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.