Tavaborole   中文名称: 他伐硼罗

Tavaborole (AN-2690) 的抗烟曲霉活性提高了 8 倍，抗新型隐孢子虫活性提高了 8 倍 [1]。 Tavaborole (AN-2690) 对表达 GlLeuRS 或 GlLeuRS-D444E 的细胞影响不大，但会严重抑制表达 GlLeuRS-D444A 的细胞 [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.

---

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.

---

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).

---

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/

---

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.

---

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

29.46

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (16.45 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.5 mg/mL (16.45 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

---

View More

配方 3 中的溶解度: ≥ 2.5 mg/mL (16.45 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。