Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Quinolone antibacterials, fluoroquinolones, ATC code: J01MA14 
Mechanism of action

Tablets:
Moxifloxacin has in vitro activity against a wide range of Gram-positive and Gram-negative pathogens.
The bactericidal action of moxifloxacin results from the inhibition of both type II topoisomerases (DNA gyrase and topoisomerase IV) required for bacterial DNA replication, transcription and repair. 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, associated with the norA or pmrA genes seen in certain Gram-positive bacteria.
Pharmacodynamic investigations have demonstrated that moxifloxacin exhibits a concentration dependent killing rate. Minimum bactericidal concentrations (MBC) were found to be in the range of the minimum inhibitory concentrations (MIC).


Effect on the intestinal flora in humans
The following changes in the intestinal flora were seen in volunteers following oral administration of moxifloxacin: Escherichia coli, Bacillus spp., Enterococcus spp., and Klebsiella spp. were reduced, as were the anaerobes Bacteroides vulgatus, Bifidobacterium spp., Eubacterium spp., and Peptostreptococcus spp..
For Bacteroides fragilis there was an increase. These changes returned to normal within two weeks.


IV:
Moxifloxacin inhibits bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) that are required for bacterial DNA replication, transcription and repair.

PK/PD
Fluoroquinolones exhibit a concentration dependent killing of bacteria. Pharmacodynamic studies of fluoroquinolones in animal infection models and in human trials indicate that the primary determinant of efficacy is the AUC24/MIC ratio.
Mechanism of resistance

IV:
Resistance to fluoroquinolones can arise through mutations in DNA gyrase and topoisomerase IV. Other mechanisms may include over-expression of efflux pumps, impermeability, and protein-mediated protection of DNA gyrase. Cross resistance should be expected between moxifloxacin and other fluoroquinolones.
The activity of moxifloxacin is not affected by mechanisms of resistance that are specific to antibacterial agents of other classes

Tablets:
Resistance mechanisms that inactivate penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not interfere with the antibacterial activity of moxifloxacin. Other resistance mechanisms such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may also effect susceptibility to moxifloxacin.
In vitro resistance to moxifloxacin is acquired through a stepwise process by target site mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Moxifloxacin is a poor substrate for active efflux mechanisms in Gram-positive organisms.
Cross-resistance is observed with other fluoroquinolones. However, as moxifloxacin inhibits both topoisomerase II and IV with similar activity in some Gram-positive bacteria, such bacteria may be resistant to other quinolones, but susceptible to moxifloxacin.


Tablets and IV Breakpoints
EUCAST clinical MIC and disk diffusion breakpoints for moxifloxacin (01.01.2012): Organism                                              Susceptible                Resistant Staphylococcus spp.                                    ≤ 0.5 mg/l                 > 1 mg/l ≥ 24 mm                   < 21 mm
S. pneumoniae                                          ≤ 0.5 mg/l                > 0.5 mg/l ≥ 22 mm                   < 22 mm
Streptococcus Groups A, B, C, G                        ≤ 0.5 mg/l                 > 1 mg/l ≥ 18 mm                   < 15 mm
H. influenzae                                          ≤ 0.5 mg/l                > 0.5 mg/l ≥ 25 mm                   < 25 mm
M. catarrhalis                                         ≤ 0.5 mg/l                > 0.5 mg/l ≥ 23 mm                   < 23 mm
Enterobacteriaceae                                     ≤ 0.5 mg/l                 > 1 mg/l ≥ 20 mm                   < 17 mm
Non-species related breakpoints*                       ≤ 0.5 mg/l                 > 1 mg/l * Non-species related breakpoints have been determined mainly on the basis of pharmacokinetic/pharmacodynamic data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and are not for use with species where interpretative criteria remain to be determined.

Microbiological Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected species and local information of resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought where the local prevalence of resistance is such that utility of the agent in at least some types of infections is questionable.
Commonly susceptible species
Aerobic Gram-positive micro-organisms
IV:
Staphylococcus aureus*+
Streptococcus agalactiae (Group B)
Streptococcus milleri group* (S. anginosus, S. constellatus and S. intermedius) Streptococcus pneumoniae*
Streptococcus pyogenes* (Group A)
Streptococcus viridans group (S. viridans, S. mutans, S. mitis, S. sanguinis, S. salivarius, S. thermophilus) 
Tablets:
Gardnerella vaginalis
Staphylococcus aureus* (methicillin-susceptible)
Streptococcus agalactiae (Group B)
Streptococcus milleri group* (S. anginosus, S. constellatus and S. intermedius) Streptococcus pneumoniae*
Streptococcus pyogenes* (Group A)
Streptococcus viridans group (S. viridans, S. mutans, S. mitis, S. sanguinis, S. salivarius, S. thermophilus) 
Aerobic Gram-negative micro-organisms
IV:
Acinetobacter baumanii
Haemophilus influenzae*
Legionella pneumophila
Moraxella (Branhamella) catarrhalis*

Tablets:
Acinetobacter baumanii
Haemophilus influenzae*
Haemophilus parainfluenzae*
Legionella pneumophila
Moraxella (Branhamella) catarrhalis*
Anaerobic micro-organisms
IV:
Prevotella spp.
Tablets:
Fusobacterium spp.
Prevotella spp.
“Other” micro-organisms
IV:
Chlamydophila (Chlamydia) pneumoniae*
Coxiella burnetii
Mycoplasma pneumoniae*

Tablets:
Chlamydophila (Chlamydia) pneumoniae*
Chlamydia trachomatis*
Coxiella burnetii
Mycoplasma genitalium
Mycoplasma hominis
Mycoplasma pneumoniae*
Species for which acquired resistance may be a problem
Aerobic Gram-positive micro-organisms
IV:
Enterococcus faecalis*
Enterococcus faecium*
Tablets:
Enterococcus faecalis*
Enterococcus faecium*
Staphylococcus aureus (methicillin-resistant)+
Aerobic Gram-negative micro-organisms
IV:
Enterobacter cloacae*
Escherichia coli*#
Klebsiella oxytoca
Klebsiella pneumoniae*#
Proteus mirabilis*

Tablets:
Enterobacter cloacae*
Escherichia coli*#
Klebsiella pneumoniae*#
Klebsiella oxytoca
Neisseria gonorrhoeae*+
Proteus mirabilis*
Anaerobic micro-organisms
IV:
Bacteroides fragilis*
Tablets:
Bacteroides fragilis*
Peptostreptococcus spp.*
Inherently resistant organisms
Aerobic Gram-negative micro-organisms
Pseudomonas aeruginosa
*Activity has been satisfactorily demonstrated in susceptible strains in clinical studies in the approved clinical indications.
++
Methicillin resistant S. aureus have a high probability of resistance to fluoroquinolones.
Moxifloxacin resistance rate of > 50% have been reported for methicillin resistant S. aureus.
#
ESBL-producing strains are commonly resistant to fluoroquinolones
+
Resistance rate > 50% in one or more countries

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption and Bioavailability
IV:
After a single 400 mg intravenous 1 hour infusion peak plasma concentrations of approximately 4.1 mg/l were observed at the end of the infusion corresponding to a mean increase of approximately 26% relative to those seen after oral administration (3.1 mg/l). The AUC value of approximately 39 mg∙h/l after i.v. administration is only slightly higher than that observed after oral administration (35 mg∙h/l) in accordance with the absolute bioavailability of approximately 91%.

In patients, there is no need for age or gender related dose adjustment on intravenous moxifloxacin.

Pharmacokinetics are linear in the range of 50 - 1200 mg single oral dose, up to 600 mg single intravenous dose and up to 600 mg once daily dosing over 10 days.

Tablets:
Following oral administration moxifloxacin is rapidly and almost completely absorbed. The absolute bioavailability amounts to approximately 91%.
Pharmacokinetics are linear in the range of 50 - 800 mg single dose and up to 600 mg once daily dosing over 10 days. Following a 400 mg oral dose peak concentrations of 3.1 mg/l are reached within 0.5 - 4 h post administration. Peak and trough plasma concentrations at steady-state (400 mg once daily) were 3.2 and 0.6 mg/l, respectively. At steady-state the exposure within the dosing interval is approximately 30% higher than after the first dose.

Distribution
IV:
Moxifloxacin is distributed to extravascular spaces rapidly. The steady-state volume of distribution (Vss) is approximately 2 l/kg. In vitro and ex vivo experiments showed a protein binding of approximately 40 - 42% independent of the concentration of the drug. Moxifloxacin is mainly bound to serum albumin.

Maximum concentrations of 5.4 mg/kg and 20.7 mg/l (geometric mean) were reached in bronchial mucosa and epithelial lining fluid, respectively, 2.2 h after an oral dose. The corresponding peak concentration in alveolar macrophages amounted to 56.7 mg/kg. In skin blister fluid concentrations of 1.75 mg/l were observed 10 h after intravenous administration. In the interstitial fluid unbound concentration time profiles similar to those in plasma were found with unbound peak concentrations of 1.0 mg/l (geometric mean) reached approximately 1.8 h after an intravenous dose.

Tablets:
Moxifloxacin is distributed to extravascular spaces rapidly; after a dose of 400 mg an AUC of 35 m∙gh/l is observed. The steady-state volume of distribution (Vss) is approximately 2 l/kg. In vitro and ex vivo experiments showed a protein binding of approximately 40 - 42% independent of the concentration of the drug. Moxifloxacin is mainly bound to serum albumin.
The following peak concentrations (geometric mean) were observed following administration of a single oral dose of 400 mg moxifloxacin:

Tissue                            Concentration               Site: Plasma ratio Plasma                               3.1 mg/l                           - Saliva                               3.6 mg/l                      0.75 - 1.3 Blister fluid                       1.61 mg/l                          1.71 Bronchial mucosa                    5.4 mg/kg                       1.7 - 2.1 Alveolar macrophages               56.7 mg/kg                     18.6 - 70.0 Epithelial lining fluid             20.7 mg/l                         5–7 Maxillary sinus                     7.5 mg/kg                          2.0 Ethmoid sinus                       8.2 mg/kg                          2.1 Nasal polyps                        9.1 mg/kg                          2.6 Interstitial fluid                  1.02 mg/l                     0.8 - 1.42,3 Female genital tract*              10.24 mg/kg                        1.724 * intravenous administration of a single 400 mg dose
1
10 h after administration
2 unbound concentration
3 from 3 h up to 36 h post dose
4 at the end of infusion

Biotransformation
Moxifloxacin undergoes Phase II biotransformation and is excreted via renal (for IV - approximately 40%) and biliary/faecal (for IV approximately 60%) pathways as unchanged drug as well as in the form of a sulpho- compound (M1) and a glucuronide (M2). M1 and M2 are the only metabolites relevant in humans, both are microbiologically inactive.
In clinical Phase I and in vitro studies no metabolic pharmacokinetic interactions with other drugs undergoing Phase I biotransformation involving cytochrome P450 enzymes were observed. There is no indication of oxidative metabolism.

Elimination
IV:
Moxifloxacin is eliminated from plasma with a mean terminal half-life of approximately 12 hours. The mean apparent total body clearance following a 400 mg dose ranges from 179 to 246 ml/min. Following a 400 mg intravenous infusion recovery of unchanged drug from urine was approximately 22% and from faeces approximately 26%. Recovery of the dose (unchanged drug and metabolites) totalled to approximately 98% after intravenous administration of the drug. Renal clearance amounted to about 24 - 53 ml/min suggesting partial tubular reabsorption of the drug from the kidneys. Concomitant administration of moxifloxacin with ranitidine or probenecid did not alter renal clearance of the parent drug.

Tablets:
Moxifloxacin is eliminated from plasma with a mean terminal half life of approximately 12 hours. The mean apparent total body clearance following a 400 mg dose ranges from 179 to 246 ml/min. Renal clearance amounted to about 24 - 53 ml/min suggesting partial tubular reabsorption of the drug from the kidneys.
After a 400 mg dose, recovery from urine (approximately 19% for unchanged drug, approximately 2.5% for M1, and approximately 14% for M2) and faeces (approximately 25% of unchanged drug, approximately 36% for M1, and no recovery for M2) totalled to approximately 96%.
Concomitant administration of moxifloxacin with ranitidine or probenecid did not alter renal clearance of the parent drug.
Tablets - Elderly and patients with low body weight
Higher plasma concentrations are observed in healthy volunteers with low body weight (such as women) and in elderly volunteers.

Renal impairment
The pharmacokinetic properties of moxifloxacin are not significantly different in patients with renal impairment (including creatinine clearance > 20 ml/min/1.73 m2). As renal function decreases, concentrations of the M2 metabolite (glucuronide) increase by up to a factor of 2.5 (with a creatinine clearance of < 30 ml/min/1.73 m2).

Hepatic impairment
On the basis of the pharmacokinetic studies carried out so far in patients with liver failure (Child Pugh A, B), it is not possible to determine whether there are any differences compared with healthy volunteers. Impaired liver function was associated with higher exposure to M1 in plasma, whereas exposure to parent drug was comparable to exposure in healthy volunteers. There is insufficient experience in the clinical use of moxifloxacin in patients with impaired liver function.