Mechanism of Action

Efinaconazoleis a novel triazole antifungal, which appeared to target the fungal heme proteins that cocatalyze 14α-demethylase, a P450 enzyme necessary for the conversion of lanosterol to ergosterol.

The azole-based antimycotic agents, which inhibited the conversion of lanosterol to ergosterol (IC₅₀ = 0.007 μg/mL), resulted in the
depletion of the ergosterols, and the increase of cell permeability, with leakage of cell contents.

Efinaconazole was approximately 10% less keratin-bound and more completely released after several washings than that observed in the same kind (antifungals).

In Vitro Efficacy

Antifungal activity of efinaconazole:

●    T. rubrum: MIC₉₀ = 0.008-0.06 μg/mL

●    T. mentagrophytes: MIC₉₀ = 0.015-0.13 μg/mL

●    C. albicans: MIC₉₀ = 0.06->0.25 μg/mL

In an in vitro human toenail model of onychomycosis, efinaconazole was more active than vehicle in reducing the burden of T. rubrum in infected nails.

Low potential for the development of resistance in specific fungal pathogens to efinaconazole:

●    Fungal pathogens: T. rubrum, T. mentagrophytes, and C. albicans

●    T.rubrum, one isolate: 4-fold MIC increased

●    Other isolates: MIC increase was 2-fold or less

In Vivo Efficacy

The efinaconazole preparations (3% and 10%) were more efficacious than all tested antifungals in a guinea pig model of onychomycosis.

The efinaconazole vehicle also decreased fungal burden in this model by approximately 1 log₁₀ viable fungal cells.

Absorption of Efinaconazole

Exhibited a linear pharmacokinetics in rats following topical dosing.  The increases in C_max and AUC appeared to be
approximately dose-proportional in the dose range of 2 to 50 mg/kg efinaconazole.

Had a low bioavailability in rats (7.3%) for topical administration and high bioavailability (104%) for subcutaneous
administration.

Was absorbed slowly (T_max = 6 h) in rats and (T_max = 12-24 h) in humans after topical administration.

Showed a half-life of 20.6 h in humans, longer than that in rats (8.1 h), after topical administration.

Had a high clearance in rats (44.4 mL/min/kg), compared to liver blood flow, after intravenous administration.

Distribution of Efinaconazole

Exhibited a high plasma protein binding in rats (>97%), dogs (98%) and humans (96%).  Note that the drug was mainly bound to serum albumin.

Had a % partition of 5.4 in rats, suggesting a hardly migration to blood cells.

In rats after topical administration:

●    Relatively higher concentration levels at 12 h were observed in liver, followed by adrenal and the skin.

●    Trace radioactivity had been detected in lungs, liver and skin only at 168 h after administration.

●    Efinaconazole could distribute to brain.

In rats after subcutaneous administration:

●    Relatively higher concentration levels at 1 h were observed in liver followed by brown fat > adrenal > kidneys > pancreas > lungs > skin.

●    Trace radioactivity had been detected in lungs, liver, kidneys and skin only at 168 h after administration.

●    Efinaconazole could distribute to brain.

Metabolism of Efinaconazole

Could be highly metabolized in human, rat, dog and minipig hepatocytes.

CYP2C19 and CYP3A4 were identified as the primary isozymes associated with oxidative metabolism.  CYP2C19 appeared to be the main CYP enzyme mediating H4 formation from efinaconazole.

After subcutaneous administration to rats, efinaconazole was rapidly metabolized and the plasma metabolites amount was more than the unchanged efinaconazole.

In vivo, H3 was the major metabolite in human plasma but it was inactive.  In vitro, H4 was the major metabolite and it was active.

There was no unique human metabolite which was not present in other animals.

Excretion of Efinaconazole

After topical administration to rats, 8.4% and 7.4% of the dose were excreted in urine and feces, respectively.  87.3% of the administered radioactivity was detected in the administration site.

After subcutaneous administration to rats, 35.1%, 60.8% and 3.9% were collected in urine, bile and feces, respecteively.

The reabsorption rate of biliary excreted radioactivity was calculated to be approximately 63.3% in BDC rats after intraduodenal administration, suggesting the possibility of the enterohepatic circulation was high in rats.

Drug-Drug interaction

Efinaconazole strongly inhibited CYP2C9 (IC₅₀ = 0.194 μM), CYP2C19 (IC₅₀ = 1.36 μM) and CYP3A4 (IC₅₀ = 0.731 μM for midazolam and 0.572 μM for testosterone), and had week inhibition for CYP2D6 (IC₅₀ = 46.1 μM).

Efinaconazole non-competitively inhibited CYP2B6 (K_i = 2.63 μM), and competitively inhibited CYP1A1/2 (K_i = 12.9 μM), 2C8 (K_i = 1.79 μM).

The major metabolite H3 competitively inhibited CYP2B6 (K_i = 21.5 μM).

Efinaconazole was not an inducer of CYP1A2 or CYP3A4 in human hepatocytes in vitro at concentration of 350 ng/mL (1000 nM).

In vitro efinaconazole exhibited induction for CYP1A2, CYP2B1 and CYP2C11 in frozen rat primary hepatocytes at 10 μg/mL, but exhibited induction for CYP3A1 at 1-10 μg/mL.

Single-Dose Toxicity

Single-dose dermaland subcutaneous administration of efinaconazole in different species:

●    Rat dermal and subcutaneouse administration MTD: 2000 and 1000 mg/kg

●    Dog dermal administration MTD: 800 mg/kg

Repeated-Dose Toxicity

Repeated-dose dermal and subcutaneous administration of efinaconazole in rats (up to 6 months), dogs (4 weeks), and minipigs (up to 9 months):

●    For rats: The NOAEL by dermal administration was 13 and 134 mg/kg/day (78 and 182 × MRHD for males and females, respectively), determined by the 24-week toxicity study.

●    For minpigs: The NOAEL was 30%, which was 208 × MRHD, determined by the 39-week toxicity study dermal administration.

●    No drug-related systemic exposure, or injection site toxicity compared to vehicles

Safety Pharmacology

Central nervous system: Efinaconazole prolonged hexobarbital sleeping time (s.c., ≥10 mg/kg) and enhanced penetrazole-induced convulsions (s.c., 100 mg/kg), due to inhibition of CYP450 drug metabolism rather than direct CNS effects.

Cardiovascular and respiration system: Increased heart rate, decreased blood pressure, and increased respiration rate in anesthetized dogs (i.v., 30 mg/kg); in vitro study, efinaconazole did not pose a significant QT prolongation risk in human.

Gastrointestinal system: Efinaconazole had no effects on gastrointestinal transport in mice (s.c., up to 100 mg/kg), but agonist simulated guinea pig ileum contractions and spontaneous rabbit ileum contractions were inhibited at 10-100 µM.

Renal system: Efinaconazole (s.c., 100mg/kg) caused decreased urine volume and electrolyte excretion in rats.

Genotoxicity

Efinaconazole was not mutagenic or clastogenic in the in vitro Ames assay, in vitro chromosome aberration in CHL cells, or in vivo mouse micronucleus assay with i.p. injection.

Reproductive and Developmental Toxicity

In segmentⅠstudies in rats: No treatment-related effects on male or female fertility parameters were noted at doses up to 25 mg/kg/day.

In segment Ⅱ studies in rats and rabbits: There were no indications of treatment-related embryo-fetal toxicity or malformations at doses up to 10 or 50 mg/kg/day.

In the pre- and postnatal toxicity studies in rats: There were no significant toxicities on duration of gestation or the ability of dams to deliver litters, or no treatment related effects on postnatal development of F1 offspring at doses up to 25 mg/kg/day.

Carcinogenicity

A dermal mouse carcinogenicity was conducted with the to-be-marketed efinaconazole solution, and severe skin irritation at the treatment site in all dose groups was found including the vehicle control group which was due to the vehicle.  No treatment-related increase in the incidence of neoplasms.

The systemic carcinogenicity waiver request was granted based on the poor oral bioavailability of efinaconazole and a significantly different metabolism profile after oral versus subcutaneous/dermal administration which made the conduct of a two-year oral rat carcinogenicity study not informative for a topical efinacozole solution.