Fosravuconazole Research Articles

Kidney injury associated with fosravuconazole L-lysine ethanolate.

Fosravuconazole L-lysine ethanolate (F-RVCZ) is a prodrug of ravuconazole and a triazole antifungal drug used for the treatment of onychomycosis. It has been reported in previous studies that the kidney injury caused by F-RVCZ is 1% or less. Serum creatinine levels were compared, and glomerular filtration rate and urine protein were estimated before and after starting the administration of F-RVCZ, as well as after the end of the administration period. The cause of kidney injury was investigated using renal pathology, and risk factors were also investigated. F-RVCZ was administered to 46 patients. Ten of these patients were excluded because three were maintenance dialysis patients and seven were not measured for serum creatinine. Remaining 36 patients were included in the analyses. Kidney injury occurred in 27.8% of patients treated with F-RVCZ; this condition persisted in 10% of patients after the end of the administration period. No changes were observed in the urinalysis after the administration of F-RVCZ. A kidney biopsy was performed in one patient, but no lesions were found that could be the cause of kidney injury. Patients who developed kidney injury were significantly more likely to be receiving angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (odds ratio 18.9, 95% confidential interval: 1.69-210, p = 0.0169). Kidney injury is caused by F-RVCZ more frequently than previously reported, but the mechanism remains unclear.

Exploratory study on short-term administration of oral fosravuconazole for tinea pedis.

We investigated the clinical efficacy of short-term, oral fosravuconazole (F-RVCZ) therapy for tinea pedis, commonly known as athlete's foot. F-RVCZ (equivalent to 100 mg ravuconazole) was administered orally once daily for 1 week for interdigital and vesicular tinea pedis and for 4 weeks for hyperkeratotic tinea pedis. Efficacy was evaluated based on mycological efficacy and clinical symptoms at Weeks 1, 4, and 8 for interdigital and vesicular tinea pedis and at Weeks 4, 8, and 12 for hyperkeratotic tinea pedis. Efficacy was confirmed at the end of treatment. Therapeutic efficacy increased over time from the end of treatment for both types of tinea pedis. All adverse drug reactions (ADRs) were within expectations and there were no cases of discontinuation due to ADRs or serious ADRs. Short-term oral F-RVCZ therapy is expected to be as effective or more effective than terbinafine and itraconazole, which have already been approved in Japan and may be a useful option for the treatment of tinea pedis.

Effects of additional oral fosravuconazole l-lysine ethanolate therapy following inadequate response to initial treatment for onychomycosis: A multicenter, randomized controlled trial.

Onychomycosis, a superficial fungal infection, develops when dermatophytes infect nail plate and beds. Fosravuconazole l-lysine ethanolate (F-RVCZ), a fourth-generation azole antifungal agent with potent antifungal activity and few drug interactions, was highly effective in a clinical trial, with a complete cure rate of 59.4% at 48 weeks after treatment initiation. However, some patients were not completely cured. To achieve a higher complete cure rate, additional therapy needs to be examined. We aimed to examine (i) the criteria for additional F-RVCZ therapy in patients with an inadequate response to initial F-RVCZ treatment for onychomycosis; (ii) the timing of additional therapy; and (iii) the effects of additional treatment. This was a multicenter, open-label, three-arm randomized clinical trial. Patients with onychomycosis were orally administered an approved dose of F-RVCZ for 12 weeks, and its efficacy was assessed at week 24. Patients who demonstrated ≥55% reduction in nail involvement ratio at week 24 were included in Group X and followed up. Patients with <55% reduction were randomly assigned to follow-up (Group A) or additional treatment (Group B) groups. The complete cure rate at week 72 in Group X was 73.3%. In Groups A and B, the complete cure rates were 29.6% and 46.7%, respectively, and were significantly different (P = 0.0414, odds ratio 2.08). During the study, 63 adverse drug reactions were recorded in 59 of the 318 patients (18.6%), for which a causal relationship with F-RVCZ could not be ruled out. In Group B, three of 75 patients (4.0%) experienced three adverse drug reactions, all observed during additional treatment; none were serious. A high complete cure rate is possible without additional F-RVCZ treatment when nail involvement decreases by ≥55% at week 24; however, when the reduction is <55% at week 24, additional F-RVCZ treatment should be considered to improve the cure rate.

Outcome of fosravuconazole treatment for onychomycosis refractory to topical antifungal agents.

Fosravuconazole L-lysine ethanolate (F-RVCZ) is an oral antifungal agent approved in Japan for the treatment of onychomycosis. We treated 36 patients (mean age 77.6 years) with onychomycosis that had been refractory to long-term topical treatment. The patients took F-RVCZ (100 mg ravuconazole) once daily for a mean of 11.3 weeks, and were followed up for an average of 48 weeks (mean 48.3 ± 2.1 weeks). The mean rate of improvement of the affected nail area at 48 weeks was 59.4%, and 12 patients achieved complete cure. Patients with total dystrophic onychomycosis (TDO) showed a significantly lower improvement rate than those with distal and lateral subungual onychomycosis (DLSO), and those with an affected nail area of 76%-100% at the first visit showed a significantly lower improvement rate than those with an affected nail area of 0%-75%. Six patients had adverse events necessitating treatment discontinuation, but the symptoms and laboratory data improved without specific treatment in all of them. The data suggest that F-RVCZ would be effective in various age groups, including the elderly, and even in patients with onychomycosis refractory to long-term topical antifungal treatment. It was also suggested that its early use in mild cases might achieve a higher rate of complete cure. Furthermore, the average cost of oral F-RVCZ therapy was lower than that for topical antifungal agents. Therefore, F-RVCZ is considered to be much more cost-effective than topical antifungal agents.

Dermatophytomas: Clinical Overview and Treatment

Dermatophytomas are characterized as a hyperkeratotic fungal mass in the subungual space, showing as dense white or yellow, typically in longitudinal streaks or patches. Masses can be visualized by traditional microscopy or histology. Newer technologies such as dermoscopy and optical coherence tomography also provide visual features for dermatophytoma diagnosis. The density of fungal mass, and lack of adherence to the nail structures, as well as possible biofilm development, may play a role in the reduction in drug penetration and subsequent lack of efficacy with traditional oral therapies such as terbinafine and itraconazole. A combination of drug treatment with mechanical or chemical debridement/avulsion has been recommended to increase efficacy. The topical antifungal solutions such as tavaborole, efinaconazole, and luliconazole may reach the dermatophytoma by both the transungual and subungual routes, due to low affinity for keratin and low surface tension. Current data indicates these topicals may provide efficacy for dermatophytoma treatment without debridement/avulsion. Similarly, fosravuconazole (F-RVCZ) has an improved pharmacological profile versus ravuconazole and may be an improved treatment option versus traditional oral therapies. The availability of improved treatments for dermatophytomas is crucial, as resistance to traditional therapies is on the increase.

Treatment Outcome with Fosravuconazole for Onychomycosis.

Fosravuconazole L-lysine ethanolate (F-RVCZ), a ravuconazole prodrug, is a newly available agent with high expectations for efficacy in the treatment of onychomycosis. However, clinical data regarding the efficacy of F-RVCZ are limited because the drug was launched only in Japan in 2018. Therefore, we analyzed the outcome of F-RVCZ therapy in the treatment of onychomycosis at outpatient dermatology clinics in Japan. We examined data for 109 patients (68 male, 41 female) with varying clinical type, including total dystrophic onychomycosis and dermatophytoma, and a wide range of age groups, including the elderly. The complete cure rate at 12weeks was 6.4% (7/109) and 67.9% (74/109) at the last visit (mean time to last visit: 32 ± 14.2weeks). Mean rate of improvement in the affected nail area was 49.1 ± 23.3% at 12weeks and 86.8 ± 22.4% at the last visit. Efficacy at 12weeks and the last visit, respectively, was as follows: none, 4 cases and 1 case; slight, 35 cases and 4 cases; moderate, 51 cases and 21 cases; significant, 12 cases and 9 cases; complete cure, 7 cases and 74 cases. There were no serious adverse events. This retrospective survey was the first large-scale analysis of actual clinical practice outcomes and had minimal exclusions. Compared to previous reports, our results demonstrated excellent efficacy of F-RVCZ therapy in a variety of patients. Considering our results and the ease of oral administration (1 capsule/day for 12weeks) and few adverse events, F-RVCZ therapy appears to be a useful option for the treatment of onychomycosis.

Efficacy and safety of fosravuconazole in patients with onychomycosis in our clinic

目的と方法：実臨床における爪白癬患者に対するホスラブコナゾールL-リシンエタノール付加物（ネイリンⓇカプセル，以下ホスラブコナゾール）の有効性および安全性を検討する目的で，2018年8月～2020年2月に当院を受診し，爪白癬の診断の下にホスラブコナゾールを処方された患者を対象としてカルテ情報を収集した． 結果：対象は爪白癬患者360例（足爪白癬340例，手爪白癬28例，そのうち両者の重複例8例）で，男女とも70歳台が最も多かった．ホスラブコナゾール12週投与を終了し投与開始から1年以上経過した足爪白癬84例における治療成績は完全治癒59例（70.2％），転帰不明22例（26.2％），無効3例（3.6％）であった．完全治癒は治療開始後3カ月と6～12カ月に確認できた例が多く，転帰不明例の多くはドロップアウト（最終来院）時に改善傾向を示していた．360例中ホスラブコナゾール12週の投与を完結できた症例は249例（69.2％）で，治験で除外されていた高齢者や若年者，手の爪白癬または難治な爪白癬に対しても本薬の高い有効性が認められた．投薬中の臨床検査にて260例中ALT/ASTは18例（6.9%）に，γ-GTPは61例（23.5％）に異常値を認めたが，皮膚症状など他の副作用を含め重篤な例はなかった． 結論：ホスラブコナゾールは実臨床においても完全治癒率と投与継続率が高く，肝機能検査など適切な対処により重篤な副作用を回避できることから，合併症などで内服が困難な例や外用薬で早期完治が期待できる例を除き，すべての爪白癬症例において早く確実に治すための第一選択薬として用いられるべき薬剤と思われる．

Development of E1224 by leveraging a strategic partnership for the medicines creation against neglected tropical diseases

Neglected tropical diseases (NTDs) are communicable diseases that are uncommon in developed countries but epidemic in developing countries in tropical and subtropical regions of the world. One of the important contributions expected of pharmaceutical companies is the development and provision of drugs effective against NTDs. Eisai's efforts toward improving global health have resulted in a rich portfolio of assets addressing six infectious diseases: malaria, tuberculosis, Chagas disease, lymphatic filariasis, leishmaniasis, and mycetoma. As the most advanced project, Eisai has developed E1224 (fosravuconazole l-lysine ethanolate), which is available in both intravenous and oral formulations, and provides ravuconazole, an active form of fosravuconazole, with a long plasma half-life. The first clinical trials of E1224, for Chagas disease, have already been completed, led by the Drugs for Neglected Diseases initiative (DNDi). As a result, parasite clearance was observed with E1224 during the treatment phase, but parasite regrowth was observed after the end of drug administration, suggesting that the mechanism of action of E1224 on Trypanosoma cruzi is static rather than parasiticidal. On the other hand, a clinical trial for eumycetoma in collaboration with DNDi is ongoing supported by the Global Health Innovative Technology Fund, and is examining the efficacy of weekly treatment with E1224 versus the current standard of care, daily treatment with itraconazole. In this manner, Eisai will continue its drug-discovery research projects in collaboration with various PDPs and academia supported by funding agencies.

Clinical effectiveness and safety of fosravuconazole L-lysine ethanolate （F-RVCZ） for onychomycosis in elderly patients

75歳以上の爪白癬患者49例（男性13例，女性36例）に対してホスラブコナゾール内服療法を行い，投与後６ヶ月〜１年３ヶ月の観察において治療効果と安全性の検討を行った．49例中42例において12週間の内服を完遂できた．内服終了時に全42例で爪混濁比の減少を認めた．１年以上観察した23例において完治が16例に見られた（69%）．７例では治療を完遂できなかったが，その理由として４例は食欲低下で中止，１例は胸部不快感で中止，１例は肝機能値異常のため中止，１例は内服薬への不信のための自己中止であった．４例で肝機能値異常が出現したが，うち１例の胆石胆嚢炎による中止例以外は治療を継続できた． 今回の治療効果並びに副作用の結果は75歳以上の高齢者においても、主に70歳以下を検討された国内第Ⅲ相臨床試験とほぼ変わらず，高齢者でも安心して治療できる薬剤であることが確認され，爪白癬の治癒も期待できる有効な治療であると考えられた．

Drug properties of fosravuconazole L-lysine ethanolate (NAILIN&lt;sup&gt;®&lt;/sup&gt; Capsules 100 mg), a new oral azole therapeutic for onychomycosis: an analysis based on non-clinical and clinical trial data

Ravuconazole is a fourth generation azole exerting strong antifungal activity, with low drug-drug interaction and hepatic dysfunction risks. Fosravuconazole l-lysine ethanolate (fosravuconazole; NAILIN® Capsules 100 mg) was developed as a ravuconazole prodrug. Ravuconazole exerts strong antifungal activity against various pathogenic fungi including dermatophytes and Candida. Through prodrug formation, pharmacokinetic improvement was achieved, and bioavailability after oral administration reached 100%. The plasma ravuconazole concentration became 10-35 times higher than with current oral anti-onychomycosis drugs, and showed good skin and nail tissue transition plus tissue retention. This improvement obtained with fosravuconazole reflects its superior pharmacokinetic properties. We conducted a clinical trial with fosravuconazole orally administered once a day (100 mg ravuconazole) for 12 weeks in Japanese onychomycosis patients. The ravuconazole concentration in nail tissues exceeded the MIC90 against dermatophytes, even after treatment completion. Furthermore, the placebo-controlled, double-blind, comparative trial showed significantly superior effects (at 48 weeks after starting treatment, with a complete cure rate of 59.4%, a marked clinical improvement rate of 83.1%, and a mycological cure rate by direct microscopy of 82.0%). The major adverse reactions were laboratory abnormalities and gastrointestinal disorders with no severe symptoms, suggesting good tolerability. Fosravuconazole has fewer drug-drug interactions, is not affected by food, and is also expected to improve medication adherence since the administration period is only 12 weeks and there is no drug-free period as required with pulse therapy. Thus, fosravuconazole has many favorable pharmacological properties and can reasonably be expected to become a new oral treatment option for onychomycosis.