Drug Profile
Efinaconazole (Jublia) for the treatment of onychomycosis Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/02/14 For personal use only.
Expert Rev. Anti Infect. Ther. 12(7), 743–752 (2014)
Aditya K Gupta*1,2 and Fiona C Simpson1 1 Mediprobe Research Inc., 645 Windermere Rd., London, ON, Canada 2 Department of Medicine, University of Toronto, Toronto, ON, Canada *Author for correspondence: Tel.: +1 519 851 9715 Fax: +1 519 657 4233 [email protected]
Efinaconazole 10% nail solution (Jublia) is a new topical triazole antifungal designed for the topical treatment of distal and lateral subungual onychomycosis. It inhibits ergosterol biosynthesis enzyme sterol 14a-demethylase. Efinaconazole has lower minimum inhibitory concentrations than terbinafine, ciclopirox, itraconazole and amorolfine in Trichophyton rubrum, Trichophyton mentagrophytes and Candida albicans. The solution based formula has low surface tension and keratin binding properties that increase penetrance through the nail plate. Safety studies have shown that this formulation is not associated with atopic dermatitis or contact sensitivity. Duplicate Phase III clinical trials in adults with mild to moderate distal and lateral subungual onychomycosis indicate that efinaconazole 10% solution is an effective therapy with a pooled complete cure rate of 17% and a pooled mycological cure rate of 54%. Efinaconazole 10% nail solution is a safe and effective new topical therapy for onychomycosis, which will fill a pressing need for more effective topical therapy in this disease. KEYWORDS: azole • dermatophyte • efinaconazole • non-dermatophyte mold • onychomycosis
Onychomycosis is the most widely diagnosed podiatric condition and is estimated to affect 4.3% of the population in North America and Europe [1]. Onychomycosis is caused by infection of the nail apparatus by dermatophytes, yeasts and non-dermatophyte molds [2–4]. Onychomycosis may result in nail discoloration, thickening, hyperkeratosis and onycholysis [4,5]. Nail plate disfigurement may lead to impaired quality of life, as patients may be embarrassed by their nails [6]. There is a significant population of individuals who are susceptible to onychomycosis due to age, peripheral vascular disease, diabetes and immunosuppression [7–12]. These individuals are also more likely to be at risk from complications like diabetic foot syndrome caused by onychomycosis [8]. Onychomycosis should be treated as an infectious medical disorder, not a cosmetic problem, as many individuals develop chronic infections that persist for years. There is a pressing need for new therapeutic options to treat onychomycosis. Many onychomycosis patients have conditions or preexisting drug regimens that contraindicate the use of oral antifungals due to adverse events and hepatic interactions. Topical therapy would be preferable in these patients, as topical treatments for onychomycosis have a low informahealthcare.com
10.1586/14787210.2014.919852
systemic absorption, which reduces the likelihood of systemic adverse events [13–15]. Overview of the market
The preferred therapy for onychomycosis is oral antifungals from the azole or allylamine drug classes. The current gold standard therapy for dermatophyte onychomycosis is oral terbinafine at 250 mg daily for 12 weeks [16,17]. The next therapy of choice is oral itraconazole or off-label oral fluconazole [17,18]. These therapies are widely considered to be the most effective from a medical and pharmacoeconomic stance [19], but all three therapies are associated with potential adverse events and drug–drug interactions [20]. There are three topical drugs approved for the treatment of onychomycosis. Ciclopirox 8% lacquer is approved in North America but requires concomitant toenail debridement to increase nail penetrance and has shown a low-to-moderate efficacy rate randomized, double-blind, multicenter, North American trials [13,21,22]. Amorolfine and bifonazole-urea are approved in the EU, but have similar efficacy profiles [14,23,24]. A new generation of topical antifungals has been specifically designed to increase transungual penetrance to increase the concentration of drug in the nail bed and matrix. This generation of compounds include efinaconazole,
2014 Informa UK Ltd
ISSN 1478-7210
743
Drug Profile
Gupta & Simpson
OH N
CH3 N
N N F
F
ciclopirox or amorolfine when incubated with keratin with unbound rates of 14.3, 0.7 and 1.9%, respectively [34]. Efinaconazole also has a higher release percentage of unbound drug at 46 versus 2.4% for ciclopirox and 9.6% for amorolfine [34]. The non-lacquer-based formulation was chosen to facilitate low surface tension to increase drug uptake. This formulation contains alcohol, cyclomethicones and esters. The esters were added to maintain the solubility of efinaconazole after the volatile alcohol, and cyclomethicone components had evaporated [35].
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/02/14 For personal use only.
Figure 1. Chemical structure of efinaconazole.
tavaborole, luliconazole, TDT-00X and NVC-422 [25–29]. These compounds have been designed as nail solutions or liposomes to increase nail plate permeability while retaining low systemic absorption. Introduction to the drug Chemistry
Efinaconazole is a triazole antifungal drug that was developed using SM-8668, a sulfonyl derivative, as a reference drug [30]. Efinaconazole is the (2R,3R) enantiomer of the 4-methylenepiperidene derivative of the 2-aryl-1-azolyl-3-(substituted amino acid)2-butanol derivative I series [30]. Its formal chemical names are 1-piperidineethanol, a-(2,4-difluorophenyl)-b-methyl-4-methylene-a-(1H-1,2,4-triazol-1-ylmethyl)-, aR,bR)- or (2R,3R)2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2, 4-triazol-1-yl)butan-2-ol [31]. The chemical structure is shown in FIGURE 1. Efinaconazole has the molecular formula C18H22F2N4O and a molecular weight of 348.39 [31]. Pharmacodynamics
Efinaconazole is a triazole antifungal that inhibits sterol 14ademethylase, an enzyme in the ergosterol biosynthesis pathway. Dose–response curves show that efinaconazole reduces the incorporation of radiolabeled [14C]acetate into 4-desmethylsterols (ergosterol), while increasing the amount of 4a-methylsterols, 4,4-dimethylsterols (lanosterol) and squalene in both Trichophyton rubrum and Candida albicans [32]. Efinaconazole was 4.9 times more active than itraconazole in inhibiting ergosterol synthesis in T. rubrum and 7.3 times more active than clotrimazole in C. albicans [32]. Scanning and transmission electron micrographs show significant cell wall damage with increasing concentrations of efinaconazole [32]. In in vitro antifungal susceptibility tests, efinaconazole showed lower minimum inhibitory concentration (MIC) than terbinafine, ciclopirox, itraconazole and amorolfine (TABLE 1) [33]. The MIC values for efinaconazole were comparatively lower than other antifungals in T. rubrum, Trichophyton mentagrophytes and C. albicans at 24 and 48 h [33]. Efinaconazole showed successful inhibition of clinical isolates of T. rubrum and T. mentagrophytes from the USA, Canada and Japan [33]. The topical formulation of efinaconazole 10% solution has a low keratin-binding profile and low surface tension. In vitro, efinaconazole had a higher percentage of unbound drug than 744
Pharmacokinetics & metabolism Absorption
Efinaconazole is a topical antifungal, so it has relatively low systemic accumulation. The mean maximum concentration was 0.67 ng/ml after 28 days of application [36,37]. The plasma halflife after 10 days of administration was 29.9 h [36,37]. In onychomycosis patients, efinaconazole and its H3 metabolite reached a steady-state concentration of 0.1–1.5 ng/ml and 0.2–7.1 ng/ml, respectively [36,37]. Distribution
Due to the low systemic absorption of efinaconazole, the binding of efinaconazole to plasma proteins is not expected to be clinically relevant. It has high plasma protein-binding affinity from 95.8 to 96.5%; primarily to albumin, a1-acid glycoprotein and g-globulin [36]. Metabolism
Efinaconazole is metabolized extensively through oxidative and reductive processes resulting in a sole H3 metabolite [36]. Efinaconazole may also undergo glucuronidation. Elimination
Efinaconazole does not have significant interactions with CYP450 enzymes in the liver. Studies in liver microsomes revealed that CYP2C8, CYP2C9, CYP2C19 and CYP3A4 were inhibited by efinaconazole at concentrations higher than the systemic concentrations achieved clinically [36]. The ratio of Cmax/ki is 0.007 for efinaconazole and 0.0005 for the H3 metabolite [37]. CYP2C9 is the most sensitive isoform and has a ki of 91 ng/ml, which is over 130 times the plasma concentration observed in Phase I studies [37]. Clinical efficacy Phase I studies
A Phase I study of efinaconazole was conducted in two studies in either healthy, adult volunteers or adults with severe onychomycosis (TABLE 2) [37]. In study 1, subjects were between the ages of 18 and 45 and were included in the study if they were considered generally healthy after a medical screening including a medical and medication history, physical exam, 12-lead EEG and clinical laboratory testing. The pharmacokinetic parameters of efinaconazole and its primary metabolite (H3) were evaluated after a single (day 1) or 7-day (day 4–10) application; no drug was applied on days 2 and 3. Each drug application was Expert Rev. Anti Infect. Ther. 12(7), (2014)
Efinaconazole (Jublia) for the treatment of onychomycosis
Drug Profile
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/02/14 For personal use only.
Table 1. Geometric mean minimum inhibitory concentration values from broth dilution testing. Species
Trichophyton rubrum
Trichophyton mentagrophytes
Candida albicans (24 h)
Epidermophyton floccosum
Microsporum canis
Fusarium oxysporum
Efinaconazole
0.003
0.005
0.0029
£0.005
0.18
1
Terbinafine
0.009
0.01
1.409
0.039
0.13
2.5
Ciclopirox
0.101
0.094
0.151
0.31
0.25
1
Itraconazole
0.037
0.063
0.014
0.08
0.35
>4
Amorolfine
0.008
0.009
0.0079
0.16
>4
>4
Data taken from [33].
conducted by a nurse or trained technician, who applied efinaconazole 10% solution to all 10 toenails each morning. The doses were 90 ml for the great toenails and 30 ml for the other nails, totaling 0.42 ml/subject. In study 2, subjects were between 18 and 70 years old with severe distal and lateral subungual onychomycosis (DLSO). The inclusion criteria for DLSO were confirmed by positive KOH microscopic evaluation of at least one great toenail. The
DLSO was required to affect ‡80% of both great toenails, with an additional four or more toenails infected. Efinaconazole 10% solution was applied daily by a nurse or study technician for 28 days. The outcome measures for both studies assessed plasma concentration and pharmacokinetic properties which are shown in TABLE 3. In both subject groups, efinaconazole and H3 showed minimal plasma accumulation and very low systemic exposure.
Table 2. Pharmacokinetic properties of efinaconazole and the H3 metabolite. Population
Drug
Parameter
Cmax (ng/ml)
Cmin (ng/ml)
tmax† (h)
AUC24 h (ng•h/ml)
t1/2 (h)
Healthy volunteers
Efinaconazole
Day 1
0.38 ± 0.39 (0.12–1.11)
0.05 (0–0.14)
24 (6–28)
2.64 ± 2.85 (0.47–7.31)
NC
Day 10
0.54 ±0.22 (0.25–0.85)
0.47 ± 0.18 (0.25–0.85)
10 (0–24)
9.48 ± 3.86 (4.89–15.78)
29.9 (29.9)‡
Day 1
0.44 ± 0.36 (0.15–1.31)
0.17 ± 0.23 (0–0.55)
48 (2–72)
5.65 ± 5.30 (0.41–12.4)
NC
Day 10
1.63 ± 0.80 (0.46–2.62)
1.54 ± 0.77 (0.39–2.62)
1 (0–28)
32.5 ± 14.7 (10–50)
82.42 ± 31.5 (46–134.9)
Day 1
0.23 ± 0.18 (0.0–0.67)
NC
23.92 (6.03-24.00)
1.79 ± 2.04 (0.30–7.05)
§
Day 14
0.62 ± 0.23 (0.14–0.99)
0.33 ± 0.17 (0.110–0.63)
4.55 (0.0–24.00)
10.29 ± 5.90 (0.39–19.54)
§
Day 28
0.67 ± 0.37 (0.18–1.47)
0.36 ± 0.20 (0.11–0.72)
16 (0.0–24.00)
12.15 ± 6.91 (1.46–25.25)
§
Day 1
0.09 ± 0.14 (0.0–0.44)
NC
23.92 (23.92–24.00)
1.50 ± 1.13 (0.06–0.361)
§
Day 14
2.20 ± 1.72 (0.58–7.45)
1.47 ± 1.27 (0.20–5.07)
1.00 (0.0–16.00)
40.03 ± 34.02 (7.42–141.49)
§
Day 28
2.36 ± 1.64 (0.53–5.55)
1.67 ± 1.17 (0.29–4.07)
0.00 (0.00–24.00)
45.80 ± 31.85 (8.53–113.40)
§
H3 metabolite
Severe onychomycosis
Efinaconazole
H3 metabolite
All values are presented as mean ± SD (range) where applicable. † Median. ‡ Evaluable in a single patient. § Not estimated due to flat plasma concentration–time curves for evaluable time period. NC: Not calculated. Data taken from [37].
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Drug Profile
Gupta & Simpson
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/02/14 For personal use only.
Table 3. Clinical trial outcome measure definitions. Outcome measure
Description
Mycological cure
Negative KOH and culture
Complete cure
0% nail plate involvement and mycological cure
Complete or almost complete cure
£5% clinical involvement and mycological cure
Treatment success
Efinaconazole (Jublia) for the treatment of onychomycosis Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/02/14 For personal use only.
Expert Rev. Anti Infect. Ther. 12(7), 743–752 (2014)
Aditya K Gupta*1,2 and Fiona C Simpson1 1 Mediprobe Research Inc., 645 Windermere Rd., London, ON, Canada 2 Department of Medicine, University of Toronto, Toronto, ON, Canada *Author for correspondence: Tel.: +1 519 851 9715 Fax: +1 519 657 4233 [email protected]
Efinaconazole 10% nail solution (Jublia) is a new topical triazole antifungal designed for the topical treatment of distal and lateral subungual onychomycosis. It inhibits ergosterol biosynthesis enzyme sterol 14a-demethylase. Efinaconazole has lower minimum inhibitory concentrations than terbinafine, ciclopirox, itraconazole and amorolfine in Trichophyton rubrum, Trichophyton mentagrophytes and Candida albicans. The solution based formula has low surface tension and keratin binding properties that increase penetrance through the nail plate. Safety studies have shown that this formulation is not associated with atopic dermatitis or contact sensitivity. Duplicate Phase III clinical trials in adults with mild to moderate distal and lateral subungual onychomycosis indicate that efinaconazole 10% solution is an effective therapy with a pooled complete cure rate of 17% and a pooled mycological cure rate of 54%. Efinaconazole 10% nail solution is a safe and effective new topical therapy for onychomycosis, which will fill a pressing need for more effective topical therapy in this disease. KEYWORDS: azole • dermatophyte • efinaconazole • non-dermatophyte mold • onychomycosis
Onychomycosis is the most widely diagnosed podiatric condition and is estimated to affect 4.3% of the population in North America and Europe [1]. Onychomycosis is caused by infection of the nail apparatus by dermatophytes, yeasts and non-dermatophyte molds [2–4]. Onychomycosis may result in nail discoloration, thickening, hyperkeratosis and onycholysis [4,5]. Nail plate disfigurement may lead to impaired quality of life, as patients may be embarrassed by their nails [6]. There is a significant population of individuals who are susceptible to onychomycosis due to age, peripheral vascular disease, diabetes and immunosuppression [7–12]. These individuals are also more likely to be at risk from complications like diabetic foot syndrome caused by onychomycosis [8]. Onychomycosis should be treated as an infectious medical disorder, not a cosmetic problem, as many individuals develop chronic infections that persist for years. There is a pressing need for new therapeutic options to treat onychomycosis. Many onychomycosis patients have conditions or preexisting drug regimens that contraindicate the use of oral antifungals due to adverse events and hepatic interactions. Topical therapy would be preferable in these patients, as topical treatments for onychomycosis have a low informahealthcare.com
10.1586/14787210.2014.919852
systemic absorption, which reduces the likelihood of systemic adverse events [13–15]. Overview of the market
The preferred therapy for onychomycosis is oral antifungals from the azole or allylamine drug classes. The current gold standard therapy for dermatophyte onychomycosis is oral terbinafine at 250 mg daily for 12 weeks [16,17]. The next therapy of choice is oral itraconazole or off-label oral fluconazole [17,18]. These therapies are widely considered to be the most effective from a medical and pharmacoeconomic stance [19], but all three therapies are associated with potential adverse events and drug–drug interactions [20]. There are three topical drugs approved for the treatment of onychomycosis. Ciclopirox 8% lacquer is approved in North America but requires concomitant toenail debridement to increase nail penetrance and has shown a low-to-moderate efficacy rate randomized, double-blind, multicenter, North American trials [13,21,22]. Amorolfine and bifonazole-urea are approved in the EU, but have similar efficacy profiles [14,23,24]. A new generation of topical antifungals has been specifically designed to increase transungual penetrance to increase the concentration of drug in the nail bed and matrix. This generation of compounds include efinaconazole,
2014 Informa UK Ltd
ISSN 1478-7210
743
Drug Profile
Gupta & Simpson
OH N
CH3 N
N N F
F
ciclopirox or amorolfine when incubated with keratin with unbound rates of 14.3, 0.7 and 1.9%, respectively [34]. Efinaconazole also has a higher release percentage of unbound drug at 46 versus 2.4% for ciclopirox and 9.6% for amorolfine [34]. The non-lacquer-based formulation was chosen to facilitate low surface tension to increase drug uptake. This formulation contains alcohol, cyclomethicones and esters. The esters were added to maintain the solubility of efinaconazole after the volatile alcohol, and cyclomethicone components had evaporated [35].
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/02/14 For personal use only.
Figure 1. Chemical structure of efinaconazole.
tavaborole, luliconazole, TDT-00X and NVC-422 [25–29]. These compounds have been designed as nail solutions or liposomes to increase nail plate permeability while retaining low systemic absorption. Introduction to the drug Chemistry
Efinaconazole is a triazole antifungal drug that was developed using SM-8668, a sulfonyl derivative, as a reference drug [30]. Efinaconazole is the (2R,3R) enantiomer of the 4-methylenepiperidene derivative of the 2-aryl-1-azolyl-3-(substituted amino acid)2-butanol derivative I series [30]. Its formal chemical names are 1-piperidineethanol, a-(2,4-difluorophenyl)-b-methyl-4-methylene-a-(1H-1,2,4-triazol-1-ylmethyl)-, aR,bR)- or (2R,3R)2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2, 4-triazol-1-yl)butan-2-ol [31]. The chemical structure is shown in FIGURE 1. Efinaconazole has the molecular formula C18H22F2N4O and a molecular weight of 348.39 [31]. Pharmacodynamics
Efinaconazole is a triazole antifungal that inhibits sterol 14ademethylase, an enzyme in the ergosterol biosynthesis pathway. Dose–response curves show that efinaconazole reduces the incorporation of radiolabeled [14C]acetate into 4-desmethylsterols (ergosterol), while increasing the amount of 4a-methylsterols, 4,4-dimethylsterols (lanosterol) and squalene in both Trichophyton rubrum and Candida albicans [32]. Efinaconazole was 4.9 times more active than itraconazole in inhibiting ergosterol synthesis in T. rubrum and 7.3 times more active than clotrimazole in C. albicans [32]. Scanning and transmission electron micrographs show significant cell wall damage with increasing concentrations of efinaconazole [32]. In in vitro antifungal susceptibility tests, efinaconazole showed lower minimum inhibitory concentration (MIC) than terbinafine, ciclopirox, itraconazole and amorolfine (TABLE 1) [33]. The MIC values for efinaconazole were comparatively lower than other antifungals in T. rubrum, Trichophyton mentagrophytes and C. albicans at 24 and 48 h [33]. Efinaconazole showed successful inhibition of clinical isolates of T. rubrum and T. mentagrophytes from the USA, Canada and Japan [33]. The topical formulation of efinaconazole 10% solution has a low keratin-binding profile and low surface tension. In vitro, efinaconazole had a higher percentage of unbound drug than 744
Pharmacokinetics & metabolism Absorption
Efinaconazole is a topical antifungal, so it has relatively low systemic accumulation. The mean maximum concentration was 0.67 ng/ml after 28 days of application [36,37]. The plasma halflife after 10 days of administration was 29.9 h [36,37]. In onychomycosis patients, efinaconazole and its H3 metabolite reached a steady-state concentration of 0.1–1.5 ng/ml and 0.2–7.1 ng/ml, respectively [36,37]. Distribution
Due to the low systemic absorption of efinaconazole, the binding of efinaconazole to plasma proteins is not expected to be clinically relevant. It has high plasma protein-binding affinity from 95.8 to 96.5%; primarily to albumin, a1-acid glycoprotein and g-globulin [36]. Metabolism
Efinaconazole is metabolized extensively through oxidative and reductive processes resulting in a sole H3 metabolite [36]. Efinaconazole may also undergo glucuronidation. Elimination
Efinaconazole does not have significant interactions with CYP450 enzymes in the liver. Studies in liver microsomes revealed that CYP2C8, CYP2C9, CYP2C19 and CYP3A4 were inhibited by efinaconazole at concentrations higher than the systemic concentrations achieved clinically [36]. The ratio of Cmax/ki is 0.007 for efinaconazole and 0.0005 for the H3 metabolite [37]. CYP2C9 is the most sensitive isoform and has a ki of 91 ng/ml, which is over 130 times the plasma concentration observed in Phase I studies [37]. Clinical efficacy Phase I studies
A Phase I study of efinaconazole was conducted in two studies in either healthy, adult volunteers or adults with severe onychomycosis (TABLE 2) [37]. In study 1, subjects were between the ages of 18 and 45 and were included in the study if they were considered generally healthy after a medical screening including a medical and medication history, physical exam, 12-lead EEG and clinical laboratory testing. The pharmacokinetic parameters of efinaconazole and its primary metabolite (H3) were evaluated after a single (day 1) or 7-day (day 4–10) application; no drug was applied on days 2 and 3. Each drug application was Expert Rev. Anti Infect. Ther. 12(7), (2014)
Efinaconazole (Jublia) for the treatment of onychomycosis
Drug Profile
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/02/14 For personal use only.
Table 1. Geometric mean minimum inhibitory concentration values from broth dilution testing. Species
Trichophyton rubrum
Trichophyton mentagrophytes
Candida albicans (24 h)
Epidermophyton floccosum
Microsporum canis
Fusarium oxysporum
Efinaconazole
0.003
0.005
0.0029
£0.005
0.18
1
Terbinafine
0.009
0.01
1.409
0.039
0.13
2.5
Ciclopirox
0.101
0.094
0.151
0.31
0.25
1
Itraconazole
0.037
0.063
0.014
0.08
0.35
>4
Amorolfine
0.008
0.009
0.0079
0.16
>4
>4
Data taken from [33].
conducted by a nurse or trained technician, who applied efinaconazole 10% solution to all 10 toenails each morning. The doses were 90 ml for the great toenails and 30 ml for the other nails, totaling 0.42 ml/subject. In study 2, subjects were between 18 and 70 years old with severe distal and lateral subungual onychomycosis (DLSO). The inclusion criteria for DLSO were confirmed by positive KOH microscopic evaluation of at least one great toenail. The
DLSO was required to affect ‡80% of both great toenails, with an additional four or more toenails infected. Efinaconazole 10% solution was applied daily by a nurse or study technician for 28 days. The outcome measures for both studies assessed plasma concentration and pharmacokinetic properties which are shown in TABLE 3. In both subject groups, efinaconazole and H3 showed minimal plasma accumulation and very low systemic exposure.
Table 2. Pharmacokinetic properties of efinaconazole and the H3 metabolite. Population
Drug
Parameter
Cmax (ng/ml)
Cmin (ng/ml)
tmax† (h)
AUC24 h (ng•h/ml)
t1/2 (h)
Healthy volunteers
Efinaconazole
Day 1
0.38 ± 0.39 (0.12–1.11)
0.05 (0–0.14)
24 (6–28)
2.64 ± 2.85 (0.47–7.31)
NC
Day 10
0.54 ±0.22 (0.25–0.85)
0.47 ± 0.18 (0.25–0.85)
10 (0–24)
9.48 ± 3.86 (4.89–15.78)
29.9 (29.9)‡
Day 1
0.44 ± 0.36 (0.15–1.31)
0.17 ± 0.23 (0–0.55)
48 (2–72)
5.65 ± 5.30 (0.41–12.4)
NC
Day 10
1.63 ± 0.80 (0.46–2.62)
1.54 ± 0.77 (0.39–2.62)
1 (0–28)
32.5 ± 14.7 (10–50)
82.42 ± 31.5 (46–134.9)
Day 1
0.23 ± 0.18 (0.0–0.67)
NC
23.92 (6.03-24.00)
1.79 ± 2.04 (0.30–7.05)
§
Day 14
0.62 ± 0.23 (0.14–0.99)
0.33 ± 0.17 (0.110–0.63)
4.55 (0.0–24.00)
10.29 ± 5.90 (0.39–19.54)
§
Day 28
0.67 ± 0.37 (0.18–1.47)
0.36 ± 0.20 (0.11–0.72)
16 (0.0–24.00)
12.15 ± 6.91 (1.46–25.25)
§
Day 1
0.09 ± 0.14 (0.0–0.44)
NC
23.92 (23.92–24.00)
1.50 ± 1.13 (0.06–0.361)
§
Day 14
2.20 ± 1.72 (0.58–7.45)
1.47 ± 1.27 (0.20–5.07)
1.00 (0.0–16.00)
40.03 ± 34.02 (7.42–141.49)
§
Day 28
2.36 ± 1.64 (0.53–5.55)
1.67 ± 1.17 (0.29–4.07)
0.00 (0.00–24.00)
45.80 ± 31.85 (8.53–113.40)
§
H3 metabolite
Severe onychomycosis
Efinaconazole
H3 metabolite
All values are presented as mean ± SD (range) where applicable. † Median. ‡ Evaluable in a single patient. § Not estimated due to flat plasma concentration–time curves for evaluable time period. NC: Not calculated. Data taken from [37].
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Drug Profile
Gupta & Simpson
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/02/14 For personal use only.
Table 3. Clinical trial outcome measure definitions. Outcome measure
Description
Mycological cure
Negative KOH and culture
Complete cure
0% nail plate involvement and mycological cure
Complete or almost complete cure
£5% clinical involvement and mycological cure
Treatment success
