Eravacycline (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline or TP-434) is a novel, fully synthetic broad-spectrum fluorocycline with potent activity against Gram positive bacteria, anaerobes, and MDR Enterobacteriaciae. We characterized the plasma pharmacokinetics and conducted a comprehensive analysis of eravacycline tissue distribution in rabbits after multiple day dosing. Eravacycline for single-dose-pharmacokinetics was administered to NZW rabbits at 1, 2, 4, 8 & 10 mg/kg intravenously (IV) QD (n = 20). Eravacycline for multi-dose-pharmacokinetics was administered at 0.5, 1, 2, and 4 mg/kg IV QD (n = 20) for 6 days. Eravacycline concentrations in plasma and tissues were analyzed by LC/MS/MS assay. Mean AUCs following a single eravacycline dose ranged from 5.39 μg·h/ml to 183.53 μg·h/ml. Within the multi-dose study, mean AUCs ranged from 2.53 μg·h/ml to 29.89 μg·h/ml. AUCs correlated linearly within the dosage range (r=0.97; p=0.0001). In the cardiopulmonary system, concentrations were greatest in lung>heart>PAMs>BAL fluid; for the intraabdominal system: bile>liver>gall bladder>spleen>pancreas; for the renal system: urine>renal cortex>renal medulla; for musculoskeletal tissues: muscle psoas>bone marrow>adipose, for the CNS system: cerebrum>aqueous humor>CSF>choroid>vitreous. Concentrations in prostate and seminal vesicles demonstrated relatively high mean concentrations. The plasma pharmacokinetic profile of 0.5 to 4 mg/kg in NZW rabbits yields comparable exposure to that of humans (1 or 2 mg/kg Q12h) and demonstrates target tissue concentrations in most sites.
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