronchial mucosa were obtained, respectively. Therefore, with its superior penetration properties, favourable pharmacokinetic parameters and broad spectrum of in vitro activity, OPC-17116 is an important new fluoroquinolone antimicrobial agent.