Pharmacology: Mechanism of Action: Moxifloxacin is a 8-methoxy-fluoroquinolone antibiotic with a broad spectrum of activity and bactericidal action. Moxifloxacin has in vitro activity against a wide range of gram-positive and gram-negative organisms, anaerobes, acid-fast bacteria and atypicals eg, Mycoplasma, Chlamydia and Legionella spp.
The bactericidal action results from the interference with topoisomerase II and IV. Topoisomerases are essential enzymes which control DNA topology and assist in DNA replication, repair and transcription.
Moxifloxacin exhibits concentration-dependent bactericidal killing. Minimum bactericidal concentrations are generally similar to minimum inhibitory concentrations (MIC).
Moxifloxacin is effective against β-lactam-resistant and macrolide-resistant bacteria. Studies in animal models of infection have demonstrated the high in vivo activity.
Resistance: Resistance mechanisms which inactivate penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not interfere with the antibacterial activity of moxifloxacin. There is no cross-resistance between moxifloxacin and these agents. Plasmid-mediated resistance has not been observed to date.
It appears that the C8-methoxy moiety contributes to enhanced activity and lower selection of resistant mutants of gram-positive bacteria compared to the C8-H moiety. The presence of the bulky bicycloamine substituent at the C-7 position prevents active efflux, a mechanism of fluoroquinolone resistance.
In vitro studies have demonstrated that resistance to moxifloxacin develops slowly by multiple step mutations. A very low overall frequency of resistance was demonstrated (10-7 to 10-10). Serial exposure of organisms to sub-MIC concentration of moxifloxacin showed only a small increase in MIC values.
Cross-resistance among quinolones has been observed. However, some gram-positive and anaerobic organisms resistant to other quinolones are susceptible to moxifloxacin.
Pharmacokinetics: Absorption and Bioavailability: Following oral administration, moxifloxacin is absorbed rapidly and almost completely. The absolute bioavailability amounts to approximately 91%.
Pharmacokinetics are linear in the range of 50-1200 mg single dose and up to 600 mg once daily dosing over 10 days. Steady state is reached within 3 days. Following a 400-mg oral dose peak concentration of 3.1 mg/L are reached within 0.5 - 4 hrs p.a. Peak and trough plasma concentrations at steady state (400 mg once daily) were 3.2 and 0.6 mg/L, respectively.
Concomitant administration of moxifloxacin together with food slightly prolongs the time to reach peak concentrations by approximately 2 hrs and slightly reduced peak concentrations by approximately 16%. Extent of absorption remained unchanged. As AUC/MIC is most predictive for antimicrobial efficacy of quinolones, this effect is clinically not relevant. Therefore, moxifloxacin can be administered independent from meals.
After a single 400 mg 1-hr IV infusion, peak concentrations of approximately 4.1 mg/L were reached in the plasma at the end of infusion which corresponds to a mean increase of approximately 26% relative to the oral application. Exposure to drug in terms of AUC at a value of approximately 39 mg·hr/L is only slightly higher compared to the exposure after oral administration (35 mg·hr/L) in accordance with the absolute bioavailability of approximately 91%.
Following multiple IV dosing (1-hr infusion), peak and trough plasma concentrations at steady-state (400 mg once daily) were between 4.1-5.9 and 0.43-0.84 mg/L, respectively. At steady state, the exposure to drug within the dosing interval is approximately 30% higher than after the first dose. In patients, mean steady-state concentrations of 4.4 mg/L were observed at the end of a 1-hr infusion.
Distribution: Moxifloxacin is distributed very rapidly to extravascular spaces. Exposure to drug in terms of AUC (AUCnorm= 6 kg·hr/L) is high with a volume of distribution at steady-state (Vss) of approximately 2 L/kg. In saliva, peak concentrations higher than those of plasma may be reached. In in vitro and ex vivo experiments over a range of 0.02-2 mg/L, a protein binding of approximately 45% independent from the concentration of the drug was determined. Moxifloxacin is mainly bound to serum albumin. Due to this low-value, high-free peak concentrations >10 x MIC are observed.
Moxifloxacin reaches high concentrations in tissues like lung (epithelial fluid, alveolar macrophages, biotic tissue), the sinuses (maxillary and ethmoid sinus, nasal polyp) and inflamed lesions (cantharide blister fluid) where total concentrations exceeding those of the plasma concentrations are reached. High free-drug concentrations are measured in interstitial body water (saliva, IM, SC). In addition, high drug concentrations were detected in abdominal tissues and fluids and female genital tract.
The peak concentrations and site versus plasma concentration ratios for various target tissues yielded comparable results for both modes of drug administration after a single dose of moxifloxacin 400 mg.
Metabolism: Moxifloxacin undergoes phase II biotransformation and is excreted via renal and biliary/faecal pathways as unchanged drug as well as in form of a sulfo-compound (M1) and a glucuronide (M2). M1 and M2 are the only metabolites relevant in humans, both are microbiologically inactive. Neither in in vitro nor in clinical phase I studies, metabolic pharmacokinetic interactions with other drugs undergoing phase I biotransformation involving cytochrome P-450 (CYP450) enzymes were observed.
Independent from the route of administration, the metabolites M1 and M2 are found in the plasma at concentrations lower than the parent drug. Preclinical investigations adequately covered both metabolites thus excluding potential implications with respect to safety and tolerability.
Elimination: Moxifloxacin is eliminated from plasma with a mean terminal t½ of approximately 12 hrs. The mean apparent total body clearance following 400-mg dose ranges from 179-246 mL/min. Renal clearance amounted to about 24-53 mL/min suggesting partial tubular reabsorption of the drug from the kidneys. Concomitant administration of ranitidine and probenecid did not alter renal clearance of the drug.
Mass balance of the mother compound and phase II metabolites of moxifloxacin yielded an almost complete recovery of approximately 96-98% independent from the route of administration with no indication of oxidative metabolism.
Elderly: Pharmacokinetics of moxifloxacin are not affected by age.
Gender: There was a 33% difference in the pharmacokinetics (AUC, Cmax) of moxifloxacin between male and female subjects. Drug absorption was unaffected by gender. These differences in the AUC and Cmax were attributable to the differences in body weight rather than gender. They are not considered as clinically relevant.
Interethnic Differences: Possible interethnic differences were examined in Caucasian, Japanese, Black and other ethnic groups. No clinically relevant interethnic differences in pharmacokinetics could be detected.
Children: Pharmacokinetics of moxifloxacin were not studied in paediatric patients.
Renal Impairment: The pharmacokinetics of moxifloxacin are not significantly changed by renal impairment (including creatinine clearance <30 mL/min/1.73 m2) and in patients on chronic dialysis ie, hemodialysis and continuous ambulatory peritoneal dialysis.
Liver Impairment: Moxifloxacin plasma concentrations of patients with mild to severe hepatic impairment (Child-Pugh A to C) did not reveal clinically relevant differences compared to healthy volunteers or patients with normal hepatic function, respectively (see also Precautions).
Toxicology: Preclinical Safety Data: In a local tolerability study performed in dogs, no signs of local intolerability were seen when moxifloxacin was administered IV. After intra-arterial injection, inflammatory changes involving the peri-arterial soft tissue were observed suggesting that intra-arterial administration of moxifloxacin should be avoided.
Carcinogenicity, Mutagenicity: Although conventional long-term studies to determine the carcinogenic potential of moxifloxacin have not been performed, it has been subject to a range of in vitro and in vivo genotoxicity tests. In addition, an accelerated bioassay for human carcinogenesis (initiation/promotion assay) was performed in rats. Negative results were obtained in 4 strains of the Ames test in the HPRT mutation assay in Chinese hamster ovary cells and in the UDS assay in rat primary hepatocytes. As with other quinolones, the Ames test with TA 102 was positive and the in vitro test in the Chinese hamster v79 cells showed chromosomal abnormalities at high concentrations (300 mcg/mL). However, the in vivo micronucleus assay in the mouse was negative. An additional in vivo assay, the dominant lethal assay in the mouse, was negative as well. It is concluded that the negative in vivo results adequately reflect the in vivo situation in terms of genotoxicity. No evidence of carcinogenicity was found in an initiation/promotion assay in rats.
ECG: At high concentrations, moxifloxacin is an inhibitor of the delayed rectifier potassium current of the heart and may thus cause prolongations of the QT-interval. Toxicological studies performed in dogs using oral doses of ≥90 mg/kg leading to plasma concentrations ≥16 mg/L caused QT-prolongations, but no arrhythmias. Only after very high cumulative IV administration of >50-fold the human dose (>300 mg/kg), leading to plasma concentrations of ≥200 mg/L (>30-fold the therapeutic level after IV administration), reversible, nonfatal ventricular arrhythmias were seen.
Arthrotoxicity: Quinolones are known to cause lesions in the cartilage of the major diarthodial joints in immature animals. The lowest oral dose of moxifloxacin causing joint toxicity in juvenile dogs was 4 times the maximum recommended therapeutic dose (400 mg/50 kg person) on a mg/kg basis with plasma concentrations 2-3 times higher than those at the recommended therapeutic dose.
Reprotoxicity: Reproductive studies performed in rats, rabbits and monkeys indicate that placental transfer of moxifloxacin occurs. Studies in rats (per OS and IV) and monkeys (per OS) did not show evidence of teratogenicity or impairment of fertility following administration of moxifloxacin. Skeletal malformations were observed in rabbits that had been treated with an IV dose of 20 mg/kg. This study result is consistent with the known effects of quinolones on skeletal development. There was an increase in the incidence of abortions in monkeys and rabbits at human therapeutic concentrations. In rats, decreased foetal weights, an increased prenatal loss, a slightly increased duration of pregnancy and an increased spontaneous activity of some male and female offspring was observed at doses which were 63 times the maximum recommended dose on a mg/kg basis with plasma concentrations in the range of the human therapeutic dose.
Microbiology: Effect on the Intestinal Flora in Humans: In 2 volunteer studies, the following changes in the intestinal flora were seen following oral dosing with moxifloxacin. E. coli, Bacillus spp, Bacteroides vulgatus, Enterococci and Klebsiella spp, were reduced as were the anaerobes Bifidobacterium, Eubacterium and Peptostreptococcus. These changes returned to normal within 2 weeks. Clostridium difficile toxin was not found.
In Vitro Susceptibility Data: Gram-Positive Bacteria: Sensitive: Streptococcus pneumoniae including multi-drug resistant Streptococcus pneumoniae (MDRSP) strains, penicillin-resistant S. pneumoniae (PRSP) and strains resistant to ≥2 of the following antibiotics: Penicillin (MIC ≥2 mcg/mL), 2nd generation cephalosporins (eg, cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole; Streptococcus pyogenes (group A)*, Streptococcus milleri, Streptococcus mitior, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus*, Streptococcus constellatus*, Staphylococcus aureus (including methicillin-sensitive strains)*, Staphylococcus cohnii, Staphylococcus epidermidis (including methicillin-sensitive strains), Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus simulans, Corynebacterium diphtheriae, Enterococcus faecalis* (vancomycin, gentamycin, susceptible strains only). Intermediate: Staphylococcus aureus (methicillin/ofloxacin resistant strains)+, Staphylococcus epidermidis (methicillin/ofloxacin resistant strains)+.
Gram-Negative Bacteria: Sensitive: Gardnerella vaginalis, Haemophilus influenzae (including β-lactamase negative and positive strains)*, Haemophilus parainfluenzae*, Moraxella catarrhalis (including β-lactamase negative and positive strains)*, Bordetella pertussis, Escherichia coli*, Klebsiella pneumoniae*, Klebsiella oxytoca, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae*, Enterobacter intermedius, Enterobacter sakazaki, Proteus mirabilis*, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Providencia stuartii. Intermediate: Pseudomonas aeruginosa, Pseudomonas fluorescens, Burkholderia cepacia, Stenotrophomonas maltophilia, Neisseria gonorrhoea*.
Anaerobes: Sensitive: Bacteroides distasonis, Bacteroides eggerthii, Bacteroides fragilis*, Bacteroides ovatus, Bacteroides thetaiotamicron*, Bacteroides uniformis, Fusobacterium spp, Peptostreptococcus spp, Porphyromonas spp, Porphyromonas anaerobius, Porphyromonas asaccharolyticus, Porphyromonas magnus, Prevotella spp, Propionibacterium spp, Clostridium perfringens*, Clostridium ramosum.
Atypicals: Sensitive: Chlamydia pneumoniae*, Chlamydia trachomatis**, Mycoplasma pneumoniae*, Mycoplasma hominis, Mycoplasma genitalum, Legionella pneumophila*, Coxiella burnettii.
Note: */**Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.
+Moxifloxacin showed in vitro activity with MIC values in the susceptible range in methicillin-resistant staphylococci expressing only the MecA gene. The use of moxifloxacin is not recommended if these strains are identified.
The frequency of acquired resistance may vary geographically and with time for certain species. However, for moxifloxacin, this has not been observed to date. Local area information on resistance of organisms is desirable, particularly when treating severe infections. The previously mentioned information is provided as a guide on the probability of an organism being susceptible to moxifloxacin.
Comparison of pharmacokinetic/pharmacodynamic surrogates for IV and oral administration of a moxifloxacin 400-mg single dose.
In patients requiring hospitalisation AUC/MIC90 parameters >125 and Cmax/MIC90 of 8-10 is predictive for clinical cure. In outpatients, these surrogate parameters are generally smaller ie, AUC/MIC90 >30-40.
The following table provides the respective pharmacokinetic/pharmacodynamic surrogates for IV and oral administration of moxifloxacin 400 mg calculated from single dose data. (See table.)
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