Mofacin

Mofacin Mechanism of Action

moxifloxacin

Manufacturer:

Nang Kuang Pharmaceutical

Distributor:

Symgens

Marketer:

Symgens
Full Prescribing Info
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Moxifloxacin is an 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 e.g. Chlamydia spp., Mycoplasma spp. 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. Moxifloxacin is effective against β-lactam and macrolide resistant bacteria. Studies in animal models of infection have demonstrated 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- 10-10). Serial exposure of organisms to sub-MIC concentrations 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.
Effect on the intestinal flora in humans: In two 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 two weeks. Clostridium difficile toxin was not found. (See Tables 1, 2, 3 and 4.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

The frequency of acquired resistance may vary geographically and with time for certain species. Local area information on resistance of organisms is desirable, particularly when treating severe infections. The above information is provided as a guide on the probability of an organism being susceptible to moxifloxacin.
Comparison of PK/PD surrogates for intravenous and oral administration of a 400 mg moxifloxacin single dose.
In patients requiring hospitalization AUC/MIC90 parameters greater than 125 and Cmax/MIC90 of 8-10 is predictive for clinical cure (Schentag).
In outpatients these surrogate parameters are generally smaller, i.e. AUC/MIC90 greater than 30-40 (Dudley and Ambrose).
The following table provides the respective PK/PD surrogates for intravenous and oral administration of 400 mg moxifloxacin calculated from single dose data: See Table 5.

Click on icon to see table/diagram/image

Pharmacokinetics: Absorption: Moxifloxacin, given as an oral tablet, is well absorbed from the gastrointestinal tract. The absolute bioavailability of moxifloxacin is approximately 90 percent. Co-administration with a high fat meal (i.e., 500 calories from fat) does not affect the absorption of moxifloxacin.
Consumption of 1 cup of yogurt with moxifloxacin does not significantly affect the extent or rate of systemic absorption (AUC).
The mean (±SD) Cmax and AUC values following single and multiple doses of 400 mg moxifloxacin given orally are summarized as follows. (See Table 6.)

Click on icon to see table/diagram/image

The mean (±SD) Cmax and AUC values following single and multiple doses of 400 mgmoxifloxacin given by 1 hour I.V. infusion are summarized as follows. (See Table 7.)

Click on icon to see table/diagram/image

Plasma concentrations increase proportionately with dose up to the highest dose tested (1200 mg single oral dose). The mean (±SD) elimination half-life from plasma is 12±1.3 hours; steady-state is achieved after at least three days with a 400 mg once daily regimen. (See Figure.)

Click on icon to see table/diagram/image

Distribution: Moxifloxacin is approximately 30-50% bound to serum proteins, independent of drug concentration. The volume of distribution of moxifloxacin ranges from 1.7 to 2.7 L/kg. Moxifloxacin is widely distributed throughout the body, with tissue concentrations often exceeding plasma concentrations. Moxifloxacin has been detected in the saliva, nasal and bronchial secretions, mucosa of the sinuses, skin blister fluid, subcutaneous tissue, skeletal muscle and abdominal tissues and fluids following oral or intravenous administration of 400 mg.
Moxifloxacin concentrations measured post-dose in various tissues and fluids following a 400mg oral or I.V. dose are summarized in the following table. The rates of elimination of moxifloxacin from tissues generally parallel the elimination from plasma. (See Table 8.)

Click on icon to see table/diagram/image

Metabolism: Approximately 52% of an oral or intravenous dose of moxifloxacin is metabolized via glucuronide and sulfate conjugation. The cytochrome P450 system is not involved in moxifloxacin metabolism, and is not affected by moxifloxacin. The sulfate conjugate (M1) accounts for approximately 38% of the dose, and is eliminated primarily in the feces. Approximately 14% of an oral or intravenous dose is converted to a glucuronide conjugate (M2), which is excreted exclusively in the urine.
Peak plasma concentrations of M2 are approximately 40% those of the parent drug, while plasma concentrations of M1 are generally less than 10% those of moxifloxacin.
In vitro studies with cytochrome (CYP) P450 enzymes indicate that moxifloxacin does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2, suggesting that moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.
Excretion: Approximately 45% of an oral or intravenous dose of moxifloxacin is excreted as unchanged drug (~20% in urine and ~25% in feces). A total of 96 ± 4% of an oral dose is excreted as either unchanged drug or known metabolites. The mean (±SD) apparent total body clearance and renal clearance are 12 ± 2.0 L/hr and 2.6 ± 0.5 L/hr, respectively.
Special Populations: Geriatric: Following oral administration of 400 mg moxifloxacin for 10 days in 16 elderly (8 males; 8 females) and 17 (8 males; 9 females) young healthy volunteers, there were no age-related changes in moxifloxacin pharmacokinetics. In 16 healthy male volunteers (8 young; 8 elderly males) given a single 200 mg dose of oral moxifloxacin, the extent of systemic exposure (AUC and Cmax) was not statistically different between young and elderly males and elimination half-life was unchanged. No dosage adjustment is necessary based on age. In large phase III studies, the concentrations around the time of the end of the infusion in elderly patients following intravenous infusion of 400 mg were similar to those observed in young patients.
Pediatric: The pharmacokinetics of moxifloxacin in pediatric subjects have not been studied.
Gender: Following oral administration of 400 mg moxifloxacin daily for 10 days to 23 healthy males (19-75 years) and 24 healthy females (19-70 years), the mean AUC and Cmax were 8% and 16% higher, respectively, in females compared to males. There are no significant differences in moxifloxacin pharmacokinetics between male and female subjects when differences in body weight are taken into consideration. A 400 mg single dose study was conducted in 18 young males and females. The comparison of moxifloxacin pharmacokinetics in this study (9 young females and 9 young males) showed no differences in AUC or Cmax due to gender. Dosage adjustments based on gender are not necessary.
Race: Steady-state moxifloxacin pharmacokinetics in male Japanese subjects were similar to those determined in Caucasians, with a mean Cmax of 4.1µg/mL, an AUC24 of 47µg·hr/mL, and an elimination half-life of 14 hours, following 400 mg oral daily.
Renal Insufficiency: The pharmacokinetic parameters of moxifloxacin are not significantly altered in mild, moderate, severe, or end-stage renal disease. No dosage adjustment is necessary in patients with renal impairment, including those patients requiring hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD).
In a single oral dose study of 24 patients with varying degrees of renal function from normal to severely impaired, the mean peak concentrations (Cmax) of moxifloxacin were reduced by 21% and 28% in the patients with moderate (CLCR 30-60 mL/min) and severe (CLCR <30 mL/min) renal impairment, respectively. The mean systemic exposure (AUC) in these patients was increased by 13%. In the patients with moderate and severe renal impairment, the mean AUC for the sulfate conjugate (M1) increased by 1.7-fold (ranging up to 2.8-fold) and mean AUC and Cmax for the glucuronide conjugate (M2) increased by 2.8-fold (ranging up to 4.8-fold) and 1.4-fold (ranging up to 2.5-fold), respectively.
The pharmacokinetics of single-dose and multiple-dose moxifloxacin were studied in patients with CLCR < 20 mL/min on either hemodialysis or continuous ambulatory peritoneal dialysis (8 HD, 8 CAPD). Following a single 400 mg oral dose, the AUC of moxifloxacin in these HD and CAPD patients did not vary significantly from the AUC generally found in healthy volunteers. Cmax values of moxifloxacin were reduced by about 45% and 33% in HD and CAPD patients, respectively, compared to healthy, historical controls. The exposure (AUC) to the sulfate conjugate (M1) increased by 1.4- to 1.5-fold in these patients. The mean AUC of the glucuronide conjugate (M2) increased by a factor of 7.5, whereas the mean Cmax values of the glucuronide conjugate (M2) increased by a factor of 2.5 to 3, compared to healthy subjects. The sulfate and the glucuronide conjugates of moxifloxacin are not microbiologically active, and the clinical implication of increased exposure to these metabolites in patients with renal disease including those undergoing HD and CAPD has not been studied.
Oral administration of 400 mg daily moxifloxacin for 7 days to patients on HD or CAPD produced mean systemic exposure (AUCss) to moxifloxacin similar to that generally seen in healthy volunteers. Steady-state Cmax values were about 22% lower in HD patients but were comparable between CAPD patients and healthy volunteers. Both HD and CAPD removed only small amounts of moxifloxacin from the body (approximately 9% by HD, and 3% by CAPD). HD and CAPD also removed about 4% and 2% of the glucuronide metabolite (M2), respectively.
Hepatic Insufficiency: In 400 mg single oral dose studies in 6 patients with mild (Child Pugh Class A), and 10 patients with moderate (Child Pugh Class B), hepatic insufficiency, moxifloxacin mean systemic exposure (AUC) was 78% and 102%, respectively, of 18 healthy controls and mean peak concentration (Cmax) was 79% and 84% of controls.
The mean AUC of the sulfate conjugate of moxifloxacin (M1) increased by 3.9-fold (ranging up to 5.9-fold) and 5.7-fold (ranging up to 8.0-fold) in the mild and moderate groups, respectively. The mean Cmax of M1 increased by approximately 3-fold in both groups (ranging up to 4.7- and 3.9-fold). The mean AUC of the glucuronide conjugate of moxifloxacin (M2) increased by 1.5-fold (ranging up to 2.5-fold) in both groups. The mean Cmax of M2 increased by 1.6- and 1.3-fold (ranging up to 2.7- and 2.1-fold), respectively. The clinical significance of increased exposure to the sulfate and glucuronide conjugates has not been studied. No dosage adjustment is recommended for mild or moderate hepatic insufficiency (Child Pugh Classes A and B). The pharmacokinetics of moxifloxacin in severe hepatic insufficiency (Child Pugh Class C) have not been studied.
Photosensitivity Potential: A study of the skin response to ultraviolet (UVA and UVB) and visible radiation conducted in 32 healthy volunteers (8 per group) demonstrated that moxifloxacin does not show phototoxicity in comparison to placebo. The minimum erythematous dose (MED) was measured before and after treatment with moxifloxacin (200 mg or 400 mg once daily), lomefloxacin (400 mg once daily), or placebo. In this study, the MED measured for both doses of moxifloxacin were not significantly different from placebo, while lomefloxacin significantly lowered the MED.
Toxicology: Preclinical Safety Data: In a local tolerability study performed in dogs, no signs of local intolerability were seen when moxifloxacin was administered intravenously. 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, the drug 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.
Phototoxicity: Moxifloxacin is very photostable and has a very low potential for photogenotoxicity. In vitro and in animal models, moxifloxacin seems to show less potency to induce phototoxicity and photogenotoxicity than other quinolones. Some quinolones have been shown to enhance the action of UV-A-induced photocarcinogenicity when administered concurrently to mice exposed to ultraviolet light. No photocarcinogenicity study has been performed with moxifloxacin. The lack of phototoxic potential has been confirmed in a Phase I study in volunteers.
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 intravenous administration of more than 50-fold the human dose (>300 mg/kg), leading to plasma concentrations of ≥ 200 mg/l (more than 30-fold the therapeutic level after intravenous administration), reversible, non-fatal ventricular arrhythmias were seen.
Arthrotoxicity: Quinolones are known to cause lesions in the cartilage of the major diarthrodial joints in immature animals. The lowest oral dose of moxifloxacin causing joint toxicity in juvenile dogs was four times maximum recommended therapeutic dose (400 mg/50 kg person) on a mg/kg basis, with plasma concentrations two to three 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 i.v.) 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 intravenous dose of 20 mg/kg. This study result is consistent with the known effects of quinolones on skeletal development (see Use in Pregnancy & Lactation). There was an increase in the incidence of abortions in monkeys and rabbits at human therapeutic concentrations. In rats, decreased fetal 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.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in