Luliconazole (DB08933): A Comprehensive Pharmacological and Clinical Monograph

Section 1: Introduction and Drug Profile

1.1 Overview and Therapeutic Class

Luliconazole is a potent, broad-spectrum antifungal agent belonging to the imidazole class, specifically classified as a topical azole antifungal.[1] Chemically, it is identified as a dichlorobenzene and an N-substituted imidazole, a structure that contributes to its distinct pharmacological profile.[1] The primary clinical application of Luliconazole is the topical treatment of superficial fungal infections of the skin, known as dermatophytoses. Its approved indications include tinea pedis (athlete's foot), tinea cruris (jock itch), and tinea corporis (ringworm), conditions predominantly caused by dermatophytes such as Trichophyton rubrum and Epidermophyton floccosum.[2]

1.2 Unique Characteristics and Place in Therapy

Luliconazole is distinguished from earlier-generation azoles by its novel chemical architecture. The molecule uniquely incorporates an imidazole moiety into a ketene dithioacetate structure, a modification that confers unusually high potency against filamentous fungi, particularly dermatophytes.[7] Furthermore, Luliconazole is the optically active (R)-enantiomer of a chiral molecule. Its predecessor, lanoconazole, is a racemic mixture of both R and S enantiomers. By isolating the pharmacologically active R-enantiomer, Luliconazole achieves significantly greater antifungal potency than the racemic compound.[4]

This enhanced potency is a foundational element of its clinical profile, directly enabling its most significant therapeutic advantage: high efficacy with short-term treatment regimens. For instance, Luliconazole is approved for a once-daily, one-week course for tinea corporis and tinea cruris, a notably shorter duration than that required for many other topical azole antifungals.[8] This is possible because its molecular structure and high potency result in strong fungicidal activity against key dermatophytes, rather than the merely fungistatic action typical of many azoles. This ability to eradicate the fungus quickly, coupled with favorable pharmacokinetic properties in the skin, allows for abbreviated treatment courses, which can improve patient adherence and potentially reduce the likelihood of relapse. This combination of structural innovation, enhanced potency, and clinical convenience defines Luliconazole's distinct place in modern dermatological therapy.

1.3 Development and Regulatory Snapshot

Luliconazole's development and regulatory journey reflect its advanced profile. It was first approved for clinical use in Japan in 2005, where it is marketed under trade names such as Lulicon®.[7] Its entry into the North American market occurred on November 14, 2013, when the United States Food and Drug Administration (FDA) granted approval for Luliconazole 1% cream under the brand name Luzu®.[1] This approval marked a significant addition to the therapeutic armamentarium for common superficial mycoses.

Section 2: Chemical Identity and Physicochemical Properties

2.1 Chemical Identifiers

To ensure unambiguous identification across global databases, regulatory filings, and scientific literature, Luliconazole is cataloged with a comprehensive set of unique identifiers.

• DrugBank ID: DB08933 [1]
• CAS Number: 187164-19-8 [1]
• Anatomical Therapeutic Chemical (ATC) Code: D01AC18 [5]
• Unique Ingredient Identifier (UNII): RE91AN4S8G [1]
• PubChem Compound ID (CID): 3003141 [1]
• European Community (EC) Number: 878-713-9 [1]
• KEGG Drug ID: D01980 [1]
• ChEBI ID: CHEBI:34825 [1]

2.2 Nomenclature and Synonyms

The formal chemical nomenclature for Luliconazole precisely describes its stereochemistry and molecular components.

• IUPAC Name: (2E)-(1H-imidazol-1-yl)acetonitrile [6]
• Formal Name: $αE$--1H-imidazole-1-acetonitrile [15]

Throughout its development and in various markets, Luliconazole has been known by several synonyms, development codes, and trade names, including:

• Development Codes: NND-502, PR-2699 [1]
• Common Synonyms/Trade Names: Lulicon, Luzu, Lulifin, Luzarn, LULY, Zyluli, Luris [1]

2.3 Molecular and Structural Properties

Luliconazole's molecular formula and structure are key to its function.

• Chemical Formula: $C_{14}H_{9}Cl_{2}N_{3}S_{2}$ [3]
• Molecular Weight: 354.27 g·mol⁻¹ [2]
• Monoisotopic/Exact Mass: 352.9615 Da [2]

The structure of Luliconazole is characterized by a central dithiolane ring attached to a dichlorophenyl group and an imidazole-acetonitrile moiety. Crucially, the molecule is a pure enantiomer with a defined stereochemistry: the chiral center on the dithiolane ring has the (R) configuration, and the exocyclic double bond adjacent to this ring is in the (E) configuration.[4] This specific stereoisomer is responsible for the drug's potent biological activity.

2.4 Physicochemical Characteristics

The physical and chemical properties of Luliconazole are critical determinants of its formulation, stability, and pharmacokinetic behavior.

• Appearance: A solid described as a white to orange to green powder or crystal.[4]
• Melting Point: The melting point range is reported as 150.0 to 154.0 °C, with a specific value of 152 °C also noted.[4]
• Solubility Profile: Luliconazole is highly lipophilic and practically insoluble in water. It demonstrates solubility in various organic solvents, including dimethylformamide (DMF) at 33 mg/mL, dimethyl sulfoxide (DMSO) at 20 mg/mL, and ethanol at 10 mg/mL. It is also soluble in acetone and slightly soluble in methanol.[4]
• Stability and Storage: The compound is stable for at least four years when stored properly. It is noted to be light-sensitive, and storage at room temperature in a cool, dark place (ideally <15°C) is recommended.[4]
• Chirality and Other Properties: Its chiral nature is confirmed by its specific optical rotation, with $[α]_{20}^{D}$ measured between -48.0 and -53.0 degrees (c=1, DMF).[4] Key computational properties that reflect its lipophilicity include a Topological Polar Surface Area (TPSA) of 92.2 Ų and an XLogP3 value of 4.[14]

The physicochemical profile, particularly the high lipophilicity and aqueous insolubility, is fundamental to Luliconazole's clinical utility. These properties necessitate its formulation as a topical cream for effective delivery into the skin. More importantly, this lipophilic character facilitates its partitioning into and retention within the lipid-rich stratum corneum, the outermost layer of the epidermis. This phenomenon creates a drug reservoir in the skin, sustaining high local concentrations of the active agent at the site of infection. This "reservoir effect" is a key pharmacokinetic feature that contributes directly to the drug's potent and sustained antifungal activity, which in turn allows for the less frequent (once-daily) and shorter-duration dosing regimens that distinguish Luliconazole clinically.[8] This represents a direct and tangible link between a fundamental chemical property and a significant clinical advantage.

Section 3: Pharmacology and Mechanism of Action

3.1 Pharmacodynamics: Primary Mechanism of Action

Luliconazole exerts its antifungal effect through a mechanism of action characteristic of the azole class: the disruption of fungal cell membrane synthesis.[2] Its specific molecular target is lanosterol 14-alpha demethylase, a crucial fungal cytochrome P450-dependent enzyme (also known as ERG11).[2] This enzyme catalyzes a vital step in the biosynthesis of ergosterol—the conversion of lanosterol to its demethylated intermediates.[19] Ergosterol is the primary sterol in fungal cell membranes, where it serves a role analogous to that of cholesterol in mammalian cells, maintaining membrane integrity, fluidity, and the function of membrane-bound enzymes.

By inhibiting lanosterol 14-alpha demethylase, Luliconazole effectively blocks the ergosterol production pathway. This blockade has a dual consequence for the fungal cell. First, it leads to a critical depletion of ergosterol, which compromises the structural and functional integrity of the cell membrane. Second, it causes the intracellular accumulation of lanosterol and other methylated sterol precursors.[20] These accumulated sterols are toxic to the cell; they physically disrupt the phospholipid bilayer, alter membrane permeability, and inhibit the activity of essential membrane-bound enzymes. The combined effect of ergosterol depletion and toxic sterol accumulation leads to the cessation of fungal growth and, ultimately, cell death.[19]

3.2 Fungicidal vs. Fungistatic Activity

A key pharmacological feature that distinguishes Luliconazole from many other members of the azole class is its activity profile against dermatophytes. While azoles are traditionally considered fungistatic (inhibiting fungal growth), Luliconazole demonstrates potent fungicidal (killing fungi) activity against clinically important dermatophytes like Trichophyton species.[8] This places its functional efficacy against these organisms on par with that of the allylamine class of antifungals (e.g., terbinafine), which are known for their fungicidal action via a different enzymatic target (squalene epoxidase).[8] This fungicidal property is a significant contributor to its ability to achieve rapid mycological cure and supports the efficacy of its short-course treatment regimens. A secondary mechanism, involving the alteration of triglyceride and phospholipid synthesis that leads to the buildup of toxic intracellular hydrogen peroxide, may also contribute to this cell-killing effect.[10]

3.3 Antifungal Spectrum and Potency (In Vitro Data)

In vitro studies have established that Luliconazole possesses a broad spectrum of activity against a wide array of fungi responsible for human disease.[15]

• Dermatophytes: Luliconazole exhibits exceptionally potent activity against the dermatophytes that cause the vast majority of superficial skin infections. This includes Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Trichophyton tonsurans, and Microsporum gypseum.[6] Its minimum inhibitory concentrations (MICs) against these organisms are remarkably low, frequently reported in the range of ≤0.00012 to 0.004 µg/mL.[3]
• Yeasts: The drug is also active against yeasts, including pathogenic species of Candida (e.g., C. albicans) and Malassezia.[8]
• Molds: Luliconazole has demonstrated activity against various molds, including species of Aspergillus such as A. fumigatus and the often-resistant A. terreus.[15]

Comparative potency studies consistently underscore Luliconazole's superior in vitro activity. Against dermatophyte isolates, its MIC values have been shown to be 7 to 10 dilutions lower than those of other topical antifungals, including amorolfine, ciclopirox, and terbinafine.[3] It is also two to four times more potent than its racemic precursor, lanoconazole.[10] The following table synthesizes comparative MIC data to illustrate this superior potency.

Table 3.3.1: Comparative Minimum Inhibitory Concentration (MIC) Ranges of Luliconazole and Other Antifungals

Fungal Species	Luliconazole (µg/mL)	Lanoconazole (µg/mL)	Terbinafine (µg/mL)	Clotrimazole (µg/mL)	Ketoconazole (µg/mL)	Bifonazole (µg/mL)
Trichophyton rubrum	≤0.00012–0.004	0.00024–0.016	0.002–>0.25	0.031–0.063	0.016–0.13	0.0078–>1
Trichophyton mentagrophytes	0.00024–0.002	0.0005–0.004	0.001–0.06	0.016–0.5	0.25–1	0.016–1
Trichophyton tonsurans	0.00024–0.00049	N/A	≤0.00098–0.016	0.13–0.25	0.13–1	0.063–1
Candida albicans	0.031–0.25	0.063–0.25	2–>64	≤0.0039–0.031	≤0.002–0.016	0.25–4
Data compiled from source.10

Pharmacologically, Luliconazole can be viewed as a functional hybrid, bridging the conventional azole and allylamine classes. While its mechanism of action is unequivocally that of an azole—inhibiting lanosterol 14-alpha demethylase—its functional outcome against dermatophytes is fungicidal, a hallmark of the allylamines.[8] This unique profile provides a significant therapeutic advantage. It combines the broad antifungal spectrum typical of imidazoles with the definitive killing action of allylamines against the most common pathogens of tinea infections. This potent, fungicidal activity is a primary driver of its clinical success, providing a strong scientific rationale for the high rates of mycological cure and the efficacy of the short treatment durations observed in pivotal clinical trials.

Section 4: Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Luliconazole is central to its efficacy and safety, characterized by high local drug concentrations at the site of action with minimal systemic exposure.

4.1 Absorption and Bioavailability

Following topical application of the 1% cream formulation, systemic absorption of Luliconazole is very low.[2] This property is ideal for a topical agent, as it maximizes local effects while minimizing the potential for systemic side effects and drug interactions. Pharmacokinetic studies conducted under maximal use conditions (application of approximately 3.5 grams of cream daily for 15 days) in adult patients with moderate to severe dermatophytoses have quantified this low level of absorption.[20]

The extent of absorption is dependent on the application site, a factor related to skin thickness and vascularity.

• In Tinea Pedis (Athlete's Foot): Application to the feet results in the lowest systemic exposure. The mean maximum plasma concentration ($C_{max}$) was 0.40 ng/mL after the first dose, rising to 0.93 ng/mL at steady state (Day 15). The time to reach this peak concentration ($T_{max}$) was approximately 16.9 hours after the first dose and 5.8 hours at steady state.[2]
• In Tinea Cruris (Jock Itch): Application to the groin, where the skin is thinner and more permeable, results in substantially higher systemic absorption. The mean $C_{max}$ was 4.91 ng/mL after the first dose and 7.36 ng/mL at steady state. The $T_{max}$ was approximately 21.0 hours and 6.5 hours, respectively.[10]

As part of post-marketing requirements by the FDA, pharmacokinetic studies were also conducted in adolescent patients (12 to <18 years of age). These studies confirmed that systemic exposure was comparable to or slightly higher than that in adults, but did not identify any new safety concerns.[12] The table below summarizes the key pharmacokinetic parameters in adults.

Table 4.1.1: Summary of Pharmacokinetic Parameters in Adults After Topical Application of Luliconazole 1% Cream

Indication	Parameter	First Dose (Mean ± SD)	Final Dose (Day 15) (Mean ± SD)
Tinea Pedis	$C_{max}$ (ng/mL)	0.40 ± 0.76	0.93 ± 1.23
	$T_{max}$ (hours)	16.9 ± 9.39	5.8 ± 7.61
	$AUC_{0-24}$ (ng·hr/mL)	6.88 ± 14.50	18.74 ± 27.05
Tinea Cruris	$C_{max}$ (ng/mL)	4.91 ± 2.51	7.36 ± 2.66
	$T_{max}$ (hours)	21.0 ± 5.55	6.5 ± 8.25
	$AUC_{0-24}$ (ng·hr/mL)	85.1 ± 43.69	121.74 ± 53.36
Data compiled from sources.10

4.2 Distribution

Once the small amount of Luliconazole is absorbed into the systemic circulation, its distribution is characterized by extensive binding to plasma proteins.

• Plasma Protein Binding: Luliconazole is greater than 99% bound to plasma proteins.[2] This high degree of binding means that only a very small fraction of the already low amount of absorbed drug is free and pharmacologically active in the bloodstream.
• Volume of Distribution: The volume of distribution ($V_{d}$) has not been quantified in humans.[2]
• Distribution into Milk: It is not known whether Luliconazole is distributed into human breast milk. However, nonclinical studies in lactating rats demonstrated that the drug was present in milk following subcutaneous administration.[20]

4.3 Metabolism

The metabolic fate of Luliconazole in humans has not been fully elucidated.[2] However, in vitro studies provide some indication of its potential metabolic pathways. These studies suggest that any systemically absorbed Luliconazole may be metabolized by the cytochrome P450 isoenzymes CYP2D6 and CYP3A4.[20] In pediatric pharmacokinetic studies, a metabolite known as z-luliconazole was detected in plasma. This metabolite is reported to be 15 to 250 times less active than the parent compound and was found only at very low concentrations (<0.1 ng/mL), suggesting it is not a major contributor to either efficacy or toxicity.[32]

4.4 Elimination

The precise route and extent of Luliconazole elimination from the body in humans have not yet been determined.[2]

• Half-life: The mean plasma elimination half-life ($t_{1/2}$), measured on day 15 of once-daily application, was approximately 32.4 hours in adults with tinea pedis and 21.1 hours in adults with tinea cruris.[20]

The complete pharmacokinetic profile of Luliconazole exemplifies the ideal characteristics for a topical antifungal agent. Its high lipophilicity promotes retention in the stratum corneum, creating a local drug reservoir that sustains its potent antifungal activity directly at the site of infection. Concurrently, its minimal systemic absorption and extensive plasma protein binding ensure that the small amount of drug that enters the circulation is largely sequestered and pharmacologically inert. This duality—high local concentration with negligible systemic burden—is the scientific foundation for its excellent clinical profile, which combines high efficacy with a superior safety record. The observed difference in absorption between the feet and the groin also provides a clear rationale for why the potential for systemic drug interactions, though low, is primarily a consideration for patients being treated for tinea cruris.[16]

Section 5: Clinical Efficacy in Approved Indications

The clinical efficacy of Luliconazole 1% cream has been rigorously established through a series of pivotal, vehicle-controlled trials for its approved indications, as well as in comparative studies against other antifungal agents.

5.1 Pivotal Trials in Interdigital Tinea Pedis

The approval of Luliconazole for interdigital tinea pedis was based on the results of two large, multicenter, randomized, double-blind, vehicle-controlled Phase 3 clinical trials.[11]

• Regimen: In these trials, patients applied either Luliconazole 1% cream or a vehicle cream once daily for a duration of two weeks.[5]
• Primary Endpoint: The primary measure of efficacy was "complete clearance," a stringent endpoint defined as the achievement of both clinical cure (a score of 0 for all signs and symptoms, including erythema, scaling, and pruritus) and mycological cure (negative potassium hydroxide [KOH] microscopy and negative fungal culture). This endpoint was assessed at four weeks post-treatment (Day 42) to evaluate sustained resolution.[11]
• Results: Both studies demonstrated the statistically significant superiority of Luliconazole over vehicle.
• In the first study, 26% of patients in the Luliconazole group achieved complete clearance, compared to only 2% in the vehicle group.[11]
• In the second study, the complete clearance rate was 14% for the Luliconazole group versus 3% for the vehicle group ($p$<0.001).[11]
• Secondary Endpoints: Luliconazole was also significantly superior to vehicle across all secondary endpoints, including rates of effective treatment (mycological cure with, at most, mild signs and symptoms), clinical cure alone, and mycological cure alone.[16]

5.2 Pivotal Trial in Tinea Cruris

The efficacy of Luliconazole for tinea cruris was established in a pivotal Phase 3 trial with a similar robust design, involving 256 patients aged 12 years and older.[11]

• Regimen: A key feature of this trial was the short treatment duration. Patients applied Luliconazole 1% cream or vehicle once daily for only one week.[16]
• Primary Endpoint: The primary endpoint was complete clearance, assessed at three weeks post-treatment (Day 28).[11]
• Results: Luliconazole demonstrated a clear and statistically significant benefit. Complete clearance was achieved by 21.2% of patients in the Luliconazole group, compared to just 4.4% in the vehicle group ($p$<0.001).[11] The mycological cure rate was also substantially higher for Luliconazole (78%) compared to vehicle (45%).[37]

5.3 Clinical Evidence in Tinea Corporis

While the initial FDA approval for tinea corporis was granted based on the strength of the data from the tinea cruris and pedis trials, the agency issued a Post-Marketing Requirement (PMR) for a dedicated study in pediatric patients to confirm its safety and efficacy for this indication.[11] This study (NCT02767947) was a multicenter, randomized, double-blind, vehicle-controlled trial in patients aged 2 to <18 years.[12]

• Regimen: Patients were treated with Luliconazole 1% cream or vehicle once daily for one week.[16]
• Results: Although the study was not powered for formal statistical hypothesis testing, the results showed a strong signal of efficacy that supported the expanded pediatric labeling. At Day 28, the complete clearance rate was 70.6% in the Luliconazole group, more than double the rate of 35.7% observed in the vehicle group.[12]

5.4 Comparative Efficacy Studies

Head-to-head studies comparing Luliconazole with other topical antifungals have provided a more nuanced understanding of its clinical positioning.

• Versus Clotrimazole: An observational study compared once-daily Luliconazole 1% with twice-daily Clotrimazole 1%. At two weeks, Luliconazole demonstrated a significantly faster and higher cure rate (56.4% vs. 23.6%). Although the final cure rates at the end of six weeks were comparable, Luliconazole's rapid onset of action and convenient once-daily dosing made it more cost-effective in the initial phase of treatment.[42]
• Versus Sertaconazole: In a study comparing two weeks of once-daily Luliconazole 1% with four weeks of twice-daily Sertaconazole 2%, the Sertaconazole group achieved a higher proportion of complete clearance (70% vs. 27.6%) and had a lower relapse rate. However, the analysis also concluded that Luliconazole was the more cost-effective option.[44]
• Versus Amorolfine: A non-inferiority trial comparing Luliconazole 1% and Amorolfine 0.25% for tinea cruris found no statistically significant difference in efficacy after two weeks of treatment, leading to the conclusion that Amorolfine was not inferior to Luliconazole in this setting.[45]

5.5 Investigational Use in Onychomycosis

Recognizing the significant challenge of treating onychomycosis (tinea unguium or fungal nail infection), Luliconazole has been investigated in higher-strength solution formulations specifically designed for nail penetration.[8] Phase 1/2 and 2/3 clinical trials have been completed using 5% and 10% solutions.[46] One study of a 5% solution applied for 48 weeks demonstrated a complete cure rate of 14.9%, significantly higher than the 5.1% seen with vehicle, and was well tolerated.[23] While Luliconazole's high molecular weight presents a barrier to nail penetration, modifications to its structure to reduce keratin affinity have been shown to enhance its permeability through the nail plate.[23]

The design of the pivotal clinical trial program for Luliconazole strategically capitalized on its high preclinical potency. By demonstrating efficacy with a one-week treatment course for tinea cruris and corporis, the drug secured a key clinical and marketing advantage as the first topical azole approved for such a short regimen.[11] This directly addresses the well-known clinical challenge of patient non-adherence with prolonged topical therapies, which is a common reason for treatment failure. This short duration is not merely a matter of convenience; it is a clinically meaningful attribute that may lead to higher rates of treatment completion, thereby improving overall outcomes and potentially reducing the risk of relapse.

Section 6: Safety, Tolerability, and Risk Profile

Luliconazole has demonstrated a favorable safety and tolerability profile across numerous clinical trials and post-marketing surveillance, consistent with a topically applied agent with minimal systemic absorption.

6.1 Adverse Event Profile

The overall safety assessment indicates that Luliconazole is very well-tolerated.

• Clinical Trial Experience: In the pivotal Phase 3 trials involving over 600 subjects, the most commonly reported adverse reactions were mild application site reactions, such as irritation, itching, or stinging.[11] Importantly, these events occurred in less than 1% of subjects and at a frequency similar to that observed in the vehicle (placebo) cream groups, indicating that the drug itself adds minimal local irritancy beyond the cream base.[11] No serious adverse events related to Luliconazole were reported in these trials.[2]
• Post-Marketing Experience: Since its approval, rare adverse reactions have been reported voluntarily from a large population of users. These include cases of contact dermatitis and cellulitis.[2] Due to the voluntary nature of this reporting, a precise frequency cannot be established.

6.2 Drug-Drug Interactions

The potential for drug-drug interactions is low due to minimal systemic absorption, but it has been thoroughly investigated.

• In Vitro Studies: Laboratory studies indicated that Luliconazole has the potential to inhibit the activity of cytochrome P450 enzymes CYP2C19 and CYP3A4. No significant inhibition of CYP1A2, CYP2C9, or CYP2D6 was expected.[20]
• In Vivo Studies: A dedicated clinical drug interaction study (NCT02394340) was conducted in adult subjects using omeprazole (a sensitive CYP2C19 substrate) as a probe. The results confirmed that, under maximal use conditions, Luliconazole acts as a weak inhibitor of CYP2C19 in adults.[16]
• Adolescent Population: A separate pharmacokinetic trial in adolescents with tinea cruris, an indication with higher systemic absorption, found that circulating blood levels of Luliconazole could approach a threshold sufficient to cause moderate inhibition of CYP2C19.[16] This nuanced finding underscores the importance of population- and indication-specific safety assessments. While clinically significant interactions are generally considered unlikely, this data suggests that caution may be warranted when Luliconazole is used over large areas in adolescents who are also taking sensitive CYP2C19 substrates, such as diazepam, certain proton pump inhibitors, clobazam, or mavacamten.[2]

6.3 Use in Special Populations

• Pediatrics: The safety and effectiveness of Luliconazole have been formally established in pediatric populations through the FDA's PMR program. It is approved for tinea corporis in children 2 years of age and older, and for tinea pedis and tinea cruris in adolescents 12 years of age and older.[12]
• Geriatrics: Clinical studies have not revealed any overall differences in safety or efficacy between elderly and younger subjects. However, as with many medications, the possibility of greater sensitivity in some older individuals cannot be entirely ruled out.[20]
• Pregnancy: Luliconazole is designated as Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. However, nonclinical animal reproduction studies did not show adverse developmental effects. In these studies, pregnant rats and rabbits received subcutaneous Luliconazole during organogenesis at doses up to 3 and 24 times the maximum recommended human dose (MRHD), respectively, without evidence of teratogenicity.[16]
• Lactation: It is unknown if Luliconazole is excreted in human breast milk following topical application. Because many drugs are excreted in milk, caution should be exercised when it is administered to a nursing woman.[20]

6.4 Nonclinical Toxicology

A standard battery of nonclinical toxicology studies was conducted to support the safety of Luliconazole.

• Carcinogenesis and Mutagenesis: Long-term studies to evaluate carcinogenic potential have not been performed, which is common for topical drugs intended for intermittent use. Luliconazole was found to be non-mutagenic and non-clastogenic in a series of standard genotoxicity assays, including the Ames test.[29]
• Impairment of Fertility: In animal studies, no treatment-related effects on fertility or reproductive function were observed in rats at doses equivalent to 0.1 times the MRHD.[34]
• Cardiovascular Safety: An in vitro hERG assay, which assesses the potential for a drug to affect cardiac repolarization, showed concentration-dependent inhibition of the potassium current with an $IC_{50}$ of 1.52 µM. However, an in vivo cardiovascular study in telemetered dogs showed no treatment-related effects on electrocardiograms (ECGs). Given the minimal systemic exposure in humans after topical application, the risk of clinically relevant QT interval prolongation is considered to be minimal.[29]

The rigorous evaluation of Luliconazole, including the FDA's requirement for post-marketing pediatric and drug-interaction studies, exemplifies a modern, thorough approach to drug safety. The specific finding of potential moderate CYP2C19 inhibition in adolescents with tinea cruris is a critical and nuanced piece of safety information. This conclusion arises from the convergence of a regulatory mandate (the PMR), a site-specific pharmacokinetic property (higher absorption in the groin), a population-specific factor (adolescents), and a specific molecular interaction (CYP2C19 inhibition). It results in a highly specific precaution in the drug's labeling that would not have been apparent from the initial adult data alone, demonstrating a sophisticated and comprehensive understanding of the drug's risk profile.

Section 7: Regulatory Status and Formulation

7.1 Global Regulatory Approvals

Luliconazole has received marketing authorization from several major regulatory agencies around the world, though its approved indications and formulations may vary by region.

• Japan: Luliconazole was first approved by Japanese regulatory authorities on April 11, 2005. It is marketed under trade names including Lulicon® and is available as both a 1% cream and a 1% solution. The approved indications in Japan are broader than in the United States and include tinea pedis, tinea corporis, tinea cruris, cutaneous candidiasis, and tinea versicolor.[7]
• United States: The U.S. FDA approved Luliconazole 1% cream on November 14, 2013, under the brand name LUZU® (NDA 204153).[1]
• The initial approval was for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by T. rubrum and E. floccosum in patients 18 years of age and older.[11]
• Following the successful completion of Post-Marketing Requirements (PMRs), the FDA approved an expanded label on February 22, 2018, to include pediatric populations: children aged 2 and older for tinea corporis, and adolescents aged 12 and older for tinea cruris and tinea pedis.[12]
• Singapore: On February 14, 2022, the Health Sciences Authority (HSA) of Singapore approved a higher-strength formulation, LUCONAC EXTERNAL SOLUTION FOR NAILS 5% W/W. This product is specifically indicated for the topical treatment of mild to moderate tinea unguium (onychomycosis) in adults.[52]
• Australia: Based on the available information, there is no evidence that a Luliconazole-containing product is currently registered on the Australian Register of Therapeutic Goods (ARTG). While some sources mention approvals from Australia's Therapeutic Goods Administration (TGA) for manufacturing facilities that may produce Luliconazole as an active pharmaceutical ingredient, this does not equate to approval of a finished drug product for sale in Australia.[53] Products may be available for personal importation, but this is distinct from local registration and marketing authorization.[54]

7.2 Product Formulation and Excipients

In the United States and many other markets, Luliconazole is formulated as a 1% w/w white cream for topical application.[3]

• Active Ingredient: Each gram of the cream contains 10 mg of Luliconazole.[13]
• Inactive Ingredients (Excipients): The cream base is composed of several excipients that provide the appropriate consistency, stability, and skin feel. These include: benzyl alcohol (as a preservative), butylated hydroxytoluene (BHT) (as an antioxidant), cetostearyl alcohol, isopropyl myristate, medium-chain triglycerides, methylparaben, polysorbate 60, propylene glycol, purified water, and sorbitan monostearate.[13] Some formulations may contain other agents, such as propylene glycol or Sepineo P 600.[50]

7.3 Dosing and Administration Guidelines

The recommended dosing and administration for Luliconazole 1% cream are indication- and age-specific.

• General Instructions: The cream is for topical use only and should not be applied to the eyes or used orally or intravaginally.[16] A thin layer should be applied to cover the entire affected area and approximately 1 inch (2.5 cm) of the immediate surrounding healthy skin to treat the advancing margin of the infection.[16]
• Interdigital Tinea Pedis: Apply once daily for two weeks in adults and adolescents 12 years of age and older.[5]
• Tinea Cruris: Apply once daily for one week in adults and adolescents 12 years of age and older.[5]
• Tinea Corporis: Apply once daily for one week in adults and children 2 years of age and older.[5]

The global regulatory history of Luliconazole reveals distinct strategic pathways. Japan, as the country of origin, pursued a broader initial approval covering multiple indications and formulations. In contrast, the FDA followed a more focused approach, initially approving a narrower set of indications for adults and then requiring extensive post-marketing data before expanding the label to pediatric populations. The recent approval of a high-strength 5% nail solution in Singapore for the challenging indication of onychomycosis signals a new phase in the drug's lifecycle, targeting areas of high unmet medical need with specialized formulations designed to overcome significant drug delivery barriers.

Section 8: Expert Synthesis and Concluding Remarks

8.1 Summary of Luliconazole's Profile

Luliconazole is a second-generation imidazole antifungal agent that represents a significant refinement within its therapeutic class. Its distinction lies in a unique chemical structure—the optically pure R-enantiomer of a molecule featuring a ketene dithioacetate group—which confers exceptionally high in vitro potency. This potency translates into a dual pharmacological profile that is particularly advantageous for treating dermatophytoses: it maintains the broad antifungal spectrum characteristic of azoles while exhibiting potent fungicidal activity against key dermatophytes, an attribute more commonly associated with the allylamine class. This is complemented by an ideal pharmacokinetic profile for a topical agent. Its high lipophilicity leads to excellent retention in the stratum corneum, creating a local drug reservoir that sustains its therapeutic effect. This is paired with minimal systemic absorption and extensive plasma protein binding of the absorbed fraction, resulting in a superior safety profile with a very low incidence of adverse events.

8.2 Clinical Significance and Positioning

The primary clinical significance of Luliconazole 1% cream is its proven efficacy in short, convenient, once-daily treatment regimens. The one-week course for tinea cruris and tinea corporis and the two-week course for interdigital tinea pedis are among the shortest available for a topical azole, directly addressing the pervasive clinical problem of patient non-adherence, which is a leading cause of treatment failure and relapse in superficial fungal infections. Comparative clinical data position Luliconazole as a more rapidly effective agent than older azoles like clotrimazole. While head-to-head trials against other modern antifungals have yielded more nuanced results, Luliconazole's compelling combination of high potency, rapid action, convenient dosing, and excellent safety profile establishes it as a first-line therapeutic choice for the management of uncomplicated tinea pedis, tinea cruris, and tinea corporis.

8.3 Future Directions and Unanswered Questions

The clinical development of Luliconazole continues to evolve, with a clear focus on addressing more recalcitrant fungal infections. The investigation and recent approval in Singapore of higher-strength (5% and 10%) solution formulations for onychomycosis represent a promising future direction, targeting a condition with a significant unmet need for safe and effective topical therapies. While its clinical and safety profile is well-characterized, minor gaps in its scientific profile remain, including a full elucidation of its metabolic and excretory pathways in humans. Furthermore, the absence of a registered product in several major markets, such as Australia, suggests opportunities for further global expansion.

8.4 Final Assessment

In conclusion, Luliconazole stands as a testament to successful drug development through stereochemical optimization and structural innovation. The progression from a racemic mixture (lanoconazole) to a pure, highly potent enantiomer, combined with a chemical structure optimized for antifungal activity and skin retention, has yielded a drug with a highly favorable benefit-risk profile. Its demonstrated ability to achieve high rates of mycological and clinical cure with short, simple treatment courses solidifies its role as a valuable and rational component of the modern therapeutic armamentarium for dermatophytosis.

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