Mechanism of Action
The mechanism of action of ciclopirox has been investigated using various in
vitro and in vivo infection models. One in vitro study suggested
that ciclopirox acts by chelation of polyvalent cations (Fe+3 or
Al+3) resulting in the inhibition of the metal-dependent enzymes
that are responsible for the degradation of peroxides within the fungal cell.
The clinical significance of this observation is not known.
Activity in vitro and ex vivo
In vitro methodologies employing various broth or solid media with and
without additional nutrients have been utilized to determine ciclopirox minimum
inhibitory concentration (MIC) values for the dermatophytic molds.(1-2)
As a consequence, a broad range of MIC values, 1-20 ug/mL, were obtained for
Trichophyton rubrum and Trichophyton mentagrophytes species. Correlation
between in vitro MIC results and clinical outcome has yet to be established
One ex vivo study was conducted evaluating 8% ciclopirox against new
and established Trichophyton rubrum and Trichophyton mentagrophytes
infections in ovine hoof material.(3) After 10 days of treatment
the growth of T. rubrum and T. mentagrophytes in the established
infection model was very minimally affected. Elimination of the molds from hoof
material was not achieved in either the new or established infection models.
Susceptibility testing for Trichophyton rubrum species
In vitro susceptibility testing methods for determining ciclopirox MIC
values against the dermatophytic molds, including Trichophyton rubrum
species, have not been standardized or validated. Ciclopirox MIC values will
vary depending on the susceptibility testing method employed, composition and
pH of media and the utilization of nutritional supplements. Breakpoints to determine
whether clinical isolates of Trichophyton rubrum are susceptible or resistant
to ciclopirox have not been established.
Studies have not been conducted to evaluate drug resistance development in
T. rubrum species exposed to 8% ciclopirox topical solution. Studies
assessing cross-resistance to ciclopirox and other known antifungal agents have
not been performed.
Antifungal Drug Interactions
No studies have been conducted to determine whether ciclopirox might reduce the effectiveness of systemic antifungal agents for onychomycosis. Therefore, the concomitant use of 8% ciclopirox topical solution and systemic antifungal agents for onychomycosis is not recommended.
As demonstrated in pharmacokinetic studies in animals and man, ciclopirox olamine
is rapidly absorbed after oral administration and completely eliminated in all
species via feces and urine. Most of the compound is excreted either unchanged
or as glucuronide. After oral administration of 10 mg of radiolabeled drug (14C-ciclopirox)
to healthy volunteers, approximately 96% of the radioactivity was excreted renally
within 12 hours of administration. Ninety-four percent of the renally excreted
radioactivity was in the form of glucuronides. Thus, glucuronidation is the
main metabolic pathway of this compound.
Systemic absorption of ciclopirox was determined in 5 patients with dermatophytic
onychomycoses, after application of PENLAC (ciclopirox topical solution) ® NAIL LACQUER (ciclopirox) Topical
Solution, 8%, to all 20 digits and adjacent 5 mm of skin once daily for six
months. Random serum concentrations and 24 hour urinary excretion of ciclopirox
were determined at two weeks and at 1, 2, 4 and 6 months after initiation of
treatment and 4 weeks post-treatment. In this study, ciclopirox serum levels
ranged from 12-80 ng/mL. Based on urinary data, mean absorption of ciclopirox
from the dosage form was < 5% of the applied dose. One month after cessation
of treatment, serum and urine levels of ciclopirox were below the limit of detection.
In two vehicle-controlled trials, patients applied PENLAC® NAIL LACQUER
(ciclopirox) Topical Solution, 8%, to all toenails and affected fingernails.
Out of a total of 66 randomly selected patients on active treatment, 24 had
detectable serum ciclopirox concentrations at some point during the dosing interval
(range 10.0-24.6 ng/mL). It should be noted that eleven of these 24 patients
took concomitant medication containing ciclopirox as ciclopirox olamine (Loprox®
The penetration of the PENLAC® NAIL LACQUER (ciclopirox) Topical Solution,
8%, was evaluated in an in vitro investigation. Radiolabeled ciclopirox
applied once to onychomycotic toenails that were avulsed demonstrated penetration
up to a depth of approximately 0.4 mm. As expected, nail plate concentrations
decreased as a function of nail depth. The clinical significance of these findings
in nail plates is unknown. Nail bed concentrations were not determined.
Clinical Trials Data
The results of use of PENLAC® NAIL LACQUER (ciclopirox) Topical Solution,
8%, in treatment of onychomycosis of the toenail without lunula involvement
were obtained from two double-blind, placebo-controlled studies conducted in
the US. In these studies, patients with onychomycosis of the great toenails
without lunula involvement were treated with ciclopirox topical solution, 8%
in conjunction with monthly removal of the unattached, infected toenail by the
investigator. PENLAC® NAIL LACQUER (ciclopirox) Topical Solution, 8%, was
applied for 48 weeks. At baseline, patients had 20-65% involvement of the target
great toenail plate. Statistical significance was demonstrated in one of two
studies for the endpoint "complete cure" (clear nail and negative
mycology), and in two studies for the endpoint "almost clear" ( ≤ 10%
nail involvement and negative mycology) at the end of study. These results are
At Week 48 (plus Last Observation Carried Forward) for the
Intent-to-Treat (ITT) Population
|Negative Mycology Alone***
|* Clear nail and negative mycology
** ≤ 10% nail involvement and negative mycology
*** Negative KOH and negative culture
The summary of reported patient outcomes for the ITT population at 12 weeks
following the end of treatment are presented below. Note that post-treatment
efficacy assessments were scheduled only for patients who achieved a complete
Post-treatment Week 12 Data for Patients Who Achieved Complete
Cure at Week 48
|Number of Treated Patients
|Complete Cure at Week 48
|Post-treatment Week 12 Outcomes:
|Patients Missing All Week 12 Assessments
|Patients with Week 12 Assessments
|*Four patients (from studies 312 and 313)who
were completely cured did not have post-treatment Week 12 planimetry data.
1. Dittmar W., Lohaus G. 1973. HOE296, A new antimycotic compound with a broad
antimicrobial spectrum. Arzneim-Forsch./Drug Res. 23:670-674.
2. Niewerth et. al., 1998. Antimicrobial susceptibility testing of dermatophytes:
Comparison of the agar macrodilution and broth micro dilution tests. Chemotherapy.
3. Yang et. al. 1997. A new simulation model for studying in vitro
topical penetration of antifungal drugs into hard keratin. J. Mycol. Med. 7:195-98.