Finafloxacin was approved by the U.S. Food and Drug Administration (FDA) on Dec 17, 2014. It was developed and marketed as Xtoro® by Alcon Laboratories.
Finafloxacin is a quinolone antimicrobial inhibiting bacterial type II topoisomerase enzymes, DNA gyraseand topoisomerase IV. It is indicated for the treatment of acute otitis externa (AOE) caused by susceptible strains of Pseudomonas aeruginosa and Staphylococcus aureus.
Xtoro® is available as a 5ml, 0.3% topical otic suspension of Finafloxacin, and the recommended dose is four drops in the affected ear(s) twice daily for seven days.
|Approval Date||Approval Type||Trade Name||Indication||Dosage Form||Strength||Company||Review Classification|
|2014-12-17||Marketing approval||Xtoro||Acute otitis externa (AOE)||Suspension/ Drops||0.3%||Alcon||Priority|
|CAS No.||209342-40-5 (Finafloxacin);|
|Chemical Name||(-)-8-cyano-1-cyclopropyl-6-fluoro-7-[(4aS,7aS)-hexahydropyrrolo[3,4-b]-1,4-oxazin-6(2H)-y]4-oxo-1,4-dihydroquinoline-3-carboxylic acid|
|Finafloxacin （Free Acid/Base）Parameters：|
|*：Calculated by ACD/Labs software V11.02.|
Mechanism of Action
Finafloxacin is a broad spectrum fluoroquinolone antibiotic which involves the inhibition of bacterial type II topoisomerase enzymes, DNA gyrase and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair and recombination.
Finafloxacin was highly selective for bacterial type II topoisomerases, and exhibited superior activity against E. coli DNA gyrase (CL50 = 25 ng/mL) and topoisomerase IV (CL50 = 8 ng/mL).
In Vitro Efficacy
● MICs at pH 5.8 were shown to be 2-3 fold lower than that at pH 7.3.
● MICs at pH 5.8:
v Staphylococcus: MIC50 = 0.016-4 μg/mL.
v Streptococcus: MIC50 = 0.125-0.25 μg/mL.
v Enterobacteriaceae: MIC50 = 0.125-8 μg/mL.
v Pseudomonas: MIC50 = 0.125-16 μg/mL.
● MICs at pH 7.3
v Staphylococcus: MIC50 = 0.125-16 μg/mL.
v Streptococcus: MIC50 = 0.5 μg/mL.
v Enterobacteriaceae: MIC50 = 1-128 μg/mL.
v Pseudomonas: MIC50 = 0.5-512 μg/mL.
The bactericidal activity:
● G+ and G- bacteria: MBC = 0.03-2 μg/mL (pH 5.8); 1-2 μg/mL (pH 7.2).
● MBC/MIC = 1-2.
● The MBC/MIC relationship was not altered at lower pH.
The activity against drug-resistant mutants:
v E.coli WT: MIC = 0.008-0.06 ug/mL.
v E.coli single mutant: MIC = 0.015-32 ug/mL.
v E.coli double mutations: MIC = 1-16 ug/mL.
● S. aureus:
v S. aureus WT: MIC ≤0.03-0.06 ug/mL.
v S. aureus mutations: MIC = 0.06-32 ug/mL.
● S. pneumoniae:
v S. pneumoniae WT: MIC = 0.06-0.125 ug/mL.
v S. pneumoniae mutations: MIC = 4-8 ug/mL.
● S. pyogenes mutations: MIC = 8-32 ug/mL.
● P. aeruginosa mutations: MIC ≤ 0.125-16 ug/mL.
In Vivo Efficacy
Acute otitis externa models:
● P. aeruginosa CFU reduction at 0.3% finafloxacin: 4-6 fold (at 24 h) or 0.5-1.5 fold (at 48 h).
● S. aureus: ED = 10 mg/kg (immunocompetent mouse) or 50 mg/kg (neutropenic mouse).
● E. coli: ED = 0.5 mg/kg (immunocompetent mouse) or 1 mg/kg (neutropenic mouse).
Respiratory tract infection:
● Finafloxacin showed a bacteriostatic effect in mouse or rat model infected by Streptococcus pneumoniae, H. influenza and P. aeruginosa.
Gastrointestinal and intra-adbominal infection:
● Peritonitis model: 100% survival at 25 mg/kg.
● Enteritis model: 83%-100% survival at 0.1-10 mg/kg.
● Cecal ligation model: 100% survival at 10 mg/kg.
● LPS-induced shock model: 83% survival at 10 mg/kg.
Skin and soft tissue infection:
● Finafloxacin showed similar efficacy as comparator fluoroquinolones in reducing the bacterial load in S. aureus and P. aeruginosa infection.
Urinary tract infection:
● E. coli: >3 log10 reduction in CFU in kidneys at 10 mg/kg.
● Proteus mirabilis: > 4 log10 reduction in CFU in kidneys at 100 mg/kg.
Absorption of Finafloxacin
Due to insufficient oto topical plasma concentration data, it was not possible to characterize systemic PK parameters or assess the relative bioavailability of finafloxacin by oto topical route.
Had high oral bioavailability in rats (57%) and dogs (73%).
Was absorbed rapidly with the Tmax occurring at 0.5 to 1 h after oral administrations in rats and humans.
Showed a half-life ranging between of 1.28-10.5 h in humans, 2.47 h in rats and 5.7 h in dogs, after oral administrations.
Distribution of Finafloxacin
Exhibited moderate plasma protein binding in humans (82%-84%), rats (44%-55%) and dogs (70%-79%).
Pigmented male Long-Evans rats following repeat oral administrations:
● The drug was rapidly and well distributed into most tissues except for the central nervous system (CNS) since the blood-brain barrier was crossed by a very small extent.
● Relatively higher concentration levels were observed in urine > bile > eye uveal tract >kidneys> liver > cartilage > epiphyseal line > small intestine > periosteum > arterial wall > other tissues.
● The concentration in eye uveal tract was very high at 24 h post-dose.
Guinea Pigs following repeat otic administrations:
● On Day 1, the concentration levels in tissues in order were tympanic membrane > external ear canal > tympanic bulla wall.
● On Day 7, the concentration levels in tissues in order were malleus > external ear canal > tympanic membrane > tympanic bulla wall > cochlea.
Metabolism of Finafloxacin
Finafloxacin was stable in hepatocytes from non-clinical species. No metabolism was detected in human, rat, rabbit or monkey hepatic microsomes.
Overall, the parent drug represented the most abundant component, with AL-91591 (β-glucuronide ester, conjugated at the carboxylic acid of finafloxacin) as the major metabolite in human plasma. Other two metabolites were detected in human plasma, but not in rat and dog plasma.
CYP1A2, 2D6, 2C19 and 3A4 were the major metabolizing enzymes.
Excretion of Finafloxacin
Was predominantly excreted in urine in rats after intravenous administration.
Finafloxacin did not inhibit the human CYP450 isoforms tested (CYP1A2, 2D6, 2C9, 2C19 or 3A4).
The safety of the AOE indication supported by two 14-day toxicology studies in NZW rabbits: 
● The first study detected minimal-to-mild local toxicity with finafloxacin hydroxide in phosphate buffer at pH 7.5. The high-dose (1.0% finafloxacin, ~2.18 mg/animal/day, 3.3 × MRHD) was the NOAEL for systemic toxicity.
● The second study tested finafloxacin. The NOAEL was the highest dose tested, 1.2% (~2.78 mg/animal/day, 4 × MRHD).
The middle-ear dosing safety profile identified by two repeat-dose middle-ear dosing studies in guinea pigs:
● The first (28-day) study tested finafloxacin hydrochloride. The NOAEL for hearing loss was the high dose, 1.2% (~1.2 mg/animal/day). This study did not identify a NOAEL for local toxicity. The lowest dose (0.6%, ~0.6 mg/animal/day) was associated with minimal hyperplasia of the tymapanic membrane, minimal hemorrhage, and increased incidence of pericanular bone fibrosis.
● The second (30-day) study tested finafloxacin free base in a different formulation (similar to the clinical formulation). Compared to saline control, the vehicle control was associated with hearing loss (at all frequencies tested) and local toxicity (bulla thickening, periosteal bone proliferation, and thickened tympanic membrane stroma). Finafloxacin did not exacerbate these toxicities.
Safety pharmacology studies were not required to support the AOE indication, but studies were completed to support other routes of exposure, and these studies were submitted to this NDA for completeness. The results were of concern for the AOE indication.
Reproductive and Developmental Toxicity
Fertility: No finafloxacin-toxicity was apparent.
● The rat toxicity studies consistently observed finafloxacin-toxicity in the male reproductive tract. A 4-week intravenous study identified the NOAEL as 30 mg/kg, based on decreased sperm count and motility ≥40 mg/kg. The Cmax for males at 30 mg/kg was 34900 ng/ml (149000 × MRHD).
● A stand-alone fertility study in rats was conducted. The NOAEL for male and female fertility was 100 mg/kg/day. The male 500 mg/kg group was completely infertile, and exhibited reduced sperm count, essentially no sperm motility.
In oral-dosing embryo-fetal studies, finafloxacin was clearly teratogenic.
● In rabbits: No developmental NOAEL was established. The NOAEL for reproductive toxicity was 3 mg/kg (based on increased preimplantation loss at 9 mg/kg). NOAEL for maternal general toxicity was 9 mg/kg.
● In rats: Developmental NOAEL = 30 mg/kg, LOAEL = 100 mg/kg, based on exencephaly. Reproductive NOAEL = 100 mg/kg, LOAEL = 500 mg/kg, based on increased preimplantation loss.
Prenatal and postnatal development studies with finafloxacin have not been conducted.
The concentration of finafloxacin was higher in milk than in dams’ blood or plasma.
No carcinogenicity testing was performed for finafloxacin, according to the current ICH SIA guidance.
● Carcinogenicity studies should be performed for any pharmaceutical whose expected clinical use was continuous for at least 6 months.
● Pharmaceuticals showing poor systemic exposure from topical routes in humans might not need studies by the oral route to assess the carcinogenic potential to internal organs.