Determination of Posaconazole Levels in Toenails of Adults with Onychomycosis following Oral Treatment with Four Regimens of Posaconazole for 12 or 24 Weeks

Abstract

Pharmacokinetic data from a randomized, parallel-group, multicenter study are presented. Adults with toenail onychomycosis (n ‫؍‬ 146) received posaconazole (100 mg, 200 mg, or 400 mg) once daily (QD) for 24 weeks or 400 mg QD for 12 weeks. The posaconazole concentration in the great toenail exhibited a dose-related increase starting at week 2 for 24 weeks and a mean toenail-to-plasma concentration ratio of approximately 3:1 at the end of treatment for the 400-mg 24-week dose.Posaconazole, a triazole antifungal, has potent in vitro activity against dermatophyte pathogens of onychomycosis (3). Pharmacokinetic (PK) data exist for the distribution of posaconazole within the skin (4), but no PK data exist for posaconazole distribution in toenails. This article presents PK data from a phase 2 clinical trial of posaconazole in the treatment of onychomycosis (ClinicalTrials.gov identifier NCT00491764).(Parts of this work were presented at the 68th Annual Meeting of the American Academy of Dermatology, Miami Beach, FL, 5 to 9 March 2010).This was a randomized, placebo-and active-controlled, parallel-group, multicenter, investigator-blinded study. After a 12-or 24-week treatment period, all patients were followed until 48 weeks after their first dose (i.e., a 24-or 36-week follow-up period). Patients received posaconazole at 100 mg, 200 mg, or 400 mg once daily (QD) for 24 weeks or 400 mg QD for 12 weeks, terbinafine (250 mg QD for 12 weeks), or a placebo (matched to posaconazole) for 24 weeks. Only patients receiving posaconazole were included in this PK analysis.The study protocol was approved by an appropriate ethics committee or institutional review board at each center and was carried out in accordance with good clinical practices. Written informed consent was obtained from each patient before enrollment. Patients were ages 18 to 75 years, had a clinical and mycologic diagnosis of onychomycosis affecting ϳ25% to 75% of at least 1 great toenail, and were otherwise in good health. Patients receiving systemic antifungal therapy within 3 months of study entry or topical foot or toenail antifungal therapy within 1 month of study entry were excluded, as were patients taking drugs known to interact with or be metabolized by cytochrome P450 3A4 within 2 weeks of randomization. Patients could not be pregnant or breastfeeding.Predose blood and toenail samples were collected from all 10 toes at each visit (day 1 and weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48). Toenail clippings (without subungual debris) were obtained and stored frozen at Ϫ20°C until they were shipped to Covance Laboratories Inc., Madison, WI, for assay. A validated standard curve was constructed with untreated human nails from healthy volunteers as the matrix. Toenail samples were mixed with 1.00 ml of 1 M sodium hydroxide per 10.0 mg of toenail, placed in a shaking water bath at 70°C for at least 1 h, and then vortexed for ϳ30 s. Hydrolyzed toenail solution (1.00 ml) was mixed with methanol-water (50:50 [vol/vol]; 0.05 ml) and ethyl acetate-...

Posaconazole Treatment of Extensive Skin and Nail Dermatophytosis Due to Autosomal Recessive Deficiency of CARD9

“…12 Previous studies demonstrated adequate skin and nail penetration of posaconazole. [13][14][15] Posaconazole should be administered orally during a high-fat meal and requires, at high-dosage use (600-800 mg/d), monitoring of blood levels (recommended concentration, 1.2-2.0 mg/L) and liver enzyme levels.…”

Tissue Penetration of Antifungal Agents

“…The concentration of posaconazole within the human dermis is comparable to that in plasma (59). However, in toenails, its concentration is both dose and time dependent, attaining a maximum approximately 3 times greater than that in plasma after 24 weeks of therapy (223). There are no human data for voriconazole, but in guinea pigs, voriconazole skin concentrations are approximately twice those in blood, while in skin microdialysates, the voriconazole concentrations are only 50% of those in blood (224).…”

Pharmacokinetics and Pharmacodynamics of Posaconazole

“…This pattern was not observed in the delayed-release tablet [28] due to the distinct differences in the gastrointestinal drug-delivery features between these two oral formulations. Figure 2 shows posaconazole distribution in various human tissues and fluids after systemic administration [52][53][54][55][56][57][58][59][60][61]. This figure shows that posaconazole accumulates in peripheral tissues, especially in lungs, kidneys, liver, and heart [52,62].…”