title: Dose escalation study of the safety, tolerability, and pharmacokinetics of nemonoxacin (TG-873870), a novel potent broad-spectrum nonfluorinated quinolone, in healthy volunteers.
abstract: 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.
authors.affiliation: TaiGen Biotechnology Co. Ltd., 7F, 138 Xing Ming Road, Neihu District, 11470 Taipei, Taiwan.
authors.forename: Luke
authors.initials: L
authors.lastname: Lin
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Chang
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Tsai
authors.forename: Ching-Hung
authors.initials: CH
authors.lastname: Hsu
authors.forename: David T
authors.initials: DT
authors.lastname: Chung
authors.forename: William S
authors.initials: WS
authors.lastname: Aronstein
authors.forename: Funmi
authors.initials: F
authors.lastname: Ajayi
authors.forename: Barbara
authors.initials: B
authors.lastname: Kuzmak
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lyon
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D015363:Quinolones; C543520:nemonoxacin