An Open-Label, Multi-Center, Multiple-Application Pharmacokinetic Study of Naftifine HCl Gel 2% in Pediatric Subjects With Tinea Pedis

in adult control subjects, mean Ae_0-24 (range) increased from 79.9 ng (0-161.9 ng) on day 1 to 974.5 ng (418.5-2456.2 ng) on day 14. The mean fraction of administered drug excreted into the urine (f_e) increased during the treatment period from 0.0005% at day 1 to 0.001% at day 14 for pediatric subjects and from 0.0001% at day 1 to 0.001% at day 14 for adult control subjects. Renal clearance (CLr) decreased during the study period in pediatric subjects and increased in adult control subjects. Geometric mean CLr results for pediatric subjects were 0.2766 mL/min on day 1 and 0.1546 mL/min on day 14 and for adult control subjects were 0.0933 mL/min on day 1 and 0.1646 mL/min on day 14. Overall, renal clearance was relatively low (Table 3).

Among pediatric subjects (N=22), while positive results were observed as early as day 7 for most efficacy measures (ie, treatment effectiveness, mycological cure, and clinical success), the proportion of subjects achieving each efficacy endpoint generally increased over time through day 28 (2 weeks post-treatment). Efficacy rates at day 28 were as follows: complete cure (27.3%), treatment effectiveness (54.5%), mycological cure (63.6%), clinical success (81.8%), and clinical cure (40.9%; Table 4).

In regards to five evaluable adult control subjects, no subjects achieved complete cure during the 28-day study period; one subject (20%) achieved effective treatment at day 28; one subject (20%) achieved mycological cure at 28; four subjects (80%) achieved clinical success at day 28; and one subject (20%) achieved clinical cure at day 28.

Naftifine gel 2% was well tolerated during the 14-day treatment regimen. Two out of twenty-two (9%) pediatric subjects and one out of six (17%) adult subject experienced treatment emergent adverse events (TEAE) during the study. None of these events was a serious adverse event, led to dose reduction or discontinuation from the study, or was considered treatment-related which is defined as a causal relationship between the investigational product and an adverse event that is at least a reasonable possibility. All TEAEs were resolved by the end of the study.

After multiple applications of naftifine hydrochloride gel 2% under maximal use conditions where approximately 4 grams total (2 grams to each foot) were applied for the treatment of tinea pedis in pediatric patients (ages 12 to 17 years, 11 months) and adult controls, the rate and extent of systemic exposure was low. These findings are especially important given that topical regimens can reduce the spread of active ingredients into the bloodstream, thus minimizing systemic exposure and undue risks for side effects.

Naftifine hydrochloride gel 2% was found to be efficacious for tinea pedis in pediatric subjects in this study. A larger proportion of pediatric subjects responded to naftifine hydrochloride gel 2% with positive results for all efficacy measures, when compared with the adult subjects. The study was underpowered for efficacy, especially with respect to the adult subjects (N=6), who were included as a comparison group, rather than the main focus of the study. While positive results were observed as early as day 7 for some efficacy measures, the proportion of subjects achieving each efficacy endpoint (i.e. complete cure, effective treatment, mycological cure, clinical success, and clinical cure) generally increased over time through day 28. The trends in these findings are consistent with the results obtained from the randomized, multicenter, double-blind, vehicle-controlled clinical trials using naftifine hydrochloride gel 2% for the treatment of tinea pedis in a population between the ages of 12 and 70 years old.¹⁹

The continued post-treatment improvement in clinical signs and symptoms observed is consistent with naftifine’s well-established residual post-treatment therapeutic activity. One possible reason for this observed prolonged treatment response may result from bio-available drug remaining in the stratum corneum for extended periods of time after treatment cessation; thus, continuously exposing dermatophytes to naftifine.²⁰

The safety evaluation demonstrated an excellent safety profile with topically applied naftifine gel 2% in both the pediatric and