DRUG EVALUATION
`
`Oru~,,~: ~0~-~*0,,’~9~
`
`@ Adis International Limited. All rights reserved.
`
`Amorolfine
`A Review of its Pharmacological Properties and Therapeutic
`Potential in the Treatment of Onychomycosis and Other
`Superficial Fungal Infections
`
`Malini Haria and Harriet M. Bryson
`
`Adis International Limited, Auckland, New Zealand
`
`Various sections of the manuscript reviewed by:
`Y.M. Clayton, Institute of Dermatology, St Thomas’ Hospital, London, England; A. del Palacio, Department
`of Microbiology, Hospital 12 de Octubre, Madrid, Spain; MoJ.D. Goodfield, Department of Dermatolog~
`Leeds General Infirmar~ Leeds, England; R.]. Hay, St John’s Institute of Dermatology, Guy’s Hospital,
`London, England; J.L. Lesher, Department of Dermatology, Medical College of Georgia, Augusta, Georgia,
`USA; H.L Maibach, Department of Dermatology, UCSF School of Medicine, San Francisco, California, USA;
`J.J. Stern, Department of Internal Medicine and Infectious Diseases, Pennsylvania Hospital, Philadelphia,
`Pennsylvania, USA; A.M. Sugar, The University Hospital, Boston, Massachusetts, USA.
`
`Contents
`Summary ................................................... 103
`1, Antifungal Activity ................... ........................... 105
`1.1 In Vitro Studies .............................................. 105
`1.1.1 Fungistatic Activity ....................................... 105
`1.1.2 Fungicidal Activity ........................................ 107
`1.2 In VivoStudies .............................................. 107
`1.3 Other Effects ............................................... 108
`1.4 Mechanism of Action ......................................... 108
`2, Pharmacokinetic Properties ......................................... 109
`2.1 Nail Tissue Penetration ......................................... 109
`2.2 Percutaneous Absorption and Cutaneous Retention ....................... 110
`3, Therapeutic Potential ............................................ 110
`3.10nychomycosis ............................................. 110
`3,1,1 Dose-Response Studies ..................................... 113
`3.1.2 Noncomparative Study .................................... 113
`3,1,3 Combination Therapy ..................................... 114
`3.2 Dermatomycoses ............................................ 114
`3,2,1 Clinical Studies .......................................... 115
`3.3 Vulvovaginal Candidiasis ....................................... 115
`4, Tolerability ................................................... 116
`5. Dosage and Administration ......................................... 116
`6, Therapeutic Potential of Amorolfine .................................... 117
`
`Summary
`Synopsis
`
`Amorolfine is a structurally unique, topically active antifungal agent, which pos-
`sesses both fungistatic and fungicidal activity in vitro. Its spectrum of in vitro
`
`ARGENTUM EX1037
`
`Page 1
`
`

`

`104
`
`Haria & Bryson
`
`activity includes dermatophyte, dimorphic, some dematiaceous and f!lamentous
`fungi, and some yeasts. In clinical trials, application of amorolfine 5% nail lac-
`quer once or twice weekly for up to 6 months produced mycological and clinical
`cure in approximately 40 to 55% of patients with mild onychomycosis 3 months
`after cessation of therapy. Overall cure and improvement was observed in ap-
`proximately 85 to 90% of patients with superficial dermatomycoses following
`treatment with amorolfine 0.25% cream for up to 6 weeks. However, few control-
`led, comparative trials are available for these different mycoses, and only small
`numbers of patients have been evaluated to date. Both preparations appear to be
`well tolerated; only minor tocalised adverse events have been reported in clinical
`trials.
`At present, the major potential indication for topical amorolfine appears to
`be onychomycosis. Within this clinical setting, amorolfine should be reserved for
`patients with mild infection without nail matrix involvement. Systemic therapy,
`however, remains essential for patients with severe intractable onychomycosis
`involving the nail bed. Evidence to date does not clarify whether the use of adju-
`vant topical amorolfine reduces the need for systemic therapy in patients with
`severely infected nails, or whether amorolfine is beneficial in individuals unre-
`sponsive to other treatment options.
`
`Amorolfine is a morpholine derivative which is chemically distinct from other
`currently available antifungal agents. It acts primarily by inhibiting ergosterol
`biosynthesis, a component of fungal cell membrane, and possesses both fungi-
`static and fungicidal activity. Despite in vitro activity against various fungi, ani-
`mal test models indicate that amorolfine is inactive when given systemically for
`life-threatening mycoses.
`Conventional in vitro susceptibility tests indicate that amorolfine has greatest
`fungistatic activity against dermatophyte and dimorphic fungi. It is also active
`against some dematiaceous and filamentous fungi, and against some yeasts. Fun-
`gicidal activity is also highest against Trichophyton mentagrophytes.
`In the guinea-pig, topical amorolfine 0.01% was effective against cutaneous
`infection induced by T. mentagrophytes. On a concentration basis, amorolfine
`showed greater activity in clearing fungal lesions in this model than naftifine,
`oxiconazole, ketoconazole, bifonazole and clotrimazole, but lower activity than
`terbinafine. In rats, a dose-dependent log reduction in vaginal yeast cell counts
`was also observed with topical amorolfine starting at concentrations of 0.01%;
`vaginal candidiasis was completely cleared at a concentration of ! %.
`
`Amorolfine penetration through human nail follows an exponential relationship
`between drug concentration and nail layer. In vitro data suggest that soft diseased
`nails will retain less drug than hard compact nails. After a single application of
`nail lacquer (formulated with methylene chloride), permeation of [3H]amorolfine
`5% through the thumbnail ranged from 20 to 100 gg/L/h.
`Mean percutaneous absorption of amorolfine through healthy human skin fol-
`lowing a single application of 0.25% cream did not exceed 10% of the total
`administered dose. Systemically absorbed radioactive amorolfine was slowly ex-
`creted via urine and faeces over 3 weeks; plasma concentrations of <0.5 gg/L
`were detected in all samples. Further studies in volunteers indicate that active
`concentrations of amorolfine may be retained in healthy skin for 2 or 3 days after
`single applications of 0.5% cream or alcohol solution, respectively.
`
`Antifungal Activity
`
`Pharmacokinetic
`Properties
`
`© Adis International Limited, All rights reserved,
`
`Drugs 49 (1) 1995
`
`Page 2
`
`

`

`Amorolfine: A Preliminary Review
`
`105
`
`Therapeutic Potential
`
`TolerabilJty
`
`Dosage and
`Administration
`
`The therapeutic efficacy of amorolfine has been investigated in patients with
`onychomycosis, dermatomycoses and vulvovaginal candidiasis. In total, only
`small patient numbers have been evaluated, and comparative data are minimal.
`Available noncomparative data in approximately 600 patients suggest that
`amorolfine 5% nail lacquer applied once or twice weekly for up to 6 months may
`be effective in mild onychomycosis without nail matrix involvement. Mycologi-
`cal and clinical cure rates of about 40 to 55% were observed in treated patients 3
`months after cessation of therapy; fingernails responded consistently better than
`toenails. Preliminary data in patients with mild disease suggest that topical
`amorolfine may also be useful in conjunction with oral griseofulvin to enhance
`cure; further double-blind studies are, however, required to ascertain the potential
`benefits of combined therapy.
`Amorolfine 0.25% cream may be beneficial in patients with other superficial
`skin infections; in 208 patients, it appeared to be comparable in efficacy with
`bifonazole 1% cream. Amorolfine alcohol aerosol solutions 0.5 and 2% may also
`be useful in patients with foot mycoses. Similarly, a single vaginal dose of
`amorolfine 50 or 100rag appeared to be as effective as one clotrimazole 500mg
`pessary in 118 women with vulvovaginal candidiasis.
`
`In clinical trials, topical amorolfine (5% nail lacquer and 0.25% cream) appeared
`to be well tolerated, with up to 5% of patients reporting minor symptoms. In
`patients using the nail lacquer, these events included burning, itching, redness
`and local pain which were tolerable and confined to the site of application. Ad-
`ditional events of scaling, weeping, blistering and oedema were also described
`for the cream. A similar adverse event profile was reported for both the alcohol
`solution and vaginal tablets.
`
`Amorolfine 5% nail lacquer should be applied to the affected nail once or twice
`weekly. Treatment should be continued without interruption until the nail has
`regenerated and affected areas are cured. This may require up to 6 months of
`treatment for fingernails and between 9 and 12 months for toenails.
`Amorolfine 0.25% cream should be applied to affected skin areas once daily
`for up to 6 weeks. Therapy should be continued until clinical cure is achieved,
`and for several days thereafter.
`
`Amorolfine is a morpholine derivative which is
`structurally distinct from other currently available
`antifungals (fig. 1). It has been developed as a top-
`ical agent for the treatment of onychomycosis and
`other superficial mycoses. Amorolfine acts primar-
`
`H CH3
`
`CH3
`
`q ?CH2OHCH2~ ICH2CH3
`
`I
`
`~ CH3
`
`d \\ I
`
`ily by inhibiting ergosterol biosynthesis, a compo-
`nent of fungal cell membrane, and possesses both
`fungistatic and fungicidal activity. Throughout this
`review the nomenclature used for the various fun-
`gal infections discussed follows the recommenda-
`tions of the International Society for Human and
`Animal Mycology ( 1992).11]
`
`I. Antifungal Activity
`
`1,1 In Vitro Studies
`
`I. I. I Fungistatic Activity
`Antifungal susceptibility tests generally pro-
`vide limited clinically useful data regarding the
`
`’,,
`H CH3
`
`OH3
`
`Fig. 1. Structural formula of amorolfine.
`
`© Adis International Limited, All rights reserved,
`
`Drugs 49 (1) 1995
`
`Page 3
`
`

`

`106
`
`Haria & Bryson
`
`susceptibility of an isolated organism from a pa-
`tient to a particular antifungal agent.[2] The reli-
`ability of in vitro testing is hampered by various
`factors including the lack of interlaboratory repro-
`ducibility. Minimum inhibitory concentration
`(MIC) values depend heavily on experimental con-
`ditions such as the medium used, pH, inoculum size
`and duration of incubation. Moreover, correlation
`between in vitro susceptibility and clinical efficacy
`is extremely variable.[3] Nevertheless, in vitro tests
`may provide preliminary data on antifungal activ-
`ity, although the results of comparative studies
`should be interpreted cautiously.
`Traditional susceptibility tests show that
`amorolfine possesses in vitro activity against a
`wide range of pathogenic fungi (table I). Available
`data have been collated from various studies using
`a variety of experimental conditions. Of the species
`tested, the most susceptible are dermatophyte and
`dimorphic fungi. The activity of amorolfine against
`yeasts and moulds is more variable, and it is gen-
`erally less active against these organisms. Al-
`though various studies have directly compared the
`activity of amorolfine with other antifungal agents,
`relevant comparisons of in vitro activity between
`all the agents tested cannot be made from
`summarised MIC values alone.
`The combination of amorolfine with griseo-
`fulvin, ketoeonazole, itraconazole or terbinafine
`resulted in a slight increase in fungistatic activity
`(as assessed by MIC values) in comparison with
`amorolfine alone. Of the organisms tested, this
`finding was consistent only for dermatophytes, but
`not yeasts.[11]
`The ability of fungi such as Candida albicans to
`exhibit structural dimorphism, i.e. to grow either
`as a budding yeast or as an elongated mycelium, is
`of importance when considering its pathogenicity.
`Of the 2 available morphological forms, the hyphal
`form appears to possess greater virulence than the
`yeast form, although both are generally present
`within an infected lesion. In vitro MIC assessments
`of antifungal activity during germ tube formation
`(the primary stage in the development of hyphae)
`may reflect in vivo efficacy more closely than con-
`
`Table I. Summary of the in vitro activity of
`pathogenic and opportunistic fungi[4"9]
`
`amorolfine against
`
`Organism
`
`Dermatophyte fungi
`Trichophyton mentagrophytes
`T. rubrum
`
`Epidermophyton floccosum
`
`Microsporum canis
`
`M. gypseum
`
`Filamentous fungi (moulds)
`Aspergillus fumigatus
`
`A. flavus
`
`A. niger
`
`A. nidulans
`Acremonium spp.
`
`Fusarium spp.
`
`Scopulanopsis brevicaulis
`Scytalidium spp.b
`
`Pathogenic yeasts
`Candida albicans
`C. glabrata (T. glabrata)
`
`C. guilliermondii
`
`C. krusei
`C. parapsi!osis
`
`C. tropicalis
`
`Cryptococcus neoformans
`
`Pityrosporum spp. ( Malassezia spp.)
`
`Dimorphic fungi
`Blastomyces dermatitidis
`Histoplasma capsulatum
`Sporothrix schenckii
`
`MIC range
`(rag/L)a
`
`0.001-0.13
`
`<0.001-0.13
`0.003-6.2
`
`0.001-0.13
`0.01-0.13
`
`16->128
`
`30->128
`
`3->100
`
`3->100
`
`0.25-2
`
`0.3-100
`
`0.03-5
`
`0.1 - 1
`
`0.001 ->100
`0.06->100
`
`0.1-2
`
`0.05-10
`
`0.02-100
`
`0.001->100
`
`<0.001-8
`
`0.005-0.5
`
`O. 13-0.5
`
`0.063
`0.63-0.5
`
`Dematiaceous fungi
`Phaeohyphomycosis complexc
`Chromoblastomycosis complexd
`
`0,63-0.25
`0.13-> 128
`a Commonly used culture media for antifungal tests include
`Casitone agar/broth,[4,s,7] Kimmig’s agar,[6,8] Sabourand’s
`agarN and Dixon’s agar[9]. MIC values generally determined
`by agar dilution methods. Incubated at 28, 30 or 37°C for 2
`to 7 days.
`
`b Data taken from a review by Polak.[lo]
`c Exophiala jeanselmeL Wangiella dermatitidis, Ciadosporium
`bantianum.
`
`d Fonsecaea pedrosoL Phialophora verrucosa.
`
`Abbreviation: MIC = minimum inhibitory concentration.
`
`ventional MIC values.[]21 These latter tests primar-
`ily target yeast forms and do not take the dimorphic
`nature of this organism into account. In this re-
`spect, the antifungal activity of amorolfine ap-
`
`© Adis International Limited. All rights reserved,
`
`Drugs 49 (1) 1995
`
`Page 4
`
`

`

`Amorolfine: A Preliminary Review
`
`107
`
`peared greater than that of terbinafine or flucon-
`azole, but comparable to itraconazole, miconazole
`or econazole, and lower than clotrimazole or keto-
`conazole.[t2]
`To improve both thepredictive value and repro-
`ducibility of classical in vitro tests, various other
`methods have also been proposed, all of which use
`criteria other than MIC values to assess antifungal
`susceptibility.[2] One method calculates the area of
`a given sector under an antifungal dose-response
`curve and expresses this as a percentage of the
`dose-response curve of a theoretical noninhibitory
`drug; the value obtained is the relative inhibition
`factor (RIF).[13] For drugs that are noninhibitory
`this value approaches 100%, but for highly active
`agents RIF approaches 0%. Antifungat RIF values
`are calculated by measuring fungal adenosine tri-
`phosphate (ATP) concentrations in tissue culture
`mediums.[141 Under these conditions, amorolfine
`showed greater activity against dermatophytes
`than Candida or Aspergillus spp. with mean re-
`spective RIF values of 29, 67 and 93%.[13j In gen-
`eral, these values were comparable with those ob-
`tained for topical azole antifungals (including
`clotrimazole, econazole, miconazole, bifonazole)
`in terms of activity against Candida and dermato-
`phytes; amorolfine, however, was less active than
`the azole antifungals against Aspergillus spp.
`Spectrophotometric assays of yeast growth rel-
`ative to control growth also produce highly repro-
`ducible values which may allow the clinical sus-
`ceptibility of an organism to an antifungal to be
`predicted. Relative growth is inversely related to
`the relative susceptibility of an organism to an in-
`hibitor, such that the greater the percentage value
`for a given isolate the lower the susceptibility of
`that isolate to the agent tested.[23 Using in vitro
`microdilution plate cultures with amorolfine at a
`concentration of 13 rag/L, preliminary findings in-
`dicate that of the Candida spp. assessed, C. al-
`bicans was the least susceptible to amorolfine (rel-
`ative growth = 70%) whereas C. krusei was the
`most susceptible (=10%). Furthermore, relative
`growth data thus obtained correlated well with
`MIC values.
`
`The susceptibility of yeasts to antifungal agents
`may be influenced by changes in incubation tem-
`perature. In the case of amorolfine, an increase in
`temperature from 25 to 37°C lowered the suscep-
`tibility of C. albicans and C. tropicalis, but not of
`C. glabrata, C. krusei or C. tropicalis as assessed
`by relative growth values.[15] These in vitro find-
`ings may reflect in vivo clinical efficacy; certainly
`the topical efficacy of amorolfine is greater than its
`systemic efficacy in deep organs at temperatures of
`37oc.[16]
`
`I. 1.2 Fungicidal Activity
`The fungicidal activity of an agent (i.e. the abil-
`ity of that drug to kill fungi) depends on both the
`concentration of drug and the duration of contact;
`lower drug concentrations may be fungicidal with
`longer contact. Of the organisms tested (Tricho-
`phyton mentagrophytes, C. albicans, Histoplasma
`capsulatum and Cryptococcus neoformans), amorol-
`fine showed greatest fungicidal activity against T.
`mentagrophytes; respective concentrations of
`amorolfine required for 90% killing of these fungi
`after a 48-hour incubation period on casitone me-
`dium were:0.001, 1, 1.7 and 30 mg/L. At 24 hours,
`90% killing was achieved with corresponding con-
`centrations of 3, 3, 10 and 100 mg/L.[161
`
`1.2 In Vivo Studies
`
`The therapeutic efficacy of amorolfine is limi-
`ted to superficial fungal infections such as derma-
`tomycoses and vaginal candidiasis. Despite its in
`vitro activity against various fungi, animal test
`models indicate that amorolfine is inactive when
`given systemically for life-threatening myco-
`ses.[ 16] This lack of systemic activity has been pos-
`
`tulated to result from rapid metabolism or exten-
`sive protein binding.[16] Other factors such as
`higher internal temperatures of 37°C may also
`lower the susceptibility of some organisms to
`amorolfine (section 1.1.1).
`In guinea-pigs cutaneously infected with T.
`mentagrophytes, fungal foci were cleared by topi-
`cal application of amorolfine for 11 days.[161 Effi-
`cacy was assessed by 2 parameters: a reduction in
`lesion severity or an increase in the number of my-
`
`© Adis international Limited. All rights reserved,
`
`Drugs 49 (t) 1995
`
`Page 5
`
`

`

`108
`
`Haria & Bryson
`
`cosis-free animals. On a concentration basis,
`amorolfine showed greater activity than naftifine,
`oxiconazole, ketoconazole, bifonazole and clo-
`trimazole, but lower activity than terbinafine when
`treatment was initiated 6 hours after infection (be-
`fore fungal foci are visible); at respective amorol-
`fine and terbinafine concentrations of 0.01 and
`0.001%, all animals were free of fungal lesions.
`Higher concentrations ranging from 0.03 to 1%
`were required to produce comparable effects for
`the other agents tested above. Similar results were
`also observed when treatment was delayed to 3
`days after infection (as lesions became visible); al-
`though foci were completely cleared by topical
`amorolfine 0.03% and terbinafine 0.1%, the latter
`was more effective in reducing the lesion
`score [10,16]
`Studies in the rat indicate that topical amorol-
`fine may also be useful in the treatment of vaginal
`candidiasis. Efficacy was assessed by reductions in
`vaginal yeast cell counts of C. albicans. Twice
`daily intravaginal application of amorolfine, with
`concentrations starting at 0.01% for 3 days, pro-
`duced a dose dependent log reduction in cel! count;
`a concentration of 1% cleared the vagina of C. al-
`bicans completely.UOJ6]
`
`1.3 Other Effects
`
`Modifications in processes such as phagocyto-
`sis and intracellular killing of fungi by antifungal
`agents may be favourable and enhance fungal
`death. Using a neutrophil monolayer assay, in vitro
`data suggest that amorolfine does not affect neutro-
`phil phagocytosis, or affect fungal cell wall biosyn-
`thesis in a manner which enhances attachment of
`fungi to neutrophil membranes.[17] Activation of
`other neutrophil functions such random migration
`and chemotaxis were, however, inhibited in an-
`other study.J18]
`The ability of fungi such as C. albicans to ad-
`here to host cells, prosthetic devices or catheters is
`a major factor in the pathogenesis of infection. In-
`cubation of C. albicans for 18 to 24 hours with
`amorotfine 2.5 mg/L produced a significant dose
`dependent reduction in adherence properties; this
`
`effect was not observed after shorter incubation
`times of 10 minutes to 2 hours. At these respective
`times, adherence values of 13 and 52% were noted
`for C. albicans.[18,191
`
`1,4 Mechanism of Action
`
`The fungistatic or fungicidal activity of amorol-
`fine depends primarily on its ability to inhibit the
`formation of ergosterol, a component of the fungal
`cell membrane.U°] Alterations in membrane sterol
`content lead to changes in membrane permeability
`which subsequently affect fungal metabolic pro-
`cesses. Within this sterol biosynthetic pathway,
`amorolfine interferes with 2 enzymes, A~4-reduc-
`tase and A7AS-isomerase, leading to depletion of
`ergosterol (fig. 2).[2°] These effects are both time
`arid concentration dependent; observed changes in
`sterol patterns correlate with inhibition of fungal
`growth. Although amorolfine exhibits significantly
`higher affinity for the isomerase than the reductase
`enzyme as seen by their respective ICso (concen-
`tration producing 50 % inhibition) values of 0.0018
`versus 2.93/.tmol/L in Saccharomyces cerevisiae (a
`nonpathogenic yeast), the earlier position of the re-
`ductase enzyme within this pathway gives it
`greater importance. At a molecular level, amorolf-
`ine does not primarily affect cellular respiration or
`synthesis of DNA, RNA, protein or carbohydrate
`at inhibitory drug concentrations.[1°]
`Secondary damage within fungal cell ultrastruc-
`ture arising from membrane disruption by inhibi-
`tion of ergosterol formation has been demonstrated
`in vitsv by electron microscopy. At concentrations
`of 0.1 to 100 rag/L, amorolfine produces varying
`degrees of damage within nuclei, mitochondria,
`cytoplasm, cytoplasmic membrane and cell wall of
`both T. mentagrophytes and C. albicans.[21] The
`resulting loss of essential physiological activity
`may ultimately lead to inhibition of growth or cell
`death. In T. mentagrophytes these effects were ap-
`parent at lower concentrations of amorolfine 0.08
`mg/L.[221 Similar effects have also been described
`for other agents such as terbinafine[23] and oxi-
`conazole.[24]
`
`© Adis International Limited, All rights reserved.
`
`Drugs 49 [1 ) 1995
`
`Page 6
`
`

`

`Amorolfine: A Preliminary Review
`
`109
`
`chomycosis and superficial dermatomycoses. Al-
`though the efficacy of an alcohol aerosol solution
`and vaginal tablets has been assessed in small pa-
`tient numbers, pharmacokinetic data are not avail-
`able for these preparations.
`
`2,1 Nail Tissue Penetration
`
`Historically, topical therapy for onychomycosis
`has met with little success, due in part, to poor
`penetration of the antifungal agent into nail tissue.
`In humans, the pharmacokinetics of amorolfine
`penetration follow an exponential relationship be-
`tween drug concentration and nail layer. Although
`highest in vitro amorolfine concentrations (0.96 to
`6.68 gg/mg) were observed in the uppermost layer
`of the nail, some microbiological activity (>0.06
`gg/mg) was also measurable in lower nail lay-
`ers.[25] Amorolfine concentrations in pretreated
`nail slices, measured by inhibiting the growth of C.
`albicans, further demonstrate that its penetration
`through human nail is dependent on the nail con-
`dition, such that soft diseased nails will retain less
`drug than hard compact nails.[25] While the amount
`of amorolfine present within the nail may be
`readily measured using this technique, these re-
`sults do not indicate whether the concentration
`measured is freely available to inhibit fungi or
`whether it is bound to keratinised tissue.[25]
`In vitro permeation of amorolfine through hu-
`man nail has also been assessed by measuring
`amorolfine flux through nails mounted within dif-
`fusion chambers.[26! Results thus obtained suggest
`that sufficient concentrations of amorolfine are
`available in both the nail plate and bed to give fun-
`gistatic and fungicidal concentrations against some
`species, such as dermatophyte and dimorphic fungi
`(sections 1.1 and 1.2). After a single application of
`nail lacquer (formulated with methylene chloride),
`permeation rates of [3H]amorolfine 5% through
`the thumbnail ranged from 20 to 100 gg/L/h (vs
`100 to 200 gg/L/h through human trunk skin); peak
`rates of 100 gg/L/h occurred between 5 to 25 hours
`after a single application. [26] A comparable profile
`was observed after multiple applications over a pe-
`riod of 8 days. Although toenails were assessed in
`
`./ T7
`I i
`I__ ;/
`
`t’ . 1-i I,, "’-(.~1").::1~,:. "4 ", ! x .’, \..~ , /-../~, .,N,- i"~i’ ,- ~’11 ~:.’1.-:,:.,
`
`/ ..L/1
`,: - E:(’~i u 0’.,~,/.
`
`[//
`
`’.. : :. ri,.-.k.: I,~ ... .~-,’ .,,’ ~.’,_,,’,,,’,..,,’,../ / . "’.,- ,,,\,- Arneroll"ine
`
`.d_’I’Pl ! 5 f.~..i
`
`..... i//
`
`".. -’ ¯ :>." ." ;:..r,! -.i
`
`~’91- ,/ *%/".." /,/’-" ix/,/-’.. AlllOr.o.IIilqe
`
`T . "Ii
`
`~’-’:10~’1’:?10
`
`ii
`
`¯ Y
`
`Fig. 2. Sterol biosynthetic pathway in fungi, showing the steps
`at which amorolfine, terbinafine and azole antifungals inhibit
`enzymes.
`
`2. Pharmacokinetic Properties
`
`At present, only two topical preparations of
`amorolfine (5% nail lacquer and 0.25% cream) are
`commercially available for the treatment of ony-
`
`© Adis International Limited, ALl rights reserved,
`
`Drugs 49 (1) 1995
`
`Page 7
`
`

`

`110
`
`Haria & Bryson
`
`this study, available data do not clarify whether
`similar concentrations to those permeating through
`thumbnails also penetrate through toenails.
`Penetration rates through the nail may also be
`vehicle dependent. In vitro permeation of amorol-
`fine was consistently lower with an ethanol vehicle
`in comparison with methylene chloride, but greater
`with penetration enhancers such as dimethyl sul-
`foxide (DMSO).[26] These differences, however,
`were not apparent in vivo. The use of two amorol-
`fine 5% lacquer formulations (ethanol vs methy-
`lene chloride) in 34 patients with mild disease pro-
`duced comparable responses in terms of fungal
`inhibition zones.[27] Whether these preparations
`will have a similar effect on infections deeply
`seated in the nail plate is, however, unclear. It
`should be noted that commercially available
`amorolfine 5% nail lacquer is formulated with a
`methylene chloride base.
`
`2.2 Percutaneous Absorption and
`Cutaneous Retention
`
`Available data suggest that the mean percutane-
`ous absorption of [t4C]amorolfine 0.25% cream
`applied to healthy skin (left intact or stripped) is
`unlikely to exceed 10%.[28] Following a single ap-
`plication in 12 volunteers, recovery of radioactive
`amorotfine from occlusive dressings and skin strip-
`pings were comparable in all subjects. In addition,
`the highest levels of radioactivity were observed
`within the topmost layer of the stratum comeum.
`After application, absorbed radioactive amorolfine
`was slowly eliminated via the urine and faeces over
`a period of 3 weeks; in all plasma samples, measur-
`able quantities of intact drug were <0.5 gg/L. Thus,
`although only small amounts of amorolfine appear
`to be absorbed through the skin, it is uncertain
`whether multiple doses will significantly affect this
`profile.
`In the guinea-pig, the cutaneous retention time
`of a single topical dose of amorolfine cream 0.5%
`was measured by infecting pretreated skin with
`fungus spores after 24 to 96 hours. The protective
`effect of amorolfine increased as the interval be-
`tween pretreatment and fungal challenge de-
`
`creased. Within this experimental model, the ap-
`pearance of fungal loci were delayed for 16 days
`when fungal spores were administered 24 hours af-
`ter amorolfine treatment.[29] Even after 96 hours,
`the cutaneous persistence of amorolfine prevented
`the appearance of foci for approximately 10 days.
`The persistence of amorolfine 0.5% cream or
`alcohol solution within human skin has also been
`assessed in 6 volunteers. After a single application
`of the cream, inhibition of dermatophyte growth
`(Trichophyton spp.) was observed in treated skin
`strippings for up to 48 hours; a corresponding value
`of up to 3 days was obtained for the alcohol solu-
`tion.[3°] While these results support once daily top-
`ical application of amorolfine, the effect of dis-
`eased skin on the retention properties of amorolfine
`requires investigation.
`
`3. Therapeutic Potential
`
`The therapeutic efficacy of various topical prep-
`arations of amorolfine (nail lacquer, cream and
`spray) have been evaluated in patients with ony-
`chomycosis and superficial dermatomycoses.
`Topical agents are generally recommended only for
`superficial localised mycoses; widespread or in-
`tractable fungal infections require systemic ther-
`apy. Additionally, systemic therapy is usually re-
`quired for fungal infections of the nail and scalp,
`whereas other infections (including tinea pedis)
`may show adequate responses to topical ther-
`apy.I31,32] In this context, it is important to bear in
`mind that available clinical trial data within these
`therapeutic areas rarely include long term follow-
`up, and thus current recommendations are based
`primarily upon clinical experience.[311 Other topi-
`cal amorolfine preparations such as vaginal tablets
`have also been assessed in patients with vulvovagi-
`nal candidiasis.
`
`3,10nychomycosis
`
`Fungal infections of the nail account for more
`than 90% of nail infections and represent about
`30% of all superficial fungal infections.J331 Ony-
`chomycosis is especially prevalent in adults and
`the elderly but relatively infrequent in children. In-
`
`© Adis International Limited, All rights reserved.
`
`Drugs 49 (1) 1995
`
`Page 8
`
`

`

`Amorolfine: A Preliminary Review
`
`111
`
`Table II. Various clinical presentations of onychomycosis[3436]
`
`Form of onychomycosis
`
`Clinical features
`
`Distal and lateral subungual
`
`Superficial white
`
`Proximal subungual
`
`Total dystrophic
`
`Commonest form. Invasion of the undersurface of nail plate starts at distal
`edge and side of nail plate, and progresses to proximal end of nail. The
`nail plate thickens and becomes friable as the infection becomes
`established
`Uncommon and mainly seen in toenails. Fungal invasion of the superficial
`surface of the nail plate alone occurs. White ’islands’ Of infection may be
`easily removed by scraping nail
`
`Uncommon. Proximal invasion of the nail plate occurs usually secondary
`to chronic paronychia. In dermatophyte infections the subungual nail plate
`is also affected; fungal invasion may extend distally and involve all nail
`layers
`
`Occurs as a result of any of the above 3 types, or may be associated with
`chronic mucocutaneous candidiasis. The entire nail plate is destroyed,
`leaving a thickened and abnormal nail bed
`
`Causative organism
`
`Trichophyton spp., E.
`floccosum, S. brevicaulis, S.
`dimidiatum
`
`T. mentagrophytes,
`
`Acremonium s pp.
`
`C. albicans, T. rubrum
`
`fections may arise from invasion of healthy nail or
`may be secondary to pre-existing nail disease or
`tinea pedis (athlete’s foot). Clinical onychomyco-
`sis is defined by the method in which fungal inva-
`sion of the nail occurs; 4 main types are recognised
`(table II). Of the organisms implicated, dermato-
`phytes (Trichophyton spp. and Epidermophyton
`floccosum) are the most common, yeasts (in partic-
`ular C. albicans) are the second most frequent
`pathogen, whereas nondermatophyte infections
`from moulds such as Scopulariopsis brevicaulis,
`Scytalidium dimidiatum (previously known as
`Hendersonula toruloidea), S. hyalinum, Aspergil-
`lus or Fusarium spp. are relatively rare and these
`organisms are generally considered to be second-
`ary invaders of previously damaged nails (table
`III). The prevalence of specific organisms is also
`dependent upon geographical location.[34,35,381
`Although not considered a serious health risk,
`onychomycosis is a chronic infection and difficult
`to eradicate completely. Cure rates for toenail in-
`fections are especially l