INTRODUCTION
Pneumonia continues to be one of the leading causes of morbidity and mortality worldwide, especially in low-income countries [1,2]. Among patients seeking medical treatment, Streptococcus pneumoniae is the most predominant bacterial pathogen, accounting for more than 25% of community-acquired pneumonia (CAP) cases [3,4].Staphylococcus aureus is usually associated with more severe CAP cases. Notably, the incidence of serious infections caused by methicillin-resistant S. aureus (MRSA), including community-acquired MRSA, is on the rise globally [5]. According to current Infectious Diseases Society of America and American Thoracic Society guidelines, monotherapy with a respiratory fluoroquinolone is strongly recommended for managing CAP in adults [6].
Nemonoxacin, one of the latest broad-spectrum non-fluorinated quinolones, has shown potent bactericidal effect on gram-positive and gram-negative bacteria, as well as atypical pathogens [7]. Nemonoxacin targets both bacterial DNA gyrase and topoisomerase IV, and as a result, blocks bacterial DNA supercoiling. Compared with its fluorinated analogs, nemonoxacin is more active in vitro against MRSA, penicillin-resistantS. pneumoniae , ciprofloxacin-resistant MRSA, and levofloxacin-resistant S. pneumoniae . Both intravenous and oral dosage forms of nemonoxacin were investigated at the standard dose of 0.5g q24h in phase I to III clinical trials [8]. The clinical outcomes have proved that nemonoxacin is more tolerable and non-inferior to other classic fluoroquinolones such as levofloxacin. At present, the capsule formulation of nemonoxacin has been approved successively in Taiwan and Mainland of China to treat CAP in adults and granted fast track designations by the US Food and Drug Administration [9-11].
Clinical trials have demonstrated the favorable pharmacokinetic (PK) profile of nemonoxacin, such as high oral bioavailability (100%), low plasma protein binding (16%), and minimal drug accumulation. No metabolite or only a minor metabolite (<5%) was observed in metabolism studies of nemonoxacin since the drug was predominantly eliminated via the kidneys in unchanged form [9,12,13]. Therefore, it is reasonable to believe that renal function has direct effect on the systemic clearance (CL) and exposure of nemonoxacin. On the other hand, a recent thorough QT/QTc study revealed that the cardiotoxicity of nemonoxacin increased in a dose-dependent manner. The cardiac repolarization characteristics at therapeutic dose (0.5 g q24h) are acceptable, while supratherapeutic dose (0.75g q24h) should raise more concerns [14]. Therefore, dose adjustment appears necessary for nemonoxacin in patients with renal impairment.
Generally speaking, renal dysfunction probably affects the pharmacodynamic (PD) properties of drugs [15]. The most clinically relevant PK/PD index of nemonoxacin is the area under the plasma concentration-time curve of the free drug over the minimum inhibitory concentration ratio (f AUC0-24h/MIC) [16]. To maximize the probability of attaining the target pharmacodynamic exposure of nemonoxacin against the clinical pathogens of CAP and minimize the risk of exposure-related toxicities, population PK/PD analysis and simulation of dosage adjustment were conducted to find the optimal dosing regimen for treatment of CAP in patients with severe renal impairment.