Tavaborole (AN-2690) exhibits an 8-fold rise in activity against Aspergillus fumigatus and an 8-fold increase against Cryptosporidium neoformans [1]. Tavaborole (AN-2690) has little effect on cells expressing GlLeuRS or GlLeuRS-D444E, but it severely inhibits cells expressing GlLeuRS-D444A [2].

Absorption, Distribution and Excretion
7.5%. Subungual onychomycosis is difficult to treat due to the poorly perfused location of the infection in the nailbed. To be effective, a topical treatment must penetrate the nail plate and reach the site of infection at a concentration sufficient to exert anti-fungal activity. Tavaborole was shown to produce anti-fungal effects after 5 days of topical administration.
Primarily renal.
The pharmacokinetics of tavaborole was investigated in 24 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 uL 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 (+ or - standard deviation) peak concentration (Cmax) of tavaborole was 3.54 + or - 2.26 ng/mL (n=21 with measurable concentrations, range 0.618-10.2 ng/mL, LLOQ=0.5 ng/mL), and the mean AUClast was 44.4 + or - 25.5 ng*hr/mL (n=21). After 2 weeks of daily dosing, the mean Cmax was 5.17 + or - 3.47 ng/mL (n=24, range 1.51-12.8 ng/mL), and the mean AUCt was 75.8 + or - 44.5 ng*hr/mL.
Renal excretion is the major route of elimination. In a clinical pharmacology trial of six healthy adult male volunteers who received a single topical application of 5% (14)C-tavaborole solution, tavaborole conjugates and metabolites were shown to be excreted primarily in the urine.
/MILK/ It is not known whether tavaborole is excreted in human milk following topical application of Kerydin.
Onychomycosis is a common infection of the toenails that causes nail thickening and discoloration. The physical appearance of the infected nail can diminish self-image and negatively impact quality of life. Patients may use nail polish to mask the appearance of infected nails. /The purpose of this study was/ to evaluate the in vitro nail penetration properties of tavaborole topical solution, 5%, through nail polish using ex vivo, non-diseased human fingernails. In study 1, tavaborole penetration was evaluated over 20 days of dosing using the Franz finite dose technique and modified Franz diffusion cells. Nails received either 1 coat of over-the-counter (OTC) typical polish or were left unpolished (controls). In study 2, tavaborole penetration was measured over 14 days of dosing using the finite dose technique and vertical diffusion cells. Nails were polished with either 4 coats or 1 coat of salon typical polish or with 2 coats or 1 coat of OTC typical polish, or they were left unpolished. In study 1, the mean + or - standard deviation (SD) cumulative tavaborole penetration at day 21 was numerically higher, though not statistically significant, through polished nails (3,526 + or - 1,433 ug/sq cm)vs unpolished nails (2,661 + or - 1,319 ug/sq cm).In study 2, the mean cumulative tavaborole penetration was also numerically higher (statistical significance not assessed) through all nails that received polish vs unpolished nails. At day 15, mean + or - SD cumulative tavaborole nail penetration was 1,179 + or - 554 ug/sq cm through 4 coats of salon typical polish, 1,227 + or - 974 ug/sq cm through 1 coat of salon typical polish, 1,493 + or - 1,322 ug/sq cm through 2 coats of OTC typical polish, 1,428 + or - 841 ug/sq cm through 1 coat of OTC typical polish, and 566 + or - 318 ug/sq cm through unpolished nails. Results from these in vitro studies demonstrated that tavaborole penetrated through human nails with up to 4 layers of nail polish.

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Metabolism / Metabolites
Tavaborole undergoes extensive metabolism. Metabolite profiling revealed trace levels of a sulfated-conjugate and a benzoic acid metabolite, consistent with the known biotransformation of tavaborole.
Tavaborole undergoes extensive metabolism. ... In a clinical pharmacology trial of six healthy adult male volunteers who received a single topical application of 5% (14)C-tavaborole solution, tavaborole conjugates and metabolites were shown to be excreted primarily in the urine.

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Biological Half-Life
28.5 hr

Toxicity Summary
IDENTIFICATION AND USE: Tavaborole, a white to off-white powder, is an oxaborole antifungal agent. Oxaboroles are boron-containing molecules with antifungal activity. Tavaborole topical solution, 5% is indicated for the treatment of onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes. HUMAN EXPOSURE AND TOXICITY: The potential of tavaborole to cause sensitization was evaluated in a randomized, single-blind, controlled study that included 234 adults 18-75 years of age. There was no evidence of sensitization. In another study, tavaborole 5% solution, vehicle solution, positive irritant control (lauryl sulfate 0.5% solution), and negative irritant control (0.9% sodium chloride) were applied simultaneously once daily at separate sites on the back of 45 healthy adults 18-75 years of age for 21 days. The sites were evaluated 30 minutes after application for signs of local irritation. Data from days 2-22 indicated that the mean irritation response to tavaborole 5% solution was higher than the mean irritation response to the positive irritant control. Tavaborole revealed no evidence of mutagenic or clastogenic potential based on the results of in vitro genotoxicity test (Human lymphocyte chromosomal aberration assay). ANIMAL STUDIES: The carcinogenicity of tavaborole was studied by both dermal and oral administration. In the dermal study, 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. In the oral study 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. In an oral pre- and post-natal development study in rats, oral doses of 15, 60, and 100 mg/kg/day tavaborole were administered from the beginning of organogenesis (gestation day 6) through the end of lactation (lactation day 20). In the presence of minimal maternal toxicity, no embryofetal toxicity or effects on postnatal development were noted at 100 mg/kg/day. In a dermal embryofetal development study in rabbits, topical doses of 1%, 5%, and 10% tavaborole solution were administered during the period of organogenesis (gestational days 6-28) to pregnant female rabbits. A dose dependent increase in dermal irritation at the treatment site was noted at 5% and 10% tavaborole solution. A decrease in fetal bodyweight was noted at 10% tavaborole solution. No drug related malformations were noted in rabbits at 10% tavaborole solution (36 times the MRHD based on AUC comparisons). No embryofetal toxicity was noted in rabbits at 5% tavaborole solution (26 times the MRHD based on AUC comparisons). 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. Tavaborole revealed no evidence of mutagenic or clastogenic potential based on the results of in vitro genotoxicity test (Ames assay) and in vivo genotoxicity test (rat micronucleus assay).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Topical tavaborole has not been studied during breastfeeding. Because blood levels are very low after topical application to the toenails, it is unlikely that a measurable amount of the drug will enter the breastmilk.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. Discovery of a new boron-containing antifungal agent, 5-fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole (AN2690), for the potential treatment of onychomycosis. J Med Chem. 2006 Jul 27;49(15):4447-50.

[2]. Post-transfer editing by a eukaryotic leucyl-tRNA synthetase resistant to the broad-spectrum drug AN2690. Biochem J. 2010 Sep 1;430(2):325-33.

Therapeutic Uses
Antifungal Agents
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Tavaborole is included in the database.
Kerydin (tavaborole) topical solution, 5% is an oxaborole antifungal indicated for the treatment of onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes. /Included in US product label/

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Drug Warnings
Adverse effects reported in at least 1% of adults treated with tavaborole 5% topical solution and more frequently than with topical vehicle solution include application site exfoliation, ingrown toenail, application site erythema, and application site dermatitis.
Tavaborole 5% topical solution may cause skin irritation; there is no evidence to date that the solution causes contact sensitization.
It is not known whether tavaborole is excreted in human milk following topical application of Kerydin. Because many drugs are excreted in human milk, caution should be exercised when Kerydin is administered to a nursing woman.
There are no adequate and well-controlled studies with Kerydin in pregnant women. Kerydin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
For more Drug Warnings (Complete) data for Tavaborole (9 total), please visit the HSDB record page.

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Pharmacodynamics
After a single dose, the mean (± standard deviation) peak concentration (Cmax) of tavaborole was 3.54 ± 2.26 ng/mL (n=21 with measurable concentrations, range 0.618-10.2 ng/mL, LLOQ=0.5 ng/mL), and the mean AUClast was 44.4 ± 25.5 ng*hr/mL (n=21). After 2 weeks of daily dosing, the mean Cmax was 5.17 ± 3.47 ng/mL (n=24, range 1.51­-12.8 ng/mL), and the mean AUCτ was 75.8 ± 44.5 ng*hr/mL.

C7H6BFO2

151.9307

152.044

174671-46-6

174671-46-6

11499245

White to off-white solid powder

1.3±0.1 g/cm3

230.8±50.0 °C at 760 mmHg

120-122 °C

93.4±30.1 °C

0.0±0.5 mmHg at 25°C

1.526

0.043

1

3

0

11

155

0

LFQDNHWZDQTITF-UHFFFAOYSA-N

InChI=1S/C7H6BFO2/c9-6-1-2-7-5(3-6)4-11-8(7)10/h1-3,10H,4H2

5-fluoro-1-hydroxy-3H-2,1-benzoxaborole

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~658.20 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (16.45 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (16.45 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (16.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)