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

stratum corneum for extended periods of time beyond the recommended treatment duration.²⁰

Clinical data on topical antifungal therapy using naftifine for tinea pedis in a pediatric population is limited. The objective of this manuscript is to present results from a study that quantified the pharmacokinetics (PK) and assessed trends in efficacy, tolerability, and safety of naftifine hydrochloride gel 2% in pediatric subjects with tinea pedis.

The data are from a four-week, open-label, multi-center, multiple application study in pediatric subjects (ages 12 years to 17 years, 11 months) with tinea pedis. The study quantified the pharmacokinetic (PK) profile of naftifine hydrochloride gel 2% in pediatric subjects with tinea pedis (both feet affected). Additionally, at small subset of adult PK evaluable subjects with the same condition were obtained to serve as the control.

All subjects stayed at the study center on day 1 (first application) and day 14 (last application). Pharmacokinetic blood samples were collected on days 1 and 14 for 24 hours at: 0 hour (pre-application), and 1, 2, 4, 6, 8, 12, and 24 hours post-application. Pre-application samples were collected on days 1, 3, 7, 11, 12, 13, and 14. Days 11 through 14 samples were used to assess steady state. In addition, samples were collected on days 21 (1-week after the last application), and day 28 (2-weeks after the last application). Pharmacokinetic urine samples were obtained on days 1 and 14 for 24 hours as follows: before on-site treatment application (only on day 1), 0-6, 6-12, and 12-24 hours after on-site application.

Efficacy was assessed based on potassium hydroxide (KOH), dermatophyte culture, signs and symptoms between baseline (first application) and day 7 (1-week into treatment), day 14 (24 hours after last application), and day 28 (2-weeks after the last application and 4 weeks after the start of the study).

The study was conducted according to the ethical guidelines of the Declaration of Helsinki and according to the good clinical practice (GCP) guidelines. Institutional review boards (IRB) and/or ethical committees of all participating sites reviewed the protocol and approved the study before enrolling the first patient. The study was registered with ClinicalTrials.gov (Identification Number: NCT01712360) and was funded by Merz Pharmaceuticals, LLC.

The study was conducted under maximal clinical use conditions for both the pediatric subjects and adult control subject. Subjects were instructed to apply 4 grams of naftifine hydrochloride gel 2% to both feet (approximately 2 grams per foot) once a day for two weeks. Subjects applied the assigned study product to the affected areas plus a half-inch margin of healthy skin.

Participants in the study were recruited from 4 clinical sites from the United States, Dominican Republic, and Honduras. Written and informed consent was obtained from all subjects (as well as by a legal guardian and/or caregiver, if applicable) prior to screening. In order to be included into the study subjects must be male and non-pregnant females’ between 12 and 17 years, 11 months of age with a clinical diagnosis (ie, baseline presence of signs and symptoms of erythema, scaling, pruritus, and KOH positive scrapings from the most representative site) of tinea pedis on both feet. For the adult control groups, subjects must have been males or non-pregnant females’ ≥18 years of age with tinea pedis. Additionally, subjects must have had an absence of clinically significant disease that could interfere with the interpretation of the results, the ability of the participants to understand the requirements of the study, and willing to comply with them.

Exclusion criteria included any life-threatening condition within the last 90 days of pre-study visit (screening); known hypersensitivity to study medication or any components; uncontrolled diabetes mellitus; hemodialysis or chronic ambulatory peritoneal dialysis; current diagnosis of immunocompromising conditions; onychomycosis; clinically significant abnormal laboratory or physical findings; any severe condition of tinea pedis (incapacitating) including bacterial skin infections such as cellulitis, mucocutaneous candidiasis, dermatophytoses, lymphagitis; or pyoderma; any dermatological disease or condition in the treatment or surrounding area(s) that may prevent application of the study product; participation in another clinical trial or the completion of another clinical study with an investigational drug or device within the past 30 days; received any treatment with the investigational products or any other allylamine or antifungal for any indication within the past 2 months; having received any treatments or medications within 1 month prior to study treatment initiation with the exception of hormonal contraception; anyone who does not use an acceptable form of contraception during the study (if necessary) and; historical or current evidence (physical or laboratory) of anemia. Enrolled subjects who had received antifungal, corticosteroids, or antibacterial therapies prior to randomization were required to undergo a washout period prior to entering the trial.

Pharmacokinetic measurements obtained at various days throughout the study included: 1) AUC_0-24: partial area under