Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-inflammatory agents and anti-infectives in combination, corticosteroids and anti-infectives in combination.

ATC code: S01C A01

Levodesa is a fixed dose combination of two active substances: levofloxacin and dexamethasone.
Levofloxacin:
Mechanism of action:
Levofloxacin, the active L-isomer of ofloxacin, is a fluoroquinolone antibacterial agent, that inhibits bacterial type II topoisomerases—DNA gyrase and topoisomerase IV. Levofloxacin preferentially targets DNA gyrase in Gram negative bacteria and topoisomerase IV in Gram positive bacteria. The spectrum of activity against ocular pathogens includes aerobic Gram-positive microorganisms (e.g. S. aureus MSSA, S. pyogenes, S.
pneumoniae, viridans group streptococci), aerobic Gram-negative bacteria (e.g. E. coli, H. influenzae, M.
catarrhalis, P. aeruginosa community isolates), other organisms (e.g. Chlamydia trachomatis).

Mechanisms of resistance
Bacterial resistance to levofloxacin can develop primarily due to two main mechanisms, namely a decrease in the intrabacterial concentration of a drug, or alterations in a drug's target enzymes. Target site alteration results from mutations in the chromosomal genes encoding the DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE; grlA and grlB in Staphylococcus aureus). Resistance due to low intrabacterial drug concentration follows either from altered outer-membrane porins (OmpF) leading to reduced entry of fluoroquinolones in Gram-negative bacteria or from efflux pumps. Efflux-mediated resistance has been described in pneumococci (PmrA), staphylococci (NorA), anaerobes, and Gram negative 
bacteria. Finally, plasmid-mediated resistance to quinolones (determined by the qnr gene) has been reported in Klebsiella pneumoniae and in E.coli.

Cross-resistance
Cross-resistance between fluoroquinolones may occur. Single mutations may not result in clinical resistance, but multiple mutations generally do result in clinical resistance to all drugs within the fluoroquinolone class. Altered outer-membrane porins and efflux systems may have a broad substrate specificity, targeting several classes of antibacterial agents and leading to multiresistance.

Susceptibility testing interpretive criteria
There are no interpretive criteria.

Dexamethasone:
Mechanism of action:
Corticosteroids like dexamethasone suppress vascular endothelial cell adhesion molecules, cyclooxygenase I or II, and cytokine expression. This action culminates in a reduced expression of proinflammatory mediators and the suppression of adhesion of circulating leukocytes to the vascular endothelium, thereby preventing their migration into inflamed ocular tissue. Dexamethasone has marked anti-inflammatory activity with reduced mineralocorticoid activity compared with some other steroids and is one of the most potent anti-inflammatory agents.

Clinical efficacy:
The efficacy of Levodesa has been investigated in a controlled study to evaluate the non-inferiority of the Levodesa vs. a standard treatment with a commercial formulation of tobramycin (0.5%) and dexamethasone (0.1%) eye drops for the prevention and treatment of inflammation and prevention of infection associated with cataract surgery in adults. The Investigator in charge of evaluating study parameters was blinded to treatment assignment. Patients who completed their cataract surgery without complications were assigned to Levodesa eye drops, 1 drop 4 times a day for 7 days, followed by dexamethasone 0.1% eye drops, 1 drop 4 times a day, for an additional 7 days, or to reference tobramycin + dexamethasone eye drops, 1 drop 4 times a day for 14 days.

Data of efficacy were available in 395 patients given Levodesa and in 393 patients given the reference product after cataract surgery. After 14 days of treatment, the proportion of patients with no signs of inflammation (primary endpoint of the study) inthe Levodesa followed by dexamethasone group compared to the tobramycin + dexamethasone group was 95.19% vs. 94.91%, respectively. The difference between the two proportions was 0.0028 (95% CI: [-0.0275; 0.0331]), which demonstrated the non-inferiority of the test vs. reference treatment regimen. No occurrence of endophthalmitis was reported during the study for either group. Signs of anterior chamber inflammation were absent in Levodesa arm in 73.16% at day 4 and in 85.57% of patients at day 8 after surgery. In tobramycin + dexamethasone arm, signs of anterior chamber inflammation were absent in 76.84% at day 4 and in 86.77% of patients at day 8. Conjunctival hyperemia was already absent at day 4 in 85.75% in Levodesa treatment arm vs. 82.19% in tobramycin + dexamethasone arm, respectively. The safety profile was similar in both groups 

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

The ocular instillation of Levodesa results in absorption of both actives to the ocular tissues and, at a much lower extent, to the systemic circulation.

After instillation to rabbit eyes, the plasma concentrations of levofloxacin increase with the dose after both single and repeated administration. Low levels of dexamethasone sodium phosphate are measured in plasma. In fact, dexamethasone sodium phosphate is rapidly metabolised in vivo to dexamethasone, which is the active metabolite. Dexamethasone exposure increaseswith the dose and after repeated doses a minor accumulation of both levofloxacin and dexamethasone is evident. Both levofloxacin and dexamethasone levels in ocular tissues (aqueous humour, cornea and conjunctiva) result to be higher than themaximum plasma levels after single and repeated doses. In particular, after 28-day treatment levofloxacin and dexamethasone levels in ocular tissues are 50 to 100-fold and 3 to 4-fold higher than the Cmax in plasma, respectively.

One-hundred-twenty-five patients undergoing cataract surgery have been randomized to 3 groups: levofloxacin, dexamethasone and Levodesa. One drop of each drug was administered 90 and 60 minutes before limbal paracentesis. The mean of the observed values for the concentration of levofloxacin was equal to 711.899 ng/mL (95% CI: 595.538; 828.260) in the Levodesa group compared to 777.307 ng/mL (95% CI: 617.220; 937.394) when levofloxacin was administered alone. The concentrations of levofloxacin in the aqueous humour are well above the minimum inhibitory concentrations for the ocular pathogens in levofloxacin's spectrum of activity.

When Levodesa was administered dexamethasone reached an aqueous humour concentration of 11.774 ng/mL (95% CI: 9.812; 13.736) compared to 16.483 ng/mL (95% CI: 13.736; 18.838) when dexamethasone was administered alone.

Both levofloxacin and dexamethasone are eliminated via urine.