Sertaconazole: updated review of a topical antifungal agent

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Drug Profile

10.1586/14787210.3.3.xxx © 2005 Future Drugs Ltd ISSN 1478-7210 1www.future-drugs.com

Sertaconazole: updated review of a topical antifungal agentAlfonso J Carrillo-Muñoz†, G Giusiano, P A Ezkurra and G Quindós

†Author for correspondenceACIA, Microbiology Dept,PO Box 10178, E-08080 Barcelona, SpainTel.: +34 934 297 [email protected]

KEYWORDS: dermatophytes, fungi, mycoses, sertaconazole, topical antifungal agent, yeast

Sertaconazole is an imidazole-type antifungal agent that has shown considerable in vitro activity against pathogenic fungi. Various studies carried out in animal models, clinical and toxicologic trials have confirmed the value of sertaconazole in the topical treatment of superficial mycoses in dermatology and gynecology. After several years of clinical experience in the topical treatment of dermatophytosis and Tinea versicolor, the substance has been approved for gynecologic candidiasis in Europe. Sertaconazole has a wide action spectrum that includes yeasts, dermatophyte fungi and it is also active against bacteria, mainly Gram-positive cocci, making it highly efficient in the treatment of polymicrobial infections. The recent approval of the molecule by the US Food and Drug Administration, and the appearance of a new formulation of sertaconazole for the treatment of onychomycoses on a weekly administrative basis are all data relevant to the process of marketing the product.

Expert Rev. Anti Infect. Ther. 3(3), xxx–xxx (2005)

The development of new antifungal agentshas been marked by increasing pathogenicityof many fungal micro-organisms, the mostimportant being emerging pathogens, thereduced sensitivity to traditional antifungalagents and the seriousness of many mycoses.These facts are due to the increase in the pop-ulation at risk, including AIDS patients, andnow with growing importance, receptors oftransplanted organs with hematologic dis-eases and other immunosuppressed persons.From an epidemiologic point of view, thechanges taking place in these types of infec-tions have been brought about by new medi-cal treatments for at-risk populations, as wellas by changes in the handling of patients,such as the introduction of new systems ofcell transplantation, progress in the practiceof organ transplants, or the use of new immu-nosuppressant agents and antimicrobialprophylaxis strategies. Two factors have heav-ily influenced the impact of invasive mycoses;the progress of base pathologies, and insuffi-cient diagnostic methods and tools that donot allow detection of the infection in its ini-tial stages. Fungal infections continue to beone of the major causes of death in patients

being treated for neoplasia. These immuno-compromised patients are frequently infectedby fungi of different species belonging to theCandida, Aspergillus or Cryptococcus genera aswell as other opportunistic pathogenic fungi.The introduction of highly active antiretrovi-ral therapy (HAART) has brought about asignificant decline in the incidence of oppor-tunistic infections among AIDS patients indeveloped countries. However, the availabil-ity of HAART is very limited in underdevel-oped countries, with a high rate of HIVinfection and opportunistic fungal infections,such as oropharyngeal candidiasis, cryptococ-cosis, histoplasmosis, penicilliosis or pneu-mocystosis, which are now an importantcause of morbidity and mortality.

The advances made in surgical techniquesand immunosuppressant treatments havedecreased the incidence of invasive candidiasisin receptors of transplanted organs with a highrisk of infection by Candida, but at the sametime there has been an increase in the fre-quency of infection by species other than Can-dida albicans as a pathogen among the Cand-ida genus. The increased use of very aggressiveimmunosuppressant agents in receptors of the

CONTENTS

Structure

Action mechanism

Antifungal action spectrum

Antifungal activity in vitro

Clinical efficacy

Safety profile

Pharmacokinetics

Tolerability studies

Market

Evolution

Expert opinion

Five-year view

Key issues

References

Affiliations

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Carrillo-Muñoz, Giusiano, Ezkurra & Quindós

2 Expert Rev. Anti Infect. Ther. 3(3), (2005)

hematopoietic cell transplants has meant a greater incidence ofinvasive mycoses caused by filamentous fungi (such as aspergil-losis, fusariosis or zygomycoses) among these pathogens.Unfortunately, antifungal agents must act against micro-organ-isms that have metabolic pathways similar to those of the hostcell, and this means that the actions with greatest effectivenessare those that exploit asymmetric reactions, that is those thatonly damage the cell viability of the fungus. This effect is suffi-cient to reduce the fungal population to concentrations man-ageable by the host’s different functional defense mechanisms.Many of the required advantages of an antifungal agent, such aswide action spectrum and in vitro and in vivo activity at fungi-cidal concentrations, suitable toxicity profile (topical and sys-temic) and a suitable profile of administration, all make theexistence of this substance utopian [1]. The different structuralfamilies of antifungal agents have the potential capacity ofbeing useful against mycoses and evidenced with the differentavailable formulations. However, from a practical point of view,current and future lines of research on new antifungal agentsare focused on the development of substances associated withpolyene macrolides, azole derivatives (imidazoles and triazoles)and inhibitors of β-glucan synthetase, even though other linesof research include consideration of the combination of anti-fungal agents and the search for a better pharmacologic profilethrough the vehicularization of already used substances [1].Many new antifungal agents use as targets for their mechanismof action specific points of the cell physiology, such as the cellmembrane. In spite of both categories being highly used, theproblems regarding their efficacy and the toxicity associatedwith polyene derivatives, as well as the resistance of pathogensto azoles, has restricted their use [1]. The idea of the perfectantifungal agent with a broad spectrum of fungicidal activity,without the possibility of its action mechanism being suscepti-ble to possible resistance mechanisms and lacking toxicity,remains unresolved. The ideal target for the activity of an anti-fungal agent, apart from being essential for cell viability, shouldalso be present in a large number of pathogens that is in bothyeasts and moulds, but not in human cells [1].

Sertaconazole is a topical antifungal agent capable of developingimportant antifungal activity in vitro. Several animal models,clinical and toxicologic studies have demonstrated its usefulnessas a topical agent for the treatment of mycoses in dermatologyand gynecology [2]. After several years of clinical experience inthe dermatologic treatment of dermatophytosis and pityriasisversicolor, it has been approved for the treatment of genital can-didiasis [2]. Sertaconazole is characterized by its wide actionspectrum that includes yeasts, fungi dermatophytes and bacte-ria, mainly Gram-positive cocci.

StructureSertaconazole nitrate (FI-7045) (nitrate salt of 7-chloro-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy-methyl]benzo[b]thiophene) (C20H16O4N3Cl3S), molecular weight500.8 Da, CAS 99592–32–2) is a topical azole derivative asso-ciated with a benzothiophene matrix (FIGURE 1). This represents

an important difference compared with other azoles used in thetreatment of mycoses [3]. The lipophilic part of the moleculemeans that it is soluble in organic solvents such as ethanol(1.7%), chloroform (1.5%) or acetone (0.95%), slightly solublein N-octanol (0.069%) and practically insoluble in water(<0.01%) [4].

Action mechanismSertaconazole inhibits the biosynthesis of ergosterol in directproportion to the antifungal concentration used, this mecha-nism being similar to that of other azole antifungal agents [5].However, due to its mixed structure, sertaconazole is capableof causing direct damage to the C. albicans cell membrane[5–7]. This second, and very important, effect is the basis of itsfungicidal effect against C. albicans [5–7].

The special structure of the cell membrane of fungi is basedon the properties of ergosterol, which is capable of regulatingthe internal fluidity of the membrane. The interaction at somestage of the biosynthetic route of ergosterol may cause a reduc-tion of the levels of this compound and, as a result, affect theintegrity of the cell. An intermediary of the biosynthesis ofergosterol (lanosterol) is produced by the interaction of azolecompounds with the cytochrome P450 complex (in mono-oxy-genase or hydroxylase 14-α-demethylase enzymes). In general,azole derivatives cause inhibition of the biosynthesis of ergos-terol and inhibition of filamentation in C. albicans, as well as insome cases, such as with sertaconazole (direct damage to thecell membrane) [7]. The bond between the azole molecule andthe iron atom of the hemo group leads to inactivation of theenzyme and the resulting accumulation of lanosterol that dam-ages cellular architecture and membrane fluidity and permea-bility. Any increase in cell permeability causes the loss of intrac-ellular ATP, destruction of the cytoskeleton and lysis of the cell

S

Cl

Cl

O

Cl

NN

•HNO3

Figure 1. Chemical structure of sertaconazole. Sertaconazole nitrate (FI-7045) (nitrate salt of 7-chloro-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy-methyl]benzo[b]thiophene) (C20H16O4N3Cl3S) molecular weight 500.8 Da, CAS 99592–32–2).

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organelles, while at the same time reducing the number of via-ble cells by up to 90%. The result of this is the fungicidal effectof sertaconazole when cells are exposed to high concentrationsof this drug [5,7]. Under these same conditions, it is also possibleto detect an interruption in the process of the formation ofhyphae, thus preventing invasion of the host tissue [5,7].

Antifungal action spectrumThe relevant antifungal activity of sertaconazole has alreadybeen demonstrated in different preclinical studies against abroad spectrum of pathogenic fungi, including yeasts, fungidermatophytes, opportunistic filamentous fungi and Gram-positive bacteria (Streptococcus and Staphylococcus) and Tri-chomonas spp. (TABLE 1) [8]. The species of fungi includedpotential producers of dermatomycoses, dermatophytosisand genital candidiasis. A complete comparison of the mini-mum inhibitory concentrations, which would enable estab-lishing the antifungal power of the substance in vitro is com-plex, as some of the different results were obtained prior tothe appearance of the Clinical and Laboratory StandardsInstitute (CLSI/NCCLS) documents, which establishedstandard experimental conditions and variables. Neverthe-less, it can be deduced from data that there is a wide activityspectrum against pathogenic fungi, an activity that takesplace at concentrations far below those reached after thetopical application of sertaconazole (TABLE 1).

Antifungal activity in vitroThe in vitro antifungal activity of sertaconazole has been widelydemonstrated by various authors using standard and nonstand-ard methods under different experimental conditions [10]

against pathogenic yeasts [11–16], including Malassezia spp. [17],dermatophyte fungi [12,18–20] and opportunistic filamentousfungi [6,21]. Susceptibility testing enables an excellent statisticalbase to be obtained indicating the tendency of a substancetowards activity or inactivity and also serves as a therapeuticguide when making clinical decisions regarding the predictionof susceptibility or resistance of the isolated strain, the selectionof the most clinically active antifungal agents, or indicating thereasons for therapeutic failure on the basis of microbiologic cri-teria [22,23]. The fungicide activity of sertaconazole has its onsetat concentrations of 8–16 µg/ml [24], whereas at lower concen-trations, in ranges equivalent to clotrimazole and miconazole, itdevelops a fungistatic action mechanism [6,13,24,25]. This anti-fungal activity of sertaconazole is higher than that of other imi-dazole derivatives, such as bifonazole, econazole orfluconazole [11–13,15,19,25,26]. In the absence of adverse effects asserious as those observed with other imidazoles such as clotrim-azole, miconazole, bifonazole or ketoconazole, in comparison,sertaconazole is more active against opportunistic filamentousfungi than miconazole [6,24]. Sertaconazole also proved to bemore active against resistant strains of dermatophytes than flu-conazole, a triazole derivative used by oral route in the treat-ment of some dermatophytoses [19]. Sertaconazole is very activeagainst this group of pathogenic fungi with partial inhibition

being detected at concentrations below 0.04 µg/ml [6,18,19].This excellent in vitro antifungal activity of sertaconazole iscompleted by a low percentage of resistances, placing it in thesame range as other topical antifungal agents such as clotrima-zole and tioconazole, and lower than those obtained foramphotericin B, itraconazole, fluconazole, econazole, micona-zole or ketoconazole [25,26]. On the other hand, it has not beenpossible to obtain evidence of induced resistance in vitro byexposure of C. albicans and Candida tropicalis to subinhibitoryconcentrations of sertaconazole [8].

Antibacterial activity in vitroSertaconazole has demonstrated in vitro antibacterial activityagainst Staphylococcus aureus, Staphylococcus epidermidis, Strepto-coccus pyogenes, Streptococcus agalactiae, Listeria monocytogenes,Gardnerella spp. and other bacteria involved in mixed infec-tions (TABLE 1). The activity of sertaconazole against Gram-posi-tive bacteria was described at concentrations below 0.97 µg/mland considered to have in vitro therapeutic value [8].

Animal modelsSome experimental models in animals (mouse and guinea pig)have been used to prove the usefulness and efficacy of topicalsertaconazole at doses of 2% against vaginal candidiasis anddermatophytosis, when tested in comparison with miconazole(2%) in different treatment regimes [24,27,28]. In the animalmodel of dermatophytosis, sertaconazole has a proven efficacyafter 12 days of treatment similar to that obtained with mico-nazole. The therapeutic improvement of the clinical and micro-biologic symptoms was better for the sertaconazole grouptreated during 3 days. The same occurred with the model ofvaginal candidiasis but with an even better prophylactic andcurative effect [24,28]. In the latter model, there was a greaterreduction in the cell count of yeasts with the vaginal administra-tion of sertaconazole (97.7 and 77.5% with sertaconazole andmiconazole respectively) promising a good clinical efficacy [28].

Clinical efficacyAnti-inflammatory effectSertaconazole has been shown to have anti-inflammatory activitywhen administered at a dose of 2% [29]. This effect is useful inthe treatment of some inflammatory forms of dermatophytoses.

Dermatology (dermatophytoses & other cutaneous mycoses)A comparison between different clinical studies to establish theefficacy of antifungal agents is difficult due to the differingnumbers of patients assessed in these studies. However, it ispossible to review comparative multicentric clinical studiesbetween sertaconazole and other azole derivatives (miconazole,sulconazole, clotrimazole, bifonazole or ketoconazole) that sup-port the clinical efficiency of sertaconazole against superficialmycoses in all its different formulations. The cream formulationwas effective in a double-blind study carried out with parallelgroups of patients suffering from different dermatophytoses(tinea cruris, tinea corporis, tinea pedis, tinea manuum, tinea

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Table 1. Comparison of the in vitro antifungal activity of sertaconazole against pathogenic fungi.

Pathogenic group Genus/species No. isolated RangeMIC (µg/ml)

Reference number

YeastsCandida albicans 10 4.64 [8]

138 0.03–5 [16]

73 0.03–15 [15]

65 0.03–5 [11]

81 0.03–5 [12]

Candida parapsilosis 3 0.4 [8]

22 0.03–2.5 [15]

47 0.03–5 [16]

25 0.03–2.5 [12]

Candida tropicalis 1 4 [8]

4 0.09 [6]

21 0.23–5 [15]

39 0.03–1.25 [16]

27 0.23–5 [12]

Candida krusei 1 1 [8]

3 0.18 [6]

22 0.03–5 [16]

13 0.11–0.93 [15]

14 0.14–0.93 [12]

Candida guilliermondii 9 0.03–0.31 [16]

5 0.03–1.97 [15]

5 0.03–1.87 [12]

Rhodotorula rubra 2 5.54 [8]

1 0.03 [16]

Cryptococcus neoformans 12 0.5 [8]

10 0.03–0.62 [16]

7 0.03–0.62 [11]

3 0.03–0.31 [12]

Candida glabrata 5 0.09 [6]

29 0.03–1.25 [16]

16 0.03–3.12 [15]

22 0.03–3.12 [12]

Cryptococcus humicola 1 5 [12]

Candida intermedia 1 2.5 [12]

MIC: Mean inhibitory concentration.

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Candida famata 1 0.03 [12]

Trichosporon beigelii 4 0.09 [6]

Dermatophytes

Epidermophyton floccosum 21 0.06–8 [18]

7 0.03–0.62 [20]

Microsporum audouinii 8 0.125–2 [18]

Microsporum canis 64 0.01–1 [18]

6 2 [8]

9 0.03–0.66 [15]

Microsporum gypseum 18 0.03–1 [18]

5 1.26 [8]

5 0.31–1.25 [15]

Trychophyton interdigitale 18 0.01–1 [18]

Trichophyon mentagrophytes 52 0.01–4 [18]

7 1.71 [8]

14 0.03–1.25 [15]

Trichophyton rubrum 100 0.01–2 [18]

17 0.03–0.62 [15]

5 0.24 [8]

Trichophyon schoenleinii 3 1 [18]

Trichophyon tonsurans 18 0.01–1 [18]

Trichophyon verrucosum 1 0.25 [18]

Trichophyon violaceum 6 0.125–1 [18]

Opportunist

Aspergillus fumigatus 2 1.41 [8]

3 2.84 [6]

Aspergillus niger 4 2 [8]

Alternaria spp. 3 6.25 [6]

Acremonium spp. 2 18.75 [6]

Fusarium spp. 2 1.56–6.25 [6]

Scopulariopsis brevicaulis 3 6.09 [6]

14 0.03–2.5 [21]

Bacteria

Staphillococcus aureus 0.5–16 [8]

Staphylococcus epidermitis 0.5–16 [8]




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barbae among other locations). The efficacy of the cream for-mulation of sertaconazole in a Multicenter Phase III, rand-omized and comparative study with miconazole in patientsinfected by Microsporum canis, C. albicans and other dermato-phyte fungi, reached ranges of 98.3 versus 94.3%, respectively,after 4 weeks of treatment. This was statistically significant [30].The ranges of clinical cure for sertaconazole were accompaniedby similar mycologic cure rates – being the percentage of thera-peutic failure, recurrence or relapses being very low (sertacona-zole 4.4 vs. miconazole 11.9% of relapses at 35 days afterbeginning the treatment, p < 0.001) [31]. Similar results wereobtained for a comparison of the clinical efficacy of sertacona-zole with sulconazole, clotrimazole or bifonazole for the treat-ment of patients suffering from cutaneous candidiasis and der-matophytosis [32]. Apart from its antifungal activity, someproperties of sertaconazole, such as reduction of the severity oferythema, reduction of desquamation, pruritus or the forma-tion of pustules, were also useful when determining the clinicalcure. The good results obtained with sertaconazole in the treat-ment of superficial mycoses were previously described inPhase II studies, which also enabled characterizing a high safetyprofile in a group of 20 patients [31–34].

The effectiveness of the gel formulations (2%) of sertaco-nazole compared with ketoconazole was demonstratedagainst seborrheic dermatitis. Clinical signs and the presenceof fungal elements were reduced in 61.1% of the 60 patientsstudied whereas for ketoconazole this occurred in 52.6% ofpatients [2].

Clinical and mycologic improvement of various superficialinfections was achieved with different formulations of sertaco-nazole in comparison with other compounds belonging toother chemical families of antifungal agents. Furthermore, itsefficacy was demonstrated in children after the application ofsingle doses of the 2% cream formulation of sertaconazole [35].

Gynecology (vaginal candidiasis)In gynecologic mycoses, such as candidal vulvovaginitis, theexcellent efficacy of sertaconazole was also demonstrated incomparative studies with clotrimazole and econazole [2,36,37].The effectiveness of sertaconazole was comparable with thatof clotrimazole in terms of clinical and mycologic cure ofthe 582 patients studied, reaching a cure rate higher than80% in both groups at 14 days after the application of a sin-gle dose of 500 mg as a vaginal tablet. Both antifungalagents were well tolerated with the adverse effect of greatest

frequency being the appearance of pruritus and erythemaahead of irritation, sensitization, edema, rubor, leukorrheaand maceration [2].

Sertaconazole and econazole demonstrated similar rates ofefficacy and safety, but the percentage of recurrence was loweramong patients treated with sertaconazole [36]. In a comparativestudy between the application of a single intravaginal dose in 369patients suffering from vaginal candidiasis (183 sertaconazole;186 econazole), the clinical and mycologic cure rate was 70.8 and64.7%, respectively, for sertaconazole and econazole, after 7 daysof treatment and the clinical cure rates were 71.6 versus 64.2%,respectively, for each of the treatments. In spite of these resultsbeing similar for both imidazole antifungal agents, it was possibleto observe statistically significant differences in favor of sertaco-nazole in regard to the relapse rates (19.8 and 32.7%, respec-tively, after 30 days; p = 0.035), a fact probably related to thefungicide capacity of sertaconazole. No differences were foundbetween both medicinal products for local tolerability.

Another study evaluated the differences between the treat-ment of vulvovaginal candidiasis with single intravaginaldoses of 300 mg (applied at night) and the combined intrav-aginal therapy of a single dose of 300 mg together with topi-cal application of sertaconazole cream (2%) to the vulva dur-ing 7 days (combined treatment) [37]. The resultsdemonstrated an efficacy of close to 99% with regard to clin-ical improvement in all patients, but the cure was faster inthe combined treatment group of pessary plus cream than inthe group of pessary alone at 7 days (76 vs. 68%, respec-tively). Furthermore, annoying symptoms such as pruritusdisappeared sooner in the combined treatment group [37].

Safety profileAcute toxicity studiesThe acute toxicity of sertaconazole was determined after theadministration of single doses by oral, subcutaneous and intra-peritoneal route in rats and mice with the median lethal dose(LD50) being higher than 8000 mg/kg in all cases. Due to itsreduced absorption, administration is safe even in the event ofaccidental overdose or ingestion [38].

Subacute toxicity & maximum tolerated doseStudies of repeated administration over a period of 28 dayswith subacute oral and dermal doses of 50, 150 and 300 mg/kgand maximum tolerable doses on a geometric progression of50, 75, 112.5, 168 and 250 mg/kg of sertaconazole revealed

Staphylococcus pyogenes 0.5–16 [8]

Streptococcus agalactiae 0.5–16 [8]

Listeria monocytogenes 0.5–16 [8]




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a reduced number of toxic effects that are not possible toreproduce after the administration of single doses [39]. Nohistopathologic changes were found in any of the cases [39].

Chronic toxicity studies after oral administrationIn this regard, the effects produced by sertaconazole are alsocommon to other azole derivatives used for the treatment ofmycoses, and were detected at a dose of 50 mg/kg in chronictoxicity studies after repeated and sustained administration byoral route doses of 50, 150 and 300 mg/kg in rats andferrets [40]. The accumulative effect, which did not produceany associated mortality, was observed in the group treatedwith bifonazole (10 mg/kg), ketoconazole (60 mg/kg) andmiconazole (100 mg/kg). There was a low increase in bodyweight in animals treated with 300 mg/kg of sertaconazoleover 5 weeks (rats) and 150 mg/kg over 11 weeks (ferrets).The histopathologic findings are similar to those produced byother imidazoles and consisted of changes in the pattern ofmicrovacuolization in the hepatocyte cytoplasm related to theinduction of microsomal enzymes [40]. The inhibitory effecton the synthesis of adrenal steroidal hormones, also commonto other azole antifungal agents and observed after the admin-istration of very high doses, produces changes in the ovaries oftreated females (ferrets) and ductal hyperplasia of the mam-mary gland and endometrium [40]. The effects, although com-mon to other imidazoles, were found at higher concentrationsof sertaconazole and this its safety profile is higher, requiringdoses of more than 50 mg/kg [40]. The data available for mico-nazole and clotrimazole show a worse toxicity profile for thesesubstances [40]. In any case, the administration of sertacona-zole is not associated with any necrogenic, inflammatory ordegenerative changes [40].

Toxicity studies in reproductionCompared with ketoconazole, bifonazole or miconazole, thelow toxicologic risk associated with the administration of serta-conazole has been demonstrated by teratologic studies in rats,rabbits and also in peri- and postnatal rats [41].

GenotoxicityThere was no evidence of induction of signs of promutagenicity,mutagenicity, clastogenicity or interference with the process ofchromosomal segregation caused by DNA damage. Neither havegenotoxicity studies carried out with sertaconazole demonstratedany increase in the frequency of bacterial retromutation or lethalmutations in spermatozoa or spermatids [42].

Skin tolerance & phototoxicityIt is possible to state that there is no risk of phototoxicity afterthe administration of the 2% cream formulation of sertacona-zole in guinea pigs [43]. Trials carried out to detect skin toler-ance demonstrated the absence of any irritation [43]. This meansthat sertaconazole may be administered safely without the pos-sible existence of degradation by-products caused by directexposure to sunlight [43,44]. Sertaconazole does not induce

contact dermatitis at therapeutic doses (2% cream) [44,45],although allergic contact dermatitis to sertaconazole wasobserved in patients who had already presented sensitivity tomiconazole and econazole [47].

PharmacokineticsSertaconazole penetrates the horny layer of the skin where somepathogenic fungi are capable of developing their effect, andtherapeutic concentrations may be found there during a longperiod of time, which is of interest in clinical practice. How-ever, such high concentrations of sertaconazole cannot bereached in the lower layers, thus avoiding the potential risk ofsystemic absorption. The concentrations found in plasma in apreclinical study with radioactively marked sertaconazole werebelow 0.011% 5 h after beginning application of 2% cream tothe skin [48]. The cutaneous absorption in humans has beendescribed after topical application at increasing doses [44]. Theresults of this study showed that the percentage of cutaneousabsorption at 24 h after the application was 72% of the doseapplied. Analysis of plasma samples did not reveal concentra-tions of sertaconazole that were detectable at a quantitationlimit of 25 ng/ml.

No hematologic, cardiac or body temperature changes wereobserved at 13 days, neither was there any alteration of the bloodtestosterone levels, thus proving its good safety profile [44]. Theantifungal agent is retained in the skin for long periods of time,reaching antifungal concentrations at 72 h after topical applica-tions of once or twice a day [49]. The different vaginal forms inwhich sertaconazole is available (tablets, pessaries and cream) forthe treatment of vulvovaginitis make it possible to reach concen-trations above those required to inhibit the development of dif-ferent species of the genus Candida spp. with a dose of 300 or500 mg. In addition, these concentrations are maintained in vagi-nal secretion for several days after a single administration withoutthere being any systemic absorption, thus resolving its necessarypresence and persistence in the vaginal mucous membrane [50].Some of the main pharmacokinetic parameters of sertaconazole inpreclinical studies are shown in (TABLE 2) [51].

The fecal and renal routes are the main routes of eliminationof the product (61 and 4%, respectively, for endovenousadministration; 30 and 0.4% for administration and 17 and0.6% for the skin) [48].

Tolerability studiesTolerability studies for sertaconazole carried out using animalmodels and healthy human volunteers showed the absence ofevidence of adverse effects associated with the administration oftotal amounts of 98 g of antifungal agent during 13 days(1–16 g each) [44]. It was also shown with healthy human vol-unteers that other therapeutically available antifungal agentssuch as econazole, ketoconazole, bifonazole, clotrimazole andmiconazole, produced adverse reactions consisting of the for-mation of vesicles after the application of their commercialforms [44]. There were no differences between sertaconazole andplacebo in regard to photosensitivity [43].

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MarketSertaconazole is available throughout the world in differentdermal and gynecologic formulations. The former include: top-ical gel, 2% topical cream (recently launched in the USA underthe name Ertaczo®), powder and solution. In gynecology: pes-saries, vaginal cream and vaginal tablets. The dose of sertacona-zole active principle contained in each unit is considered sufficientfor the complete and individual treatment of each patient.

EvolutionDuring the above-mentioned period (1996–2001), there werereports of a reduced percentage of possible adverse effects totreatment in different clinical formulations of sertaconazole(0.5% per 100,000 patients). A total of 88.7% of thesereported adverse effects were for use of the 2% cream and con-sisted of erythema, exudation, urticaria, maculopapular rash,pruritus, contact dermatitis, burning, allergy, flush, wetting,vesication, swelling, pain, hyperpigmentation and decoloration.These adverse effects are the same as those observed after theapplication of other azole derivatives.

Studies have been carried out on the new formulations ofsertaconazole to complement the range of infections with thetreatment of onychomycoses [52]. The in vitro antifungalactivity shown against dermatophyte fungi, producers ofinfections in the nails, and the higher than inhibitory concen-trations reached in the nails, are the basis for the developmentof a formulation for onychomycoses consisting of adhesivepatches that contain concentrations of 1.65 mg/cm2 of serta-conazole. These patches, with an application schedule of oneper week during periods of 6 or 12 months, could produceconcentrations in the nails of close to 100–150 ng/mg afterthe first 2–6 weeks. These concentrations are above the mini-mum inhibitory concentrations for pathogenic fungi of thenails. Data on the prevalence of fungal infections in the nailsand the ease with which the patient could comply with thetreatment could be promising in the absence of formulationsof similar characteristics of other antifungal agents with a sim-ilar antifungal profile and pharmacologic properties, and inthis way, be advantageous in front of the oral treatment insome dermatophytoses.

Expert opinionAlthough some topical antifungal agents are available for themanagement of superficial fungal infections, sertaconazoleoffers an antifungal activity that occurs at concentrations thatare reached and exceeded after topical administration. Someother azole antifungal agents have an affinity for their targets insome fungal pathogens such as dermatophyte fungi lower thanthat of sertaconazole, and the double mode of action of sertaco-nazole could be an advantage. Dermal formulation of sertaco-nazole is retained for a long time in stratum corneum and othersertaconazole qualities such as its anti-inflammatory activity,good tolerance, antibacterial activity and safety profile are help-ful for the management of superficial fungal or mixed infec-tions. Successful results are obtained with sertaconazole dermalformulations in clinical trials confirming the good in vitro dataas predictive for clinical outcome. This contrasts with the long-term therapy profile and the low correlation of the in vitro andclinical outcome reached with other antifungal agents for themanagement of superficial mycoses (candidosis or dermatophy-toses). Frequency of recovering of resistant strains is extremelylow in in vitro tests compared with other azole derivatives.

Five-year viewThere is a relative shortage of antifungal agents for the manage-ment of fungal infections. Currently, a formidable technical chal-lenge is faced by the pharmaceutical industry in the discovery ofnew antifungal targets and the development of effective antifun-gal agents. The number of new antifungal agents at differentstages of the development pipeline is high in clear contrast to thefact that during more than 40 years, amphotericin B has beenalmost the only available therapy for invasive mycoses. Neverthe-less, great efforts are now underway to develop investigationalprograms in azole derivatives for superficial mycoses by topicaladministration. New trends are focused among the importantareas of investigation in antifungal agents, which are: the devel-opment of new azole or polyene derivatives, development of newformulations of old antifungal agents, investigation of newchemical structures including those having new genomic targets,and antifungal combination therapy or adjunctive immunothera-pies and immune-reconstitution. Although the need for new

Table 2. Pharmacokinetic parameters of sertaconazole in an animal model (rat) by different routes of administration.

Cutaneous

IntravenousSolution

Cream Solution Powder Gel

Absorption (%) 1.47 1.97 0.665 0.885

Cmax (µg/ml) 0.011 0.01 0.0033 0.0042

Tmax (h) 5 5 18 18

t1/2 (h) 7.276

AUC (0–24) (µg/ml/h) 7.559 0.1114 0.1493 0.0503 0.0668

AUC(0–24): Area under the curve over 24 h; Cmax: Maximum concentration; t1/2: Half-life; Tmax: Time of maximum concentration.

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Sertaconazole


drugs is obvious, progress in this area is slow and unpredictable.Targets may abound, but the difficulty in translating those targetsinto meaningful new drugs is well illustrated by the paucity ofnew classes of compounds over the past 20 years [1]. In this man-ner, sertaconazole is one of the latest appeared imidazole mem-bers. Its wide fungal spectrum, antifungal activity, safety toxico-logic profile and pharmacokinetics and mixed mode of action areuseful in comparison with other imidazole antifungal agents.

Onychomycoses are currently treated by lacquer formulations ortheir long therapies requiring daily administration. Antifungalcompliance is very difficult for infected patients (<51%). Epidemi-ologic data revealed a significative prevalence of the infection, ahigh clinical failure over the 25%, due to problems in nail penetra-tion and retention times of active antifungal concentrations.Indeed, some patients are treated with oral therapy (clinical failure

or extense affected areas involving nail matrix) with antifungaldrugs with lower activity against fungal nail pathogens, without noreduction times of dosage and with more severe reported adverseeffects compared with the topical administration of sertaconazole.On the basis of criteria, sertaconazole could be well accepted. Bynow, is also promising the interest of different companies to licensethe product.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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Affiliations• Alfonso J Carrillo-Muñoz, MD

ACIA, Microbiology Dept, PO Box 10178, E-08080 Barcelona, SpainTel.: +34 934 297 [email protected]

• G GiusianoUniversidad Nacional del Nordeste, 2 Mycology Dept, Instituto de Medicina Regional, Resistencia [email protected]

• P A EzkurraUniversidad del País Vasco, 3 Dept, Immunology, Microbiology and Parasitology, Faculty of Medicine, Bilbao, [email protected]

• G QuindósUniversidad del País Vasco, 3 Dept, Immunology, Microbiology and Parasitology, Faculty of Medicine, Bilbao, Spain

Sertaconazole: updated review of a topical antifungal agent

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