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

96 q 1999 British Association of Dermatologists

 ITRACONAZOLE DOSING FOR ONYCHOMYCOSIS
which suggests that itraconazole penetrates the nail not
only through the nail matrix but also through the nail
bed.12,14 In addition, therapeutic concentrations of
itraconazole have been shown to persist in fingernails
for 3 months after treatment and in toenails for up to
6 months after treatment.15 Itraconazole concentrations
detected in finger and toenail tips with itraconazole
200 mg daily for 3 months were 10 times higher than
those detected with itraconazole 100 mg daily for
3 months and were associated with a better outcome.
The results of these pharmacokinetic studies led to
the suggestion that continuous therapy with itra-
conazole 200 mg daily for 3 months might not be
necessary to maintain therapeutic levels of itraconazole
in the nail. As a result, a new concept in the treatment
of onychomycosis has emerged, namely intermittent
therapy with itraconazole 200 mg twice daily for
1 week per month, followed by a 3-week drug-free
period, for 3 months. This novel intermittent itra-
conazole dosing schedule has been compared with the
conventional continuous itraconazole regimen in a
multicentre, double-blind, randomized, parallel-group,
phase III trial; results from the efficacy and safety
evaluation (reported previously)16 showed that the
schedules were similarly safe, well tolerated and effec-
tive in the treatment of onychomycosis. Here, we
present the results of assessments performed to investi-
gate the pharmacokinetics of itraconazole during con-
tinuous and intermittent dosing.
Patients and methods
Patients
Patients were randomized to continuous therapy with
itraconazole 200 mg daily for 3 months or 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. Patients also received placebo
capsules to maintain double-blind conditions. In both
groups, the 3-month treatment phase was followed by a
9-month drug-free follow-up period.
Men and women aged 18–60 years with distal sub-
ungual onychomycosis of the toenails, confirmed by
microscopy and positive culture for a dermatophyte,
were included in the study. The involvement of at least
30% of the surface of one toenail was also required.
Concurrent onychomycosis of the fingernails or a fungal
lesion of the pilose or glabrous skin, or both, were
optional. Patients were excluded if moulds or Candida
species were cultured in the nail samples or if the
q 1999 British Association of Dermatologists, British Journal of Dermatology, 140, 96–101
97
patients had received systemic antifungal therapy
within the 6 months or topical antifungal therapy
within the 2 weeks before the start of the trial. Con-
current use of other systemic or topical antifungal
therapies, local corticosteroids, digoxin, oral anticoagu-
lants, terfenadine, cyclosporin A, H2-receptor antago-
nists, cisapride, simvastatin or lovastatin, midazolam or
triazolam, oral hypoglycaemic agents or enzyme-
inducing drugs, such as rifampicin and phenytoin,
was not permitted. Patients were also excluded if they
had psoriasis, abnormal liver function or a serious
disease that might prevent completion of the trial.
Women were excluded if they were possibly pregnant
or lactating. The trial was performed in accordance with
the Declaration of Helsinki and its revisions. Ethics
committee approval was obtained, and patients gave
their informed consent to participate.
Bioanalysis
Venous blood samples of 10 mL were collected at the
start of the study and at weeks 1, 4, 5, 8, 9 and 12 to
determine itraconazole and hydroxy-itraconazole
plasma concentrations using high-performance liquid
chromatography (HPLC).17 Hydroxy-itraconazole, the
main metabolite of itraconazole, has similar in vitro
antifungal activity to itraconazole and may contribute
significantly to in vivo antifungal activity.13 The lower limit
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,
12, 24, 36 and 48 to determine itraconazole nail tip
concentrations using HPLC.17 The lower limit of quan-
tification for itraconazole in nails was a 2·0 ng/sample.
Nails with entire distal parts missing or destroyed
(including the target toenail, which was used for the
mycological examination) were excluded. Mean concen-
tration–time curves were constructed for itraconazole
in plasma and nails, and for hydroxy-itraconazole in
plasma, for both treatment schedules. No formal phar-
macokinetic parameters could be derived from these
curves, because they were constructed from too few
sample points.
Statistical analysis
The treatment groups were compared at baseline using
the Mann–Whitney U-test for age, weight and height
and the chi-squared test for sex. Blood sampling was not
always performed at the prescribed time points, so time
intervals were constructed around each time point. The
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
0 0 0 0
1 1 7 13
4 14 28
5 32 35
8 39 56
9 60 63
12 67 84
24 102 168
36 210 252
48 294 336
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
Patient characteristics and disposition
Of the 129 patients recruited to the study, 65 patients
were assigned to continuous therapy and 64 patients
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
phase, one patient in the continuous therapy group and
three patients in the intermittent therapy group with-
drew because of adverse events. During the 9-month,
drug-free, follow-up period, one patient withdrew from
the continuous therapy group because of abnormal
laboratory values and one patient withdrew from each
treatment group because of insufficient response. In
addition, a protocol deviation was noted in one patient
in each treatment group; these patients failed to meet
the selection criteria because they were culture negative
for a dermatophyte at the start of the trial.
Plasma concentration–time profiles
Mean plasma concentration–time data for itraconazole
and hydroxy-itraconazole for the two dosing schedules
q 1999 British Association of Dermatologists, British Journal of Dermatology, 140, 96–101
Upper
31
38
59
66
101
209
293
377
Figure 1. Plasma concentrations (mean 6 SEM) of (A) itraconazole
and (B) hydroxy-itraconazole 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. *No intermittent
therapy was administered during these weeks.
are presented in Figure 1. With the intermittent sche-
dule, increases of consistent magnitude were seen in the
mean itraconazole and hydroxy-itraconazole plasma
concentrations at the end of each 1-week treatment
phase (weeks 1, 5 and 9; mean ranges 1130–1416 ng/
mL and 2061–2402 ng/mL, respectively). By the end of
each 3-week drug-free period (weeks 4, 8 and 12), the
mean plasma concentrations of both itraconazole and
hydroxy-itraconazole had returned towards baseline
values in most patients. With the continuous schedule,
plasma steady-state levels of itraconazole and hydroxy-
itraconazole were obtained within 4–5 weeks of the
start of treatment. The mean plasma concentrations of
both compounds remained reasonably constant
between weeks 4 and 12, ranging from 842 to
992 ng/mL for itraconazole and from 1446 to
1706 ng/mL for hydroxy-itraconazole.
 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
for itraconazole for the two dosing schedules are pre-
sented in Table 2. Intermittent therapy resulted in a
steady increase in the mean itraconazole concentration
in fingernail tips from 59 ng/g to 213 ng/g between
weeks 0 and 24. Between weeks 24 and 36, the con-
centration of itraconazole in fingernails declined
sharply and, by week 48, had returned to baseline
values in all patients. Intermittent therapy produced a
similar itraconazole concentration profile in toenails,
with a maximum mean concentration of 305 ng/g at
week 24. However, the decrease in the itraconazole
concentration was slower in toenail tips than in finger-
nail tips.
Continuous therapy resulted in a maximum mean
itraconazole concentration of 524 ng/g in the fingernail
tips after 12 weeks of therapy. In almost all patients,
itraconazole concentrations in the fingernails returned
towards baseline values within 36 weeks after the end of
continuous therapy (week 48). In contrast, in the toe-
nails, continuous therapy produced a maximum mean
itraconazole concentration of 698 ng/g at week 36,
which did not return towards baseline by week 48.
In the group of patients receiving intermittent therapy,
plasma concentrations of itraconazole (Fig. 2) and
hydroxy-itraconazole (data not shown) tended to be
higher in responders than in non-responders, but no
such difference was observed in patients receiving con-
tinuous therapy. Conversely, in the group receiving
continuous therapy, responders had higher itraconazole
concentrations in finger and toenails than non-
responders, but this difference was not seen in the
intermittent therapy group (data not shown). Neither
difference was statistically significant.
Discussion
In the present study, 3 months of intermittent therapy
with itraconazole 200 mg twice daily for 1 week
followed by a 3-week drug-free period resulted in
higher maximum itraconazole plasma concentrations
but lower total systemic exposure to itraconazole than
3 months of continuous treatment with itraconazole
200 mg once daily. This lower systemic exposure was
reflected in the lower concentrations of itraconazole
observed in nails with intermittent therapy than with

q 1999 British Association of Dermatologists, British Journal of Dermatology, 140, 96–101

100 V.HAVU et al.
Figure 2. Plasma concentrations (mean 6 SEM) of itraconazole in
responders and non-responders during (A) continuous treatment
with itraconazole 200 mg once daily for 3 months and (B) 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.
continuous therapy. In general, the rate of decrease in
itraconazole concentration after the end of treatment
was slower in toenails than in fingernails, probably
because of the slower growth rate of toenails than of
fingernails.
No clear relationship could be observed between
plasma concentrations of itraconazole or hydroxy-
itraconazole, or nail concentrations of itraconazole,
and response to therapy. However, the efficacy and
safety evaluation indicated that both dosing schedules
were effective in the treatment of onychomycosis, with a
trend for efficacy in favour of the intermittent
schedule.16 The fact that the intermittent schedule
was not associated with a lower cure rate indicates
that nail concentrations remained within the thera-
peutic range, despite the lower total systemic exposure
to itraconazole and hydroxy-itraconazole. Moreover, the
minimum inhibitory concentration of itraconazole for
q 1999 British Association of Dermatologists, British Journal of Dermatology, 140, 96–101
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
dosing schedule. However, the lack of a lower cure
rate with the intermittent schedule indicates that
itraconazole nail concentrations remained within the
therapeutic range.
Acknowledgments
This study was partially funded by Janssen Research
Foundation, Beerse, Belgium.
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