Ducressa Mechanism of Action

Pharmacotherapeutic group: Anti-inflammatory agents and anti-infectives in combination, corticosteroids and anti-infectives in combination. ATC code: S01C A01.
Pharmacology: Pharmacodynamics: (Ducressa) eye drops solution 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 Levofloxacin + Dexamethasone (Ducressa) eye drops solution has been investigated in a controlled study to evaluate the non-inferiority of the Levofloxacin + Dexamethasone (Ducressa) eye drops solution vs. a standard treatment with a commercial formulation of tobramycin (0.3%) 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 Levofloxacin + Dexamethasone (Ducressa) eye drops solution, 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 Levofloxacin + Dexamethasone (Ducressa) eye drops solution 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) in the Ducressa 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 Ducressa 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 Levofloxacin + Dexamethasone (Ducressa) eye drops solution treatment arm vs. 82.19% in tobramycin + dexamethasone arm, respectively. The safety profile was similar in both groups.
Pharmacokinetics: The ocular instillation of Levofloxacin + Dexamethasone (Ducressa) eye drops solution 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 increases with 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 the maximum 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 Levofloxacin + Dexamethasone (Ducressa) eye drops solution. 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 Levofloxacin + Dexamethasone (Ducressa) eye drops solution 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 Levofloxacin + Dexamethasone (Ducressa) eye drops solution 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.
Toxicology: Preclinical safety data: Repeated-dose ocular toxicity studies with the levofloxacin/dexamethasone fixed dose combination for up to 28 days in rabbits revealed systemic toxicities attributable to exaggerated pharmacological effects of dexamethasone (focal tubular cell necrosis and glomerulopathy with necrosis and/or hyaline depositions in kidneys, hepatic hypertrophy with intracellular hyaline inclusions and single cell necrosis, atrophy of adrenal gland cortex and lymphocyte decreases due to atrophy of spleen, thymus and lymph nodes).
Such effects were observed only at about 3-fold higher exposures than achieved at the maximum recommended human ocular dose, indicating little relevance to clinical use.
Gyrase inhibitors have been shown to cause growth disorders of weight bearing joints in animal studies. In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and cavities) in rats and dogs after high oral doses.
Genotoxicity and carcinogenicity: Dexamethasone and levofloxacin did not reveal any clinically relevant genotoxic or carcinogenic potential.
Reproductive toxicity: Levofloxacin did not influence fertility and only impaired embryo-foetal development in animals at exposures, considerably in excess of those achievable at the recommended ocular therapeutic dose in humans. Topical and systemic administration of dexamethasone impaired male and female fertility and induced teratogenic effects including formation of cleft palate, intra-uterine growth retardation and foetal mortality. Peri- and postnatal toxicity of dexamethasone was also observed.
Phototoxic potential: Studies in the mouse after both oral and intravenous dosing showed levofloxacin to have phototoxic activity only at very high doses.