Pharmacokinetics and Safety of NM441, a New Quinolone, in Healthy Male Volunteers

Abstract

The safety and pharmacokinetics of NM441, a prodrug of a new thiazeto-quinoline carboxylic acid derivative, NM394, were evaluated in healthy male volunteers given the drug orally in single doses of 20, 50, 100, 200, and 400 mg, and multiple doses of 300 mg twice daily for 6.5 days. No remarkable abnormalities were observed in symptoms, physical tests, laboratory tests, electrocardiogram (ECG), electroencephalogram (EEG), or equilibrium test. The mean plasma concentrations of active metabolite NM394 peaked between 0.5 and 1.0 hours, and the maximum concentrations were 0.68, 1.09, and 1.88 micrograms/mL at doses of 100, 200, and 400 mg, respectively. The mean half-lives were 7.7 to 8.9 hours and were not affected by dose. The mean urinary excretion rates of NM394 were 46.0, 38.3, and 30.6% of the doses within 48 hours, respectively, and other metabolites were excreted in urine by 7% of the doses. The mean salivary concentrations of NM394 were approximately 20% of the plasma concentrations. The mean fecal excretion rates of NM394 and NM441 were 52.9 and 4.2%, respectively within 72 hours after dosing of 400 mg. The Cmax, AUC, and urinary excretion rates were not altered by food intake, whereas the Tmax was prolonged slightly. In the multiple-dose study, the steady state of plasma concentration of NM394 was achieved on day 3 or 4, and further accumulation did not occur thereafter. The mean urinary excretion rate of NM394 was 49.0% during and 48 hours after the multiple administration. The acceptable safety and tolerance and defined pharmacokinetic characteristics of NM441 support further testing.

In vitro and in vivo activities of levofloxacin against Mycobacterium tuberculosis

“…These observations have been confirmed, both in vitro and in vivo, by other investigators who tested LVFX against a wide range of microorganisms, including M. tuberculosis (3,11,13,15,18,21,23), and the differences in the antimicrobial activities of the two drugs have been shown to be related to the differences in the anti-DNA gyrase activities of LVFX and OFLO (7). Because of the greater in vitro activity of LVFX compared with that of OFLO, because the absorption rates for the two are similar (3,14,18,21), and because there is no evidence that the adverse reactions of fluoroquinolones are correlated with their anti-DNA gyrase activities, greater therapeutic effect may be achieved if LVFX is administered at the same dosage as OFLO. LVFX may be applied to the treatment of infections, such as tuberculosis, for which OFLO cannot be prescribed at the optimal therapeutic dosage.…”

“…The superior in vivo activity of LVFX is probably due to its greater in vitro activity and also to its favorable physicochemical and pharmacokinetic properties. LVFX is 10 times more soluble in water than OFLO (21), is as well absorbed in mice and humans as OFLO (3,14,18,21), and reached significantly higher intracellular concentrations than OFLO (16).…”

Involvement of Breast Cancer Resistance Protein (ABCG2) in the Biliary Excretion Mechanism of Fluoroquinolones

“…However, it has been reported that the concentrations of ciprofloxacin in the bile are far greater than the usual minimal inhibitory concentration of common biliary pathogens in humans, presumably because of active transport as the ratio of the concentrations of ciprofloxacin in bile/liver was greater than unity (Dan et al, 1987). Prulifloxacin, an ester type prodrug of ulifloxacin, is immediately metabolized to ulifloxacin in the intestine, and 10% is recovered in the bile (Nakashima et al, 1994). Grepafloxacin and sparfloxacin are mainly eliminated from the liver by metabolism and biliary excretion, but very little is excreted into urine (Efthymiopoulos et al, 1997;Kamberi et al, 1998).…”

In Vitro Antibacterial Activities of AF 3013, the Active Metabolite of Prulifloxacin, against Nosocomial and Community Italian Isolates

“…Other fluoroquinolones, which had further-enhanced activity against gram-positive bacteria and were also variably active against anaerobes, were developed in the 1990s (10). However, several of these newer quinolones ended up being limited in their clinical use due to various, unexpected toxicity problems (1).AF 3013, a fluoroquinolone formerly called NM394 (5,8,11), is the active compound derived from the transformation of the prodrug prulifloxacin (also called NM441 or AF 3012) after its oral administration and intestinal absorption. Prulifloxacin and AF 3013 were developed in the late 1980s in Japan.…”

“…AF 3013, a fluoroquinolone formerly called NM394 (5,8,11), is the active compound derived from the transformation of the prodrug prulifloxacin (also called NM441 or AF 3012) after its oral administration and intestinal absorption. Prulifloxacin and AF 3013 were developed in the late 1980s in Japan.…”