Skin concentrations and pharmacokinetics of posaconazole after oral administration

  • Krishna G
  • Beresford E
  • Lei M
 et al. 
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Abstract

A randomized, single-center, open-label study of posaconazole (POS) was performed to determine the concen-tration of POS in the skin of 30 healthy adult human subjects receiving 400 mg POS oral suspension twice daily for 8 days with a high-fat meal. Blood samples for plasma POS level determination were collected at prespecified times on day 1 and day 8. From each subject, two 4-mm skin punch biopsy samples were obtained, one immediately before or after both the first and last doses of POS. A MIC 90 value of 250 ng/ml, which encompasses the majority of common dermatophytes, was used to calculate the time above the MIC 90 in plasma and skin. On days 1 and 8, POS attained peak plasma concentrations at median times of 8 and 5 h, respectively. On days 1 and 8, POS peak skin concentrations were attained at 12 and 3 h, respectively; peak skin concentrations were produced from a single composite profile. On day 8, POS concentrations in skin and plasma for the entire dosing interval were severalfold higher than the MIC 90 . POS dosed at 400 mg twice daily per os was well tolerated in healthy subjects. Two subjects reported increased alanine aminotransferase (ALT) levels. The findings of this study demonstrate adequate skin penetration and have certain implications for the treatment of dermatophytic skin and nail infections. Posaconazole, an extended-spectrum triazole antifungal, is approved in Europe and the United States as prophylaxis for invasive fungal infection (IFI) in high-risk patients and for the treatment of oropharyngeal candidiasis (15, 16); in Europe, it is also approved for the treatment of refractory IFI (16). Posaconazole has a large apparent volume of distribution (1,774 liters), suggesting extensive extravascular distribution and penetration into body tissues, and a long mean half-life of 35 h (9, 15). Pharmacokinetic data exist for the distribution of posaconazole within plasma, epithelial lining fluid, and alveo-lar cells (3, 6, 10–12), but there are no clinical data on the bioavailability of posaconazole for skin or its effectiveness against fungal pathogens that affect skin. Newer azoles, such as itraconazole and fluconazole, have been used to treat superficial infections of the skin, hair, and nails that are caused by dermatophytes (20). Although topical and oral agents are available to treat these fungal infections, oral drugs such as terbinafine (an allylamine) and itraconazole (a triazole) (20) appear to be more efficacious. Posaconazole has potent in vitro activity against dermatophytes from the genera Trichophyton (T. rubrum and T. mentagrophytes), Epi-dermophyton, and Microsporum, which are primarily associated with dermatophytosis, and against yeast (Candida albicans) (7). Given the antidermatophyte and antiyeast activity of posacon-azole in vitro and its characteristic tissue distribution and phar-macokinetic profiles in vivo, it is of clinical interest to deter-mine the concentration of posaconazole in the skin after oral dosing. The objectives of this study were to compare skin and plasma concentrations of posaconazole obtained after oral ad-ministration of 400 mg of posaconazole twice daily and to relate posaconazole levels in skin and plasma to the MIC required to inhibit 90% of relevant pathogenic dermatophytes (MIC 90). This is the first report of posaconazole levels in hu-man skin following oral administration.

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Authors

  • Gopal Krishna

  • Eric Beresford

  • Ma Lei

  • Donna Vickery

  • Monika Martinho

  • Xin Yu

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