Gemifloxacin

TABLE 4.5. MIC90 of GEM Compared with Other Marketed Quinolones Against Respiratory Microbes Associated with Pneumonia 

In terms of pharmacokinetics, with a single daily dose of 320 mg, GEM has a bioavailability (%F) of 71% (Yoo et ah, 2004), an AUC of 9.30 mg h/L (File and Tillotson, 2004), a half-life of 6.65 h (File and Tillotson, 2004), peak plasma concentration (Cmax) of 1.48 -1.6 mg/L (File and Tillotson, 2004), T ax of 1 h (File and Tillotson, 2004), a volume of distribution of 4.97 L/kg (Bhavnani and Andes, 2005), and a clearance of 151 mL/min (Bhavnani and Andes, 2005). Protein binding is moderate at 55 — 73% (Bryskier, 2005). As with other fluoroquinolones, its bioavailabilty (%F) is decreased significantly in the presence of antacids (Bryskier, 2005). The primary observed metabolites include the -isomer (4-6%), the acyl glucuronide (2-6%), and A-acetyl gemifloxacin (2-5%) (Yoo et ah, 2004). 

Molecular formula C18H20FN5O4 Molecular weight 389.38 CAS Registry No 175463-14-6 Merck Index 13,4400 

Sample preparation Vortex 50 [xL plasma and 250 xL 250 ng/mL IS in MeCN for 10 s, shake for 30 min, let stand at room temperature for 10 min, centrifuge at 14000 g for 15 min, add the supernatant to 200 m-L buffer in a silanized tube, inject a 10 aliquot. (The buffer was 10 mM ammonium acetate adjusted to pH 2.5 with trifluoroacetic acid.) 

Mobile phase MeCNibuffer 30 70 (The buffer was 10 mM ammonium acetate adjusted to pH 2.5 with trifluoroacetic acid.) 

Detector MS, PE Sciex API 300 tandem, heat-assisted nebulization, electrospray, positive ion mode, nebulizer gas at 60 psi, curtain gas at 40 psi, coUision gas thickness 4, auxiliary gas 7 L/min, dwell 400 ms, pause 5 ms, m/z 390-313 

Fowles, S.E. McDonnell, D.F. McCarthy, R. White, SA. Rapid determination of gemifloxacin in human plasma by high-performance hquid chromatography-tandem mass spectrometry, J.Chromatogr.B, 2000, 746, 191-198. 

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Five different types of reactors, including tube reactors, static mixers and a microstructured reactor, were tested for the synthesis of an intermediate to 3deld a quinolone antibiotic drug, named Gemifloxacin (FACTIVE ) [13,14]. 

Complicated exacerbation FEV, less than 50% predicted Comorbid cardiac disease Greater than or equal to 3 exacerbations per year Antibiotic therapy in the previous 3 months Above organisms plus drug-resistant pneumococci, P-lactamase-producing H. influenzae and M. catarrhalis, Escherichia coli, Proteus spp., Enterobacter spp., Klebsiella pneumoniae Oral P-Lactam/P-Iactamase inhibitor (amoxicil 1 i n-clavulanate) Fluoroquinolone with enhanced pneumococcal activity (levofloxacin, gemifloxacin, moxifloxacin) Intravenous P-Iactam/P-Iactamase inhibitor (ampicillin-sulbactam) Second- or third-generation cephalosporin (cefuroxime, ceftriaxone) Fluoroquinolone with enhanced pneumococcal activity (levofloxacin, moxifloxacin)... 

High-dose penicillin (12 million units/day for adults) or ceftiiaxonec or cefotaximec Levofloxaan,1 moxifloxacin,1 gemifloxacin,1 telithromyan, or vancomycin Penicillin-resistant (MIC >1.0 mcg/mL)... 

In complicated exacerbations where drug-resistant pneumococci, /J-lacta-mase-producing H. influenzae and M. catarrhalis, and some enteric gramnegative organisms maybe present, recommended therapy includes amox-icillin/clavulanate or a fluoroquinolone with enhanced pneumococcal activity (levofloxacin, gemifloxacin, moxifloxacin). 

The final coupling reaction of l-cyclopropyl-6-fluoro-7-chloro-l,4-dihy-dro-4-oxo-l,8-naphthyridine-3-carboxylic acid (7a) and 4-( er -butoxycarbo-nylaminomethyl)pyrrolidin-3-one-0-methyloxime (15a) proceeds according to the methods described by Sanchez et al. [13], Domogala et al. [16], and Kimura et al. [17], followed by acid hydrolysis to afford gemifloxacin, 7 - (4 - (aminomethyl) - 3 - (methoxyimino)pyrrolidin -1 - yl) -1 - cyclopropyl - 6 -fluoro-4-oxo-l,4-dihydro[l,8]naphthyridine-3-carboxylic acid and other corresponding derivatives, according to Scheme 5. 

Gemifloxacin, 21 224 Geminal dihydroperoxides, 13 455-456 Geminal silanol groups, 22 380, 381 silica surface chemistry and, 22 373 Geminate recombination, 14 620 Gemopatrilat, 5 159... 

GEMIFLOXACIN Gemifloxacin can be taken with or without food and should be swallowed whole with a liberal amount of liquid. 

QUINOLONE ANTIBIOTICS LEVOFLOXACIN (LEVAQUIN ), MOXIFLOXACIN (AVELOX ), GEMIFLOXACIN (FACTIVE ), AND GARENOXACIN (T-3811)... 

USAN Gemifloxacin mesylate Trade name Factive ... 

Figure 4.4. 2004 global quinolone sales. Note that, based on Oscient s press releases, 2005 sales of gemifloxacin (Factive ) were approximately 22 million U.S. dollars (Oscient, 2005, 2006). Source IMS Health, based on 15 leading quinolone products.)... 

Gram-positive bacteria Gram-negative bacteria Other organisms GEM, gemifloxacin CIP, ciprofloxacin LVX, levofloxacin GAT, gatifloxacin MXF, moxifloxacin. 

The coupling reaction between 122 and 130 proceeded smoothly in the presence of DBU in acetonitrile at ambient temperature to give gemifloxacin 3 in 85% yield (Scheme 4.27). 

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