The phannacokinetic properties of current systernic antifungal agents 
Review 
THE PHARMACOKINETIC PROPERTIES 
OF CURRENT SYSTEMIC ANTIFUNGAL AGENTS 
L. Korošec 
SUMMARY 
Human fungal infections have increased dramatically and are difficult to treat. The spread of HIV/AIDS 
infection, the use of immunosuppressive drugs and broad-spectrum antibiotics have contributed to the spread 
of fungal infections. Spontaneous remissions are rare, and recurrence after treatment is common. The 
pharmacotherapy of the fungal diseases bas been revolutionized by the introduction of the relatively non-toxic 
oral azoles. The systemic treatment with the new antifungal agents - fluconazole, itraconazole, and terbinafine 
- and the knowledge of their pharmacological and pharmacokinetic properties make possible the pulse therapy 
in the treatment of the fungal infections. This will be of great benefit for patients from pharmacological as 
well as pharmacoeconomic aspects. 
KEY WORDS 
dermatomycosis, onychomycosis, systemic treatment, azoles, ketoconazole, fluconazole, itraconazole, 
pulse therapy, terbinafine 
INTRODUCTION 
The incidence and severity of human fungal 
infections have dramatically increased in recent years, 
mainly due to advances in surgery, cancer treatment, 
and critical care accompanied by increases in the 
use of broad-spectrum antimicrobials and the HIV 
epidemic. 
Pharmacotherapy of fungal diseases has been 
revolutionized by the introduction of the relatively 
non-toxical oral azole and allylamine drugs. 
The antifungal drugs available belong to severa! 
acta dennatovenerologica A.P.A. Vol 7, 98, No 3-4 
categories: systemic drugs for systemic infections, 
oral and topical drugs for mucocutaneous infections. 
The need for new antifungal agents with better 
therapeutic profiles arose from the requirement for 
intravenous and peroral systemic administration and 
the toxicity of the older antifungal agents. The 
relatively non-toxic oral azoles represented the first 
major advance in this direction. These medi~ations 
have played an increasingly important role in the 
systemic therapy of fungal diseases, since they were 
introduced in 1980s. 
145 
The phannacokinetic properties of cwrent systemic antifungal agents 
Table l . The pharmacokinetic properties of the commonly used systemic azole drugs. 
fluconazole 
itraconazole 
ketoconazole 
high 
low 
low 
high 
variable 
variable 
> 0.7 
< 0.01 
< 0.1 
CLASSIFICATION 
Azoles are synthetic compounds. They can be 
classified as imidazoles or triazoles according to the 
number of nitrogen atoms in the five-membered 
azole ring (1) (Fig 1). The imidazoles are represented 
by ketoconazole, miconazole, and clotrimazole. The 
triazoles include itraconazole and fluconazole. They 
are both in common use for systemic treatment of 
fungal diseases (2). 
Each of the azole's pharmacology is unique and 
accounts for some variations in clinical use. Table 1 
and table 2 summarize the pharmacological properties 
of some commonly prescribed antifungal agents. 
The systemic antifungal agents are generally divided 
to: 
l. Allylamines: terbinafine (Lamisil® tbl., Novartis) 
2. Azoles: 
3. Triazoles: 
ketoconazole (Oronazol® tbl., Krka) , 
and miconazole (Daktarin® amp., 
Krka) 
fluconazole (Diflucan® caps., amp., 
Pfizer, Dimycon® caps. , amp. 
Alkaloid), itraconazole (Sporanox® 
caps., Janssen) 
The most important pharmacological characteristics 
of these new oral antifungal systemic drugs are 
good absorption from the gastrointestinal tract, 
pronounced keratophilic properties, slow elimination 
Figure l. Azole nucleus. 
146 
X = C, imidazole 
X= N, triazole 
22 - 31 
24 - 42 
2-8 
renal 
hepatic 
hepatic 
oral, i.v. 
oral 
oral 
rate from keratinic tissues, prolonged therapeutic 
effects even after discontinuation of therapy, and 
higher selectivity and specificity against fungal 
cytochrome P-450 than mammalian cytochrome P-
450. 
The most common fungal skin infections are: 
dermatophytoses, pityriasis versicolor and candidiasis. 
Nail infections - onychomycoses - are notoriously 
difficult to treat (3 ,4,5). Infections of the fingernails 
take up to 6 months to respond to oral griseofulvin 
and those of the toenails a year or longer. About 
60% of nail infections fail to respond or relapse 
after initial treatment course. The combined therapy 
with oral griseofulvin and a topical azole may produce 
a better response (6). The oral use of ketoconazole 
for nail infections is limited by its potential hepato-
toxicity. Itraconazole is reported to be an effective 
alternative over a shorter treatment period (7,8,9) , 
and also terbinafine may be effective over the same 
treatment period (10-14). Although topical treatment 
is generally ineffective in nail infections amorolfine 
applied as a lacquer has produced encouraging 
results (15,16). Another approach was the dissolution 
of the nail plate with 40% urea paste, usually in 
combination with bifonazole (17,18). Table 3 shows 
the main antifungal drugs used in the treatment of 
fungal infections (19-21). 
THE "OLD" THERAPY 
OF ONYCHOMYCOSIS 
Onychomycosis is very difficult to treat; the cure 
rates are low and relapse frequent. Topical antifungals 
cannot penetrate the nail plate and eradicate the 
infection in the nail bed; they are us~ful only in 
milder forms of disease. The older oral antifungal 
medications - griseofulvin and ketoconazole - penetrate 
the nail plate via the nail matrix, but both necessitate 
prolonged treatment courses ( 4 to 6 months for 
fingernails, 10 to 18 months for toenails). Mycological 
cure rates have been as low as 3% for toenails and 
40% for fingernails (4) . 
acta dennatovenerologica A.P.A. Vol 7, 98, No 3-4 
The phannacokinetic properlies of current systemic antifungal agents 
Table 2. The antifungal drugs for systemic (p.o.) treatment. 
NEW ORAL ANTIFUNGAL AGENTS 
The treatment of onychomycosis was changed by 
the introduction of the triazole and allylamine classes 
of antifungal agents. Three new drugs - fluconazole, 
itraconazole and terbinafine - have the advantage of 
shorter treatment courses, fewer side effects (the 
most common are gastrointestinal upset, headache, 
and allergic skin eruptions ), and higher cure rates. 
They also exhibit the "reservoir effect"; which means 
that therapeutic concentration of the medication 
remains in the distal nail plate over weeks to 
months after treatment has been stopped. 
TRIAZOLES 
ltraconazole and fluconazo le are synthetic triazole 
antifungals that interfere with the 14-cx demethylase 
system, a cytochrome P-450 enzyme that is necessary 
for the conversion of lanosterol to ergosterol, an 
essential component of fungal cytoplasmic cell 
membranes. They have a greater affinity for fungal, 
as opposed to mammalian, cytochrome P-450. 
Inhibition of ergosterol synthesis results in increased 
cellular permeability, which causes leakage of cellular 
contents. Other antifungal effects of azole compounds 
have been reported: inhibition of endogenous 
respiration, interaction with membrane phospholipids, 
inhibition of yeast transformation to mycelial forms, 
inhibition of purine uptake and impairment of 
trigliceride and/or phospholipid biosynthesis (22). 
Itraconazole shows maximal oral bioavailability when 
taken with a full meal. Absorption is impaired if it 
is taken on an empty stomach or with drugs that 
alter gastric pH ( e.g., antacids, histamine H, blockers, 
or proton pump inhibitors - PPI). Itraconazole 
undergoes extensive hepatic metabolism. Pharma-
acta dennatovenerologica A.P.A. Vol 7, 98, No 3-4 
cokinetic studies showed that itraconazole penetrates 
the nail plate via the nail matrix and the nail bed. 
The drug was detected in nails as early as 1 week 
after oral administration. 
Itraconazole reaches the MIC for dermatophytes 
and most Candida species within 7 to 21 days. 
Inhibitory concentrations were maintained for up to 
6 months in fingernails and for up to 9 months in 
toenails. Itraconazole can be given by pulse dosing 
because it remains in the nails but is rapidly eliminated 
from the plasma. Mycological cure rates with two 
pulses have ranged from 78% ± 10% to 87%± 8% 
for fingernails and with three pulses up to 77% for 
toenail onychomycosis (n= 1389) (20,23,24). 
Recommended dosing regimens are 200 mg per 
day continuously for 12 weeks for toenail onycho-
mycosis or 200 mg twice daily, for the first week of 
each month for 2 months for fingernail onychomycosis 
(19). Pulse dosing for toenail onychomycosis is used 
frequently, usually three pulses are applied. Table 4. 
De Doncker (24) recommends for itraconazole in 
dermatomycoses the 1-2-3 concept: 1-cycle for 
superficial skin infection, 2-cycles for fingernail 
infections and 3-cycles for toenail infections. 
Fluconazole is a bis-triazole, which, like itraco-
nazole, blocks the enzyme 14-cx demethylase. Fluco-
nazole is more resistant to first-pass metabolism and 
has low protein-binding capacity. Thus it distributes 
quickly into tissues, and it is rapidly cleared from 
plasma. Its oral absorption is not affected by the 
absence of stomach acid. Peak serum concentration 
and AUC increase in proportion to the dose. Steady-
state fluconazole plasma concentrations are achieved 
within 5-10 days . Therapeutic levels remain in the 
nails up to 6 months (25), possibly contributing to 
the increasing cure rates after treatment is discon-
tinued. Fluconazole is well suited to intermittent 
(i.e ., once weekly) dosing. Recent studies indicate 
that the optimum regimen is 150 to 300 mg once 
147 
The phannacokinetic properties of current systemic antifungal agents 
Table 3. Main drugs far the treatment of Junga! infections. 
Sporotrichosis 
cutaneous 
extracutaneous 
terbinafi ne, potassium chloride 
amphoteric in 
weekly until the fungal infection clears - approximately 
3 months far fingernails and 6 months far toenails. 
ALL YLAMINES 
Terbinafine is a synthetic allylamine antifungal 
agent that is administered either orally or topically. 
It is pharmacologically similar to naftifine. Oral 
terbinafine is highly effective far treating onycho-
mycosis due to fungicida! activity and abili ty to 
become concentrated within the nail and has been 
faund to be superior to griseofulvin far treatment 
of onychomycosis. The relapse rate was higher with 
griseofulvin than terbinafine (26,27). The mechanism 
of its action is the inhibition of the enzyme squalene 
epoxidase (monooxygenase ), thereby preventing ergo-
sterol synthesis. It also causes an accumulation of 
squalene, which has a fungicida! activity against 
dermatophytes. Oral terbinafine is well absorbed 
from the gut, reaching peak plasma concentrations 
within 2 hours. Although terbinafine is to 99% 
protein-bound it is widely distributed, including the 
central nervous system. Terbinafine rapidly distributes 
into the nail plate via the nail bed and the nail 
148 
matrix, reaching mm1mum inhibitory concentration 
(MIC) quickly, and remains in the nail plate far up 
to 10 months (28). Most of the oral dose (70%) is 
metabolized through oxidation and hydrolysis to the 
dihydrodiol, and excreted in the urine. There are 
no significant active metabolites. Mycological cure 
rates of 70% far toenails and 79% far fingernails 
are reported (26,27). 2-year mycological cure rates 
far infections caused by Candida species are more 
variable and have been reported as 52% far toenails 
and 65% far fingernail (29). Relapse is unlikely 
after terbinafine treatment. 
Pulse dosing regimens (typically, 1 week on therapy, 
3 weeks off therapy) are reported to be as effective 
as continuous dosing (30). Pulse therapy is possible 
because terbinafine remains in the nail plate far 
extended periods. Pulse dosing may also reduce side 
effects. Although terbinafine does not have many 
side effects, its pharmacokinetic profile does not 
readily suggest that it should be dosed this way (it 
may remain longer in the blood than the triazoles 
do (20,24,25). Dosage adjustment is not need~d in 
elderly patients since the pharmacokinetics in elderly 
patients have been shown to be comparable to 
healthy volunteers (31). 
acta dennatovenerologica A.P.A. Vol 7, 98, No 3-4 
The pharmacokinetic properties of current systemic antifungal agents 
Table 4. New antifungal agents far systemic treatment of onychomycoses: dosage, activity, and contraindications. 
Fungicida/ against dermato-
phytes, some Candida species, 
and some moulds 
Fungistatic against C. albicans 
and some moulds 
Fungistatic against 
dermatophytes, yeasts, some 
nondermatophytic fungi 
fluconazole Fungistatic against dermato-
phytes, most Candida species, 
some nondermatophytic fungi 
CONCLUSIONS 
The new generation of oral antifungal agents is 
basically safe for treatment of onychomycosis. We 
can say that new systemic drugs, because of their 
pharmacokinetic properties and their biphasic pene-
tration, can be a key to rational therapy, presupposing 
a rational dosing strategy. The reduction from previous 
long-term therapies to a three-month therapy and 
now the pulse therapy represents a great advance. 
Pharmacokinetic studies showed that the optimal 
treatment regimens for superficial fungal infections 
of the skin and of onychomycosis of the fingernails 
and toenails differ. Thus, the total amount of antifungal 
agent required depends on the site of infection. 
The concept with pulse therapy provides a globa! 
and unique strategy in dermatomycoses, and offers 
severa! advantages, most notably: 
- reduction in the total drug dosage and 
hence reduced potential of drug's side effects 
- improved patient compliance 
- increased flexibility and 
- reduced total therapeutic costs. 
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AUTHOR'S ADDRESS 
Ladko Korošec MD, MSc, pharmacologist, Dpt. Pharmacology, Medica! Faculty, University of Ljubljana, 
Korytkova 2, S1-1000 Ljubljana, Slovenia. 
acta dermatovenerologica A.P.A. Vol 7, 98, No 3-4 151