Pharmacokinetics, Safety and Tolerability of Moxifloxacin, a Novel 8-Methoxyfluoroquinolone, after Repeated Oral Administration

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Abstract
To investigate the pharmacokinetics, safety and tolerability of moxifloxacin after single and repeated doses. This series comprised 3 separate placebo-controlled studies, 2 studies with a randomised crossover design (up to 400 mg/day) and 1 study with a group comparison design (600mg once daily). Healthy male volunteers were included in these studies. Participants received 5-day treatment courses of moxifloxacin 100mg (n = 8) or 200mg (n = 8) twice daily or 400mg once daily (n = 7), or a 10-day treatment course of moxifloxacin 600mg once daily (n = 7). Pharmacokinetics were characterised after the first dose (24-hour profile) and the last dose (96-hour profile), with additional trough and peak measurements during the courses. All treatments were well tolerated. No clinically relevant changes in the standard laboratory tests, vital signs or ECG were observed. Minimum plasma concentrations required to inhibit 90% of susceptible micro-organisms (e.g. 0.125 mg/L for Streptococcus pneumoniae) were attained rapidly and exceeded until the end of treatment. Repeated doses of 100 and 200mg twice daily and 400mg once daily resulted in stable trough and peak concentrations within 3 days of the first dose. The concentrations at steady state were moderately higher (approximately 30% for 400mg once daily) than after the first dose. Steady-state peak concentrations were between 0.9 mg/L (100mg twice daily) and 5.7 mg/L (600mg once daily). The terminal elimination half-life was 14 to 15 hours, supporting once daily administration of the drug. Accumulation ratios ranged between 87% for the lowest dosage and 111% after repeated doses of 600mg once daily, indicating the absence of clinically relevant accumulation due to non-linear pharmacokinetics. Across the studies, the average exposure after single and repeated doses was proportional to the dose administered. These studies indicate that, based on the safety profile and the pharmacokinetic behaviour of moxifloxacin, a dosage regimen of 400mg given once daily should be effective and well tolerated for the treatment of various infections.