Developmental toxicity of fleroxacin and comparative pharmacokinetics of four fluoroquinolones in the cynomolgus macaque (Macaca fascicularis).
The potential developmental toxicity of fleroxacin was studied (Phase I) and its pharmacokinetics was compared to ciprofloxacin, temafloxacin, and norfloxacin (Phase II) in the cynomolgus macaque (Macaca fascicularis). Phase I studies involved oral administration of fleroxacin (35 and 70 mg/kg-day) during Gestational Days (GD) 20-34 or 35-49 (N = 10/group); controls received vehicle only. Increased maternal toxicity (weight loss, anorexia, emesis) and embryolethality (4/10, 40%; GD 20-34) were observed at 70 mg/kg-day. Urinary excretion of estrogen conjugates was reduced for females with nonviable pregnancies during both treatment periods (GD 20-34 and 35-49), although steroid hormone levels in serum remained unchanged during treatment; no malformations or growth retardation were observed at gross examination. For Phase II studies, the pharmacokinetics of fleroxacin (70 mg/kg), ciprofloxacin (100 mg/kg), temafloxacin (100 mg/kg), and norfloxacin (150 mg/kg) were studied during a 3-day oral treatment regimen in the nonpregnant (N = 12; 3/quinolone) and pregnant (N = 3; fleroxacin only) macaque. Serial blood samples were collected on the first and third days of treatment in all animals; for pregnant females, the conceptus was removed on GD 31 for analysis of fleroxacin levels. Marked differences between the quinolones were noted in the AUC0-24 hr for nonpregnant females. Based on AUC0-24 hr on the first day of treatment, the rank order was fleroxacin > temafloxacin > ciprofloxacin > norfloxacin. On the third of treatment, the rank order for exposure was temafloxacin > fleroxacin > ciprofloxacin > norfloxacin. Overall, results indicated (1) no marked differences in pharmacokinetic parameters in pregnant versus nonpregnant females, (2) fleroxacin levels in embryonic tissues were similar to maternal plasma levels, and (3) there was a correlation between exposure and embryolethal doses for all fluoroquinolones which resulted in embryolethality except norfloxacin.
F. Hoffmann-LaRoche Ltd, Basel, Switzerland.
H
H
Hummler
W F
WF
Richter
A G
AG
Hendrickx
D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000493:pharmacokinetics*; D002939:Ciprofloxacin / Q000097:blood / Q000493:pharmacokinetics; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D016576:Fleroxacin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D024841:Fluoroquinolones; D008252:Macaca fascicularis; D009643:Norfloxacin / Q000097:blood / Q000493:pharmacokinetics; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects* / Q000378:metabolism; D015363:Quinolones / Q000097:blood / Q000493:pharmacokinetics
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; C054745:temafloxacin; D002939:Ciprofloxacin; D009643:Norfloxacin; D016576:Fleroxacin