KERYDIN Topical solution Ref.[10215] Active ingredients: Tavaborole

At therapeutic doses, KERYDIN is not expected to prolong QTc to any clinically relevant extent.

Tavaborole undergoes extensive metabolism. Renal excretion is the major route of elimination of the metabolites.

In a clinical pharmacology trial of six healthy adult male volunteers who received a single topical application of 5% ¹⁴C-tavaborole solution, tavaborole conjugates and metabolites were shown to be excreted primarily in the urine.

The pharmacokinetics (PK) of tavaborole was investigated in 24 adult subjects with distal subungual onychomycosis involving at least 4 toenails (including at least 1 great toenail) following a single dose and a 2-week daily topical application of 200 μL of a 5% solution of tavaborole to all ten toenails and 2 mm of skin surrounding each toenail. Steady state was achieved after 14 days of dosing. After a single dose, the mean (± standard deviation) peak concentration (C_max) of tavaborole was 3.5 ± 2.3 ng/mL (n=21 with measurable concentrations, range 0.618–10.2 ng/mL, LLOQ=0.5 ng/mL), and the mean AUC_last ± SD was 44.4 ± 25.5 ng*hr/mL (n=21). After 2 weeks of daily dosing, the mean C_max ± SD was 5.2 ± 3.5 ng/mL (n=24, range 1.5–12.8 ng/mL), and the mean AUC_τ ± SD was 75.8 ± 44.5 ng*hr/mL.

In another study PK of tavaborole was investigated in 22 subjects aged 12 years to less than 17 years with distal subungual onychomycosis involving at least 4 toenails (including at least 1 great toenail with at least 20% involvement) following once daily application of 5% solution of tavaborole to all ten toenails and 2 mm of skin surrounding each toenail for 29 days. On Day 29, the mean ± SD C_max was 5.9 ± 4.9 ng/mL (n=21 with measurable concentrations, range 1.0 –16.4 ng/mL, LLOQ=0.5 ng/mL), and the mean ± SD AUC_0-24 was 76.0 ± 62.5 ng*hr/mL.

Drug Interaction Studies

In Vitro Studies

In vitro studies have shown that tavaborole, at therapeutic concentrations, neither inhibits nor induces cytochrome P450 (CYP450) enzymes.

Mechanism of Action

The mechanism of action of tavaborole is inhibition of fungal protein synthesis. Tavaborole inhibits protein synthesis by inhibition of an aminoacyl-transfer ribonucleic acid (tRNA) synthetase (AARS).

Activity in vitro and in clinical infections

Tavaborole has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]:

Trichophyton rubrum
Trichophyton mentagrophytes

Mechanism of Resistance

Trichophyton mentagrophytes and Trichophyton rubrum strains from isolates collected in the clinical trials have not demonstrated resistance following repeated exposure to tavaborole.

In an oral carcinogenicity study in Sprague-Dawley rats, oral doses of 12.5, 25, and 50 mg/kg/day tavaborole were administered to rats once daily for 104 weeks. No drug related neoplastic findings were noted at oral doses up to 50 mg/kg/day tavaborole (14 times the MRHD based on AUC comparisons).

In a dermal carcinogenicity study in CD-1 mice, topical doses of 5%, 10%, and 15% tavaborole solution were administered to mice once daily for 104 weeks. No drug related neoplastic findings were noted at topical doses up to 15% tavaborole solution (89 times the MRHD based on AUC comparisons).

Tavaborole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Human lymphocyte chromosomal aberration assay) and one in vivo genotoxicity test (rat micronucleus assay).

No effects on fertility were observed in male and female rats that were administered oral doses up to 300 mg/kg/day tavaborole (107 times the MRHD based on AUC comparisons) prior to and during early pregnancy.

The efficacy and safety of KERYDIN was evaluated in two multicenter, double-blind, randomized, vehicle-controlled trials. KERYDIN or vehicle was applied once daily for 48 weeks in subjects with 20% to 60% clinical involvement of the target toenail, without dermatophytomas or lunula (matrix) involvement.

A total of 1194 subjects (795 KERYDIN, 399 Vehicle) 18 to 88 years of age, 82% male, 84% white, participated in these two trials. Efficacy assessments were made at 52 weeks following a 48-week treatment period.

The Complete Cure efficacy endpoint included negative mycology (negative KOH wet mount and negative fungal culture) and Completely Clear Nail (no clinical evidence of onychomycosis as evidenced by a normal toenail plate, no onycholysis, and no subungual hyperkeratosis). Efficacy results from the two trials are summarized in Table 2.

Table 2. Efficacy Outcomes:

* Complete cure defined as 0% clinical involvement of the target toenail plus negative KOH and negative culture.
^† Complete or almost complete cure defined as ≤10% affected target toenail area involved and negative KOH and culture.
^‡ Mycologic cure defined as negative KOH and negative culture.