Pharmacokinetics, pharmacodynamics and therapeutics of pradofloxacin in the dog and cat

Pradofloxacin is a third-generation fluoroquinolone, licensed in the EU for use in a range of indications in the dog and cat and authorized more recently in the USA for one therapeutic indication (skin infections) in the cat. This review summarizes and appraises current knowledge on the physico-chemical, pharmacological [pharmacokinetics (PK) and pharmacodynamics (PD)], safety and therapeutic properties of pradofloxacin in the target species. Pradofloxacin contains two centres of asymmetry and is the pure SS enantiomer. After oral dosing of tablets (dog) or tablets and oral suspension (cat), maximum plasma concentrations (Cmax ) are achieved in less than 3.0 h, and terminal half-life is of the order of 5-10 h. Accumulation is slight or absent with once daily oral dosing. Free drug concentrations in plasma are in the range of 63-71% of total concentration. As for other fluoroquinolones, Antibacterial activity is attributable to inhibition of Bacterial replication at two sites, subunit A of Topoisomerase II and Topoisomerase IV. The antimicrobial spectrum includes gram-negative and gram-positive organisms, anaerobes, Mycoplasma spp. and some intracellular organisms (Rickettsia spp. and Mycobacterium spp.). The killing action is of the concentration-dependent type. Pradofloxacin has high potency (low MIC values) in comparison with first- and second-generation fluoroquinolones. Integration of in vivo PK and in vitro PD data provides values of Cmax /MIC and area under plasma concentration-time curve (AUC24 h )/MIC ratios predictive of good clinical efficacy against sensitive organisms, when administered at recommended dose rates. Clinical trial evaluation of pradofloxacin, in comparison with other authorized antimicrobial drugs, has demonstrated either noninferiority or superiority of pradofloxacin. Data indicating clinical and, in some instances, bacteriological cure have been reported: (i) in cats, for wound infections, abscesses, upper respiratory tract infections, conjunctivitis, feline infectious anaemia and lower urinary tract infections and (ii) in dogs, for wound infections, superficial and deep pyoderma, acute urinary tract infections and adjunctive treatment of infections of gingival and periodontal tissues. At clinical dose rates pradofloxacin was well tolerated in preclinical studies and in clinical trials. Among the advantages of pradofloxacin are (i) successful treatment of infections caused by strains resistant to some other fluoroquinolones, as predicted by PK/PD data, but depending on the specific MIC of the target strain and (ii) a reduced propensity for resistance development based on MPC measurements. The preclinical and clinical data on pradofloxacin suggest that this drug should commonly be the fluoroquinolone of choice when a drug of this class is indicated. However, the PK/PD data on pradofloxacin, in comparison with other fluoroquinolones, are not a factor that leads automatically to greater clinical efficacy.