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British Journal of Dermatology 1999; 140: 96–101.

Continuous and intermittent itraconazole dosing schedules for


the treatment of onychomycosis: a pharmacokinetic comparison
V.HAVU, H.BRANDT*, H.HEIKKILĆ, A.HOLLMEN‡, R.OKSMAN, T.RANTANEN§,
S.SAARI, S.STUBB†, K.TURJANMAA¶ AND T.PIEPPONEN**
Turku University Central Hospital and Lääkäriasema Pulssi, Kiinamyllynkatu 8, FIN-20520, Turku, Finland
*Helsingin Lääkärikeskus, Helsinki, Finland
†Helsinki University Central Hospital, Helsinki, Finland
‡Vuorikadun Lääkäriasema, Kuopio, Finland
§Savonlinna Central Hospital, Savonlinna, Finland
¶Koskiklinikka, Tampere, Finland
**Department of Clinical Research, Janssen Research Foundation, Espoo, Finland
Accepted for publication 28 August 1998

Summary This multicentre, double-blind, randomized study compared the pharmacokinetics of itraconazole
given at 200 mg once daily for 3 months and intermittently at 200 mg twice daily for 1 week per
month followed by a 3-week drug-free period for 3 months in the treatment of onychomycosis.
Patients were followed for 9 months after treatment. Itraconazole and hydroxy-itraconazole plasma
concentrations and itraconazole nail tip concentrations were determined at regular intervals. With
intermittent therapy (n ¼ 64), increases of consistent magnitude were seen in the mean itraconazole
and hydroxy-itraconazole plasma concentrations at the end of each 1-week treatment phase; values
returned towards baseline during each subsequent 3-week drug-free period. The mean concentration
of itraconazole in fingernail tips increased steadily from week 4, reached a maximum value at week
24 (213 ng/g), declined sharply between weeks 24 and 36 and returned to baseline by week 48; the
mean concentration profile was similar for toenail tips (maximum value 305 ng/g at week 24) but
decreased at a slower rate. With continuous therapy (n ¼ 65), steady-state mean plasma concentra-
tions of itraconazole and hydroxy-itraconazole were obtained within 4–5 weeks of the start of
treatment and remained reasonably constant between weeks 4 and 12. The mean concentration of
itraconazole in fingernail tips reached a maximum value at week 12 (524 ng/g) and returned
towards baseline by week 48; in contrast, the maximum mean concentration of itraconazole in
toenail tips was 698 ng/g at week 36 and did not return to baseline by week 48. No clear relationship
was observed between response to treatment and concentration of itraconazole or hydroxy-
itraconazole in plasma or itraconazole in nails, suggesting that concentrations exceeded therapeutic
levels. In conclusion, intermittent therapy resulted in higher maximum itraconazole plasma
concentrations but lower total drug exposure, and hence lower itraconazole nail concentrations,
than continuous therapy. However, the intermittent schedule was not associated with a lower cure
rate, which indicates that itraconazole nail concentrations remained within the therapeutic range.

Key words: continuous and intermittent dosing, itraconazole, onychomycosis.

Onychomycosis, an infection of the nail caused by any antifungal agents for the treatment of onychomycosis.
fungus, including dermatophytes, yeasts and moulds, Itraconazole is a triazole-derived oral antifungal agent
most often manifests as the distal subungual type,1 with with a broad spectrum of antifungal activity in vitro and
the fungus usually invading the distal nail bed and in vivo, encompassing dermatophytes, yeasts and
possibly proceeding proximally in the nail bed or to moulds.5–11 Itraconazole has strong lipophilic proper-
the nail plate. Fungal nail infections are chronic and ties and a high affinity for keratinized tissue.12,13 Nail
recalcitrant to treatment2–4 and, as such, present a matrix kinetics have revealed that itraconazole can be
particular therapeutic challenge. Research has there- found in the distal part of the fingernail within 1 week of
fore been focused on the development of new, improved the start of therapy with 100 mg of itraconazole daily,

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ITRACONAZOLE DOSING FOR ONYCHOMYCOSIS 97

which suggests that itraconazole penetrates the nail not patients had received systemic antifungal therapy
only through the nail matrix but also through the nail within the 6 months or topical antifungal therapy
bed.12,14 In addition, therapeutic concentrations of within the 2 weeks before the start of the trial. Con-
itraconazole have been shown to persist in fingernails current use of other systemic or topical antifungal
for 3 months after treatment and in toenails for up to therapies, local corticosteroids, digoxin, oral anticoagu-
6 months after treatment.15 Itraconazole concentrations lants, terfenadine, cyclosporin A, H2-receptor antago-
detected in finger and toenail tips with itraconazole nists, cisapride, simvastatin or lovastatin, midazolam or
200 mg daily for 3 months were 10 times higher than triazolam, oral hypoglycaemic agents or enzyme-
those detected with itraconazole 100 mg daily for inducing drugs, such as rifampicin and phenytoin,
3 months and were associated with a better outcome. was not permitted. Patients were also excluded if they
The results of these pharmacokinetic studies led to had psoriasis, abnormal liver function or a serious
the suggestion that continuous therapy with itra- disease that might prevent completion of the trial.
conazole 200 mg daily for 3 months might not be Women were excluded if they were possibly pregnant
necessary to maintain therapeutic levels of itraconazole or lactating. The trial was performed in accordance with
in the nail. As a result, a new concept in the treatment the Declaration of Helsinki and its revisions. Ethics
of onychomycosis has emerged, namely intermittent committee approval was obtained, and patients gave
therapy with itraconazole 200 mg twice daily for their informed consent to participate.
1 week per month, followed by a 3-week drug-free
period, for 3 months. This novel intermittent itra-
Bioanalysis
conazole dosing schedule has been compared with the
conventional continuous itraconazole regimen in a Venous blood samples of 10 mL were collected at the
multicentre, double-blind, randomized, parallel-group, start of the study and at weeks 1, 4, 5, 8, 9 and 12 to
phase III trial; results from the efficacy and safety determine itraconazole and hydroxy-itraconazole
evaluation (reported previously)16 showed that the plasma concentrations using high-performance liquid
schedules were similarly safe, well tolerated and effec- chromatography (HPLC).17 Hydroxy-itraconazole, the
tive in the treatment of onychomycosis. Here, we main metabolite of itraconazole, has similar in vitro
present the results of assessments performed to investi- antifungal activity to itraconazole and may contribute
gate the pharmacokinetics of itraconazole during con- significantly to in vivo antifungal activity.13 The lower limit
tinuous and intermittent dosing. of quantification was 10 ng/mL for both compounds.
Distal nail clippings were collected from toenails and
fingernails at the start of the study and at weeks 4, 8,
Patients and methods 12, 24, 36 and 48 to determine itraconazole nail tip
concentrations using HPLC.17 The lower limit of quan-
Patients
tification for itraconazole in nails was a 2·0 ng/sample.
Patients were randomized to continuous therapy with Nails with entire distal parts missing or destroyed
itraconazole 200 mg daily for 3 months or intermittent (including the target toenail, which was used for the
therapy with itraconazole 200 mg twice daily for the mycological examination) were excluded. Mean concen-
first week of each month followed by a 3-week drug-free tration–time curves were constructed for itraconazole
period for 3 months. Patients also received placebo in plasma and nails, and for hydroxy-itraconazole in
capsules to maintain double-blind conditions. In both plasma, for both treatment schedules. No formal phar-
groups, the 3-month treatment phase was followed by a macokinetic parameters could be derived from these
9-month drug-free follow-up period. curves, because they were constructed from too few
Men and women aged 18–60 years with distal sub- sample points.
ungual onychomycosis of the toenails, confirmed by
microscopy and positive culture for a dermatophyte,
Statistical analysis
were included in the study. The involvement of at least
30% of the surface of one toenail was also required. The treatment groups were compared at baseline using
Concurrent onychomycosis of the fingernails or a fungal the Mann–Whitney U-test for age, weight and height
lesion of the pilose or glabrous skin, or both, were and the chi-squared test for sex. Blood sampling was not
optional. Patients were excluded if moulds or Candida always performed at the prescribed time points, so time
species were cultured in the nail samples or if the intervals were constructed around each time point. The

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98 V.HAVU et al.

Table 1. Boundaries of intervals used in the evaluation of the data

Time point (week) Interval boundaries (study days)

Lower Mid-point Upper

0 0 0 0
1 1 7 13
4 14 28 31
5 32 35 38
8 39 56 59
9 60 63 66
12 67 84 101
24 102 168 209
36 210 252 293
48 294 336 377

boundaries of these time intervals are given in Table 1.


Descriptive statistics were calculated for each treatment
group and time interval for itraconazole and hydroxy-
itraconazole concentrations in plasma and for
itraconazole concentrations in finger and toenails. A
subgroup analysis was performed for responders and
non-responders; response was defined as at least
markedly improved in the overall evaluation at the
end of the follow-up period.16

Results Figure 1. Plasma concentrations (mean 6 SEM) of (A) itraconazole


and (B) hydroxy-itraconazole during continuous treatment with
Patient characteristics and disposition itraconazole 200 mg once daily for 3 months and intermittent therapy
with itraconazole 200 mg twice daily for the first week of each month
Of the 129 patients recruited to the study, 65 patients followed by a 3-week drug-free period, for 3 months. *No intermittent
were assigned to continuous therapy and 64 patients therapy was administered during these weeks.
were assigned to intermittent therapy. No clinically
relevant differences were found between the treatment
groups in terms of patient and disease characteristics at
baseline.16 During the 3-month, double-blind treatment are presented in Figure 1. With the intermittent sche-
phase, one patient in the continuous therapy group and dule, increases of consistent magnitude were seen in the
three patients in the intermittent therapy group with- mean itraconazole and hydroxy-itraconazole plasma
drew because of adverse events. During the 9-month, concentrations at the end of each 1-week treatment
drug-free, follow-up period, one patient withdrew from phase (weeks 1, 5 and 9; mean ranges 1130–1416 ng/
the continuous therapy group because of abnormal mL and 2061–2402 ng/mL, respectively). By the end of
laboratory values and one patient withdrew from each each 3-week drug-free period (weeks 4, 8 and 12), the
treatment group because of insufficient response. In mean plasma concentrations of both itraconazole and
addition, a protocol deviation was noted in one patient hydroxy-itraconazole had returned towards baseline
in each treatment group; these patients failed to meet values in most patients. With the continuous schedule,
the selection criteria because they were culture negative plasma steady-state levels of itraconazole and hydroxy-
for a dermatophyte at the start of the trial. itraconazole were obtained within 4–5 weeks of the
start of treatment. The mean plasma concentrations of
both compounds remained reasonably constant
Plasma concentration–time profiles
between weeks 4 and 12, ranging from 842 to
Mean plasma concentration–time data for itraconazole 992 ng/mL for itraconazole and from 1446 to
and hydroxy-itraconazole for the two dosing schedules 1706 ng/mL for hydroxy-itraconazole.

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ITRACONAZOLE DOSING FOR ONYCHOMYCOSIS 99

Table 2. Itraconazole concentrations (mean 6 SD) in finger and toenail tips during continuous treatment with itraconazole 200 mg once daily for
3 months and intermittent therapy with itraconazole 200 mg twice daily for the first week of each month followed by a 3-week drug-free period, for
3 months

Itraconazole group

Continuous Intermittent
Time since
start of therapy No. of patients Concentration (ng/g) No. of patients Concentration (ng/g)

Fingernails

Week 0 9 13 6 39 11 59 6 112
Week 4 53 354 6 295 38 93 6 68
Week 8 52 443 6 285 40 118 6 71
Week 12 54 524 6 408 40 146 6 97
Week 24 40 334 6 288 34 213 6 341
Week 36 27 157 6 190 21 41 6 91
Week 48 17 97 6 234 19 6 6 15

Toenails

Week 0 6 30 6 73 4 060
Week 4 11 96 6 724 9 24 6 42
Week 8 27 179 6 100 15 124 6 95
Week 12 36 354 6 267 21 146 6 91
Week 24 39 524 6 335 27 305 6 245
Week 36 47 698 6 593 33 298 6 234
Week 48 22 419 6 472 21 154 6 144

Nail tip concentration–time profiles Concentration–response relationships


Mean finger and toenail tip concentration–time values In the group of patients receiving intermittent therapy,
for itraconazole for the two dosing schedules are pre- plasma concentrations of itraconazole (Fig. 2) and
sented in Table 2. Intermittent therapy resulted in a hydroxy-itraconazole (data not shown) tended to be
steady increase in the mean itraconazole concentration higher in responders than in non-responders, but no
in fingernail tips from 59 ng/g to 213 ng/g between such difference was observed in patients receiving con-
weeks 0 and 24. Between weeks 24 and 36, the con- tinuous therapy. Conversely, in the group receiving
centration of itraconazole in fingernails declined continuous therapy, responders had higher itraconazole
sharply and, by week 48, had returned to baseline concentrations in finger and toenails than non-
values in all patients. Intermittent therapy produced a responders, but this difference was not seen in the
similar itraconazole concentration profile in toenails, intermittent therapy group (data not shown). Neither
with a maximum mean concentration of 305 ng/g at difference was statistically significant.
week 24. However, the decrease in the itraconazole
concentration was slower in toenail tips than in finger-
nail tips.
Discussion
Continuous therapy resulted in a maximum mean In the present study, 3 months of intermittent therapy
itraconazole concentration of 524 ng/g in the fingernail with itraconazole 200 mg twice daily for 1 week
tips after 12 weeks of therapy. In almost all patients, followed by a 3-week drug-free period resulted in
itraconazole concentrations in the fingernails returned higher maximum itraconazole plasma concentrations
towards baseline values within 36 weeks after the end of but lower total systemic exposure to itraconazole than
continuous therapy (week 48). In contrast, in the toe- 3 months of continuous treatment with itraconazole
nails, continuous therapy produced a maximum mean 200 mg once daily. This lower systemic exposure was
itraconazole concentration of 698 ng/g at week 36, reflected in the lower concentrations of itraconazole
which did not return towards baseline by week 48. observed in nails with intermittent therapy than with

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100 V.HAVU et al.

most dermatophytes and Candida species correlates with


100 ng/g nail keratin.18 The mean nail concentrations
for both intermittent and continuous therapies in the
present study were at or above this level for most
measurements during the treatment phase and
12 weeks into the follow-up phase.
The total itraconazole dose given in the intermittent
schedule is half that given in the continuous schedule.
This reduction in total drug intake may be beneficial in
reducing side-effects and improving cost-effectiveness.
In an economic evaluation of antifungal agents in the
treatment of toenail onychomycosis, the itraconazole 1-
week intermittent schedule yielded a more favourable
average cost-effectiveness ratio than the conventional
continuous itraconazole schedule.19 In addition, the
duration of active treatment is reduced with the inter-
mittent schedule, which may also help to improve safety
and to promote patient compliance; indeed, treatment
duration has recently been identified as the critical
factor in determining patient preference for treatment
schedules for onychomycosis.20
In conclusion, the results of the present pharma-
cokinetic assessment show that the 1-week intermittent
itraconazole dosing schedule produces higher maxi-
mum itraconazole plasma concentrations but lower
total drug exposure and hence lower itraconazole nail
tip concentrations than the continuous itraconazole
Figure 2. Plasma concentrations (mean 6 SEM) of itraconazole in
dosing schedule. However, the lack of a lower cure
responders and non-responders during (A) continuous treatment rate with the intermittent schedule indicates that
with itraconazole 200 mg once daily for 3 months and (B) intermittent itraconazole nail concentrations remained within the
therapy with itraconazole 200 mg twice daily for the first week of each therapeutic range.
month followed by a 3-week drug-free period, for 3 months.

continuous therapy. In general, the rate of decrease in Acknowledgments


itraconazole concentration after the end of treatment This study was partially funded by Janssen Research
was slower in toenails than in fingernails, probably Foundation, Beerse, Belgium.
because of the slower growth rate of toenails than of
fingernails.
No clear relationship could be observed between References
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