Skin concentrations and pharmacokinetics of posaconazole after oral administration

Abstract number: P1666

Krishna G., Ma L., Beresford E., Tavakkol A., Martinho M., Yu X., Komjathy S.

Objectives: The primary objective of this study was to determine the concentration of posaconazole (POS) in 4-mm skin punch biopsy in human subjects given POS 400 mg twice daily (BID) orally (PO). Secondary objectives were to compare skin concentration and plasma levels of POS to the MIC90 of relevant pathogens.

Methods: This was a randomised, single-centre, open-label study of POS in healthy adults. Subjects received 400 mg POS BID 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 skin samples were obtained, one immediately before or after both the first and last doses of POS. A MIC90 value of 250 ng/ml, which encompasses the majority of common dermatophytes [1], was used to calculate the PK/PD parameters AUC (0–24 hr)/MIC90 and time-above-MIC90 in plasma and skin.

Results: A total of 30 adult subjects (18 to 60 yr) were dosed. On Days 1 and 8, POS attained peak plasma concentrations at a median Tmax of 8 and 5 hours, respectively. On Days 1 and 8, POS peak skin concentrations were attained at 12 and 3 hours; peak skin concentrations were obtained from a single composite profile. On Day 1, the AUC/MIC90 ratio was 29 and 14 in plasma and skin, respectively. On Day 8, these AUC/MIC90 values increased to 149 and 187 in plasma and skin, respectively. On Day 8, POS concentrations in skin and plasma were several-fold higher than the MIC90 for the entire dosing interval. POS dosed at 400 mg BID PO was safe and well tolerated among healthy subjects.

Figure 1. Mean plasma ± 1 SD) and skin concentration-time profiles of posaconazole on Day 8 after oral administration of posaconazole (400 mg BID) in healthy subjects.

Conclusions: AUC/MIC90 ratio in skin and plasma was similar. POS skin concentration on Day 8 remained several-fold above the MIC90 value¹ for dermatophytes commonly seen in cutaneous infections. These findings demonstrate adequate skin penetration and have implications for treatment of dermatophytic skin and nail infections.

References

1. A. K. Gupta, Y. Kohl, and R. Batra. In vitro activities of posaconazole, ravuconazole, terbinafine, itraconazole and fluconazole against dermatophyte, yeast and non-dermatophyte species. Medical Mycology March 2005, 43 (179–185).