Dose escalation study of the safety, tolerability, and pharmacokinetics of nemonoxacin (TG-873870), a novel potent broad-spectrum nonfluorinated quinolone, in healthy volunteers.
Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, penicillin- and quinolone-resistant Streptococcus pneumoniae, and vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. The safety, tolerability, and pharmacokinetics of nemonoxacin were investigated in a double-blind, ascending-single-dose study involving 56 healthy subjects (48 males and 8 females) who were randomly assigned to 1 of 7 dose cohorts. In each successive cohort, two subjects received a placebo and six received single oral doses of 25, 50, 125, 250, 500, 1,000, or 1,500 mg nemonoxacin. Nemonoxacin was well tolerated up to the maximum dose of 1,500 mg. No severe or serious adverse events were observed. The most frequent adverse events were contact dermatitis, pruritus, and erythema. No clinically significant abnormalities were noted in the electrocardiograms, vital signs, or laboratory tests. The plasma concentrations increased over the dose range, and at 500 mg, the free area under the plasma concentration-time curve/MIC(90) ratios and free maximum nemonoxacin concentration/MIC(90) ratios against drug-sensitive/drug-resistant S. pneumoniae and S. aureus were greater than 227 and 24, respectively. The peak time and elimination half-life of nemonoxacin were 1 to 2 h and 9 to 16 h, respectively. The oral clearance was approximately 0.22 liter/h/kg. The plasma protein binding was approximately 16%. The results of this study support further evaluation of the multiple-dose safety, tolerability, and pharmacokinetics of nemonoxacin.
Lin
Luke
L
TaiGen Biotechnology Co. Ltd., 7F, 138 Xing Ming Road, Neihu District, 11470 Taipei, Taiwan.
Chang
Li-Wen
LW
Tsai
Cheng-Yuan
CY
Hsu
Ching-Hung
CH
Chung
David T
DT
Aronstein
William S
WS
Ajayi
Funmi
F
Kuzmak
Barbara
B
Lyon
Robert A
RA
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D024881:Drug Resistance, Bacterial; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D011485:Protein Binding; D015363:Quinolones / Q000009:adverse effects* / Q000493:pharmacokinetics*; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D020713:Vancomycin Resistance; D055815:Young Adult
D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D015363:Quinolones; C543520:nemonoxacin