Tavaborole

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Anti infectives for systemic use -> Antibacterials for systemic use

Slightly soluble in water

Freely soluble in ethanol, propylene glycol

Breast Feeding; Lactation; Anti-Infective Agents; Antifungal Agents;

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Danger

H302+H312+H332 (87.9%): Harmful if swallowed, in contact with skin or if inhaled [Warning Acute toxicity, oral; acute toxicity, dermal; acute toxicity, inhalation]

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P354+P338, P317, P321, P330, P332+P317, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 33 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tavaborole, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

In a 21-day cumulative irritation test that included 45 healthy adults 18-73 years of age, 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, semi-occluded, and 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 5% topical solution may cause skin irritation; ... .

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

Store at 20-25 °C (68-77 °F); excursions permitted to 15-30 °C (59-86 °F)

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature -20 °C. Store with desiccant.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: No special environmental precautions required. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: No special environmental precautions required.

Precautions for safe handling: Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: General industrial hygiene practice.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

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).

/HUMAN EXPOSURE STUDIES/ The potential of tavaborole 5% topical solution to cause sensitization was evaluated in a randomized, single-blind, controlled study that included 234 adults 18-75 years of age. Tavaborole 5% topical solution, vehicle solution, positive control (lauryl sulfate 0.1%), and negative control (0.9% sodium chloride) were applied simultaneously at separate sites on the back, semi-occluded, and the sites were then evaluated for signs of local irritation. The study consisted of an induction phase (21 days), rest period (10-14 days), and challenge phase. There was no evidence of sensitization.

/HUMAN EXPOSURE STUDIES/ In a 21-day cumulative irritation test that included 45 healthy adults 18-73 years of age, 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, semi-occluded, and 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.

/GENOTOXICITY/ 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).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 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).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 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).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. The effects of tavaborole on gestation, parturition (delivery, labor), offspring development, and survival during the perinatal and postnatal periods were assessed in mated female rats. Females (F0 generation) were administered single daily oral (gavage) doses of 15, 60, or 100 mg/kg/day from gestation day 6 through lactation day 20. The females were allowed to deliver naturally and rear their offspring until lactation day 21, at which time the F0 females were euthanized. One male and female from each litter were selected (F1 generation) and retained for assessments, including growth, neurobehavior, fertility, and their ability to produce an F2 generation. Reproductive and offspring parameters were determined for the F1 and F2 generations, as applicable. F1 females and F2 pups were euthanized on postnatal day 7. In the F0 females, decreased activity was observed in the 100 mg/kg/day dose group. Excess salivation was observed in the 60 and 100 mg/kg/day dose groups (slight to moderate), however, this finding was not considered adverse. There were no tavaborole-related effects on the growth, viability, development, neurobehavioral assessments, or reproductive performance of the F1 generation. Survivability and mean body weight of the F2 pups were unaffected. The no observed adverse effect level (NOAEL) for maternal toxicity (F0 generation) was 60 mg/kg/day, based on the decreased activity observed in the 100 mg/kg/d dose group. The NOAEL for the offspring effects was > or = 100 mg/kg/day, based on the lack of test article-related changes.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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.

For more Non-Human Toxicity Excerpts (Complete) data for Tavaborole (9 total), please visit the HSDB record page.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tavaborole, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

D - Dermatologicals

QD - Dermatologicals

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.

Tavaborole exerts its antifungal activity by blocking cellular protein synthesis through the formation of an adduct with cytoplasmic leucyl-aminoacyl transfer RNA (tRNA) synthetase.

The broad-spectrum benzoxaborole antifungal AN2690 /tavaborole/ blocks protein synthesis by inhibiting leucyl-tRNA synthetase (LeuRS) via a novel oxaborole tRNA trapping mechanism in the editing site. Herein, one set of resistance mutations is at Asp487 outside the LeuRS hydrolytic editing pocket, in a region of unknown function. It is located within a eukaryote/archaea specific insert I4, which forms part of a cap over a benzoxaborole-AMP that is bound in the LeuRS CP1 domain editing active site. Mutational and biochemical analysis at Asp487 identified a salt bridge between Asp487 and Arg316 in the hinge region of the I4 cap of yeast LeuRS that is critical for tRNA deacylation. We hypothesize that this electrostatic interaction stabilizes the cap during binding of the editing substrate for hydrolysis.

The mechanism of action of tavaborole against susceptible fungi involves inhibition of fungal protein synthesis by inhibition of an aminoacyl-transfer ribonucleic acid (tRNA) synthetase (AARS). Tavaborole inhibits the editing domain of leucyl-tRNA synthetase and exhibits good relative selectivity for this fungal enzyme.

Leucyl-tRNA synthetase (LeuRS) specifically links leucine to the 3' end of tRNA(leu) isoacceptors. The overall accuracy of the two-step aminoacylation reaction is enhanced by an editing domain that hydrolyzes mischarged tRNAs, notably ile-tRNA(leu). We present crystal structures of the editing domain from two eukaryotic cytosolic LeuRS: human and fungal pathogen Candida albicans. In comparison with previous structures of the editing domain from bacterial and archeal kingdoms, these structures show that the LeuRS editing domain has a conserved structural core containing the active site for hydrolysis, with distinct bacterial, archeal, or eukaryotic specific peripheral insertions. It was recently shown that the benzoxaborole antifungal compound AN2690 (5-fluoro-1,3-dihydro-1-hydroxy-1,2-benzoxaborole) inhibits LeuRS by forming a covalent adduct with the 3' adenosine of tRNA(leu) at the editing site, thus locking the enzyme in an inactive conformation. To provide a structural basis for enhancing the specificity of these benzoxaborole antifungals, we determined the structure at 2.2 A resolution of the C. albicans editing domain in complex with a related compound, AN3018 (6-(ethylamino)-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol), using AMP as a surrogate for the 3' adenosine of tRNA(leu). The interactions between the AN3018-AMP adduct and C. albicans LeuRS are similar to those previously observed for bacterial LeuRS with the AN2690 adduct, with an additional hydrogen bond to the extra ethylamine group. However, compared to bacteria, eukaryotic cytosolic LeuRS editing domains contain an extra helix that closes over the active site, largely burying the adduct and providing additional direct and water-mediated contacts. Small differences between the human domain and the fungal domain could be exploited to enhance fungal specificity.

Aminoacyl-transfer RNA (tRNA) synthetases, which catalyze the attachment of the correct amino acid to its corresponding tRNA during translation of the genetic code, are proven antimicrobial drug targets. We show that the broad-spectrum antifungal 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), in development for the treatment of onychomycosis, inhibits yeast cytoplasmic leucyl-tRNA synthetase by formation of a stable tRNA(Leu)-AN2690 adduct in the editing site of the enzyme. Adduct formation is mediated through the boron atom of AN2690 and the 2'- and 3'-oxygen atoms of tRNA's3'-terminal adenosine. The trapping of enzyme-bound tRNA(Leu) in the editing site prevents catalytic turnover, thus inhibiting synthesis of leucyl-tRNA(Leu) and consequentially blocking protein synthesis. This result establishes the editing site as a bona fide target for aminoacyl-tRNA synthetase inhibitors.

A new class of antimicrobial benzoxaborole compounds was identified as a potent inhibitor of leucyl-tRNA synthetase (LeuRS) and therefore of protein synthesis. In a novel mechanism, AN2690 (5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole) blocks fungal cytoplasmic LeuRS by covalently trapping tRNA(Leu) in the editing site of the enzyme's CP1 domain. However, some resistant mutation sites are located outside of the CP1 hydrolytic editing active site. Thus, their mode of action that undermines drug inhibition was not understood. A combination of X-ray crystallography, molecular dynamics, metadynamics, biochemical experiments, and mutational analysis of a distal benzoxaborole-resistant mutant uncovered a eukaryote-specific tyrosine "switch" that is critical to tRNA-dependent post-transfer editing. The tyrosine "switch" has three states that shift between interactions with a lysine and the 3'-hydroxyl of the tRNA terminus, to inhibit or promote post-transfer editing. The oxaborole's mechanism of action capitalizes upon one of these editing active site states. This tunable editing mechanism in eukaryotic and archaeal LeuRSs is proposed to facilitate precise quality control of aminoacylation fidelity. These mechanistic distinctions could also be capitalized upon for development of the benzoxaboroles as a broad spectrum antibacterial.

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.

K124A4EUQ3

TAVABOROLE

Established Pharmacologic Class [EPC] - Oxaborole Antifungal

Mechanisms of Action [MoA] - Protein Synthesis Inhibitors

Chemical Structure [CS] - Boron Compounds

Tavaborole is an Oxaborole Antifungal. The mechanism of action of tavaborole is as a Protein Synthesis Inhibitor.

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.

Antifungal Agents

MEDICATION

For the topical treatment of onychomycosis, tavaborole is commercially available as a 5% solution. Each mL of the clear, colorless solution contains 43.5 mg of tavaborole in an alcohol-based vehicle. The topical solution also contains edetate calcium disodium and propylene glycol.

Topical: Solution, 5%, (Kerydin), Anacor.