Advertisement

Clinical Pharmacokinetics

, Volume 44, Issue 2, pp 211–220 | Cite as

Oral Bioavailability of Posaconazole in Fasted Healthy Subjects

Comparison Between Three Regimens and Basis for Clinical Dosage Recommendations
  • Farkad Ezzet
  • David Wexler
  • Rachel Courtney
  • Gopal Krishna
  • Josephine Lim
  • Mark Laughlin
Original Research Article

Abstract

Background and objective

Posaconazole is a potent, extended-spectrum triazole antifungal agent currently in clinical development for the treatment of invasive fungal infections. This study was conducted to compare the bioavailability and resulting serum concentrations of posaconazole 800mg following administration of three different dose regimens to fasting adults.

Study design

This was a randomised, open-label, three-way crossover study.

Methods

Subjects fasted 12 hours before and 48 hours after the administration of posaconazole oral suspension (800mg) given as a single dose (regimen A), 400mg every 12 hours (regimen B) or 200mg every 6 hours (regimen C). Plasma posaconazole concentrations were determined for 48 hours after the initial dose and subjects completed a 1-week washout period between treatment regimens. A one-compartment oral model with first-order rate of absorption and first-order rate of elimination was fitted to the plasma concentration-time data. Differences in exposure were investigated by allowing the bioavailability fraction to vary among regimens.

Study participants

A total of 18 healthy men were enrolled in and completed the study.

Main outcome measures and results

Posaconazole relative bioavailability was estimated to be significantly different among regimens (p < 0.0001) and increased with the number of doses, such that regimen B/regimen A = 1.98 ± 0.35, representing a 98% increase, and regimen C/regimen A = 3.20 ± 0.69, or a 220% increase. With use of the one-compartment model, the population steady-state values for area under the concentration-time curve over 24 hours were predicted to be 3900, 7700 and 12 400 μg · h/L, with average plasma concentrations of 162, 320 and 517 μg/L for regimens and C, respectively.

Conclusion

These data suggest that divided daily dose administration (every 12 or 6 hours) significantly increases posaconazole exposure under fasted conditions.

Keywords

Posaconazole Invasive Fungal Infection Dose Administration Absorption Rate Constant Bioavailability Fraction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors would like to thank the Arkansas Research Medical Testing Center for conducting the study. This work was supported by the Schering-Plough Research Institute.

References

  1. 1.
    Carrillo AJ, Guarro J. In vitro activities of four novel triazoles against Scedosporium spp. Antimicrob Agents Chemother 2001; 45: 2151–3PubMedCrossRefGoogle Scholar
  2. 2.
    Connolly P, Wheat LJ, Schnizlein-Bick C, et al. Comparison of a new triazole, posaconazole, with itraconazole and amphotericin for treatment of histoplasmosis following pulmonary challenge in immunocompromised mice. Antimicrob Agents Chemother 2000; 44: 2604–8PubMedCrossRefGoogle Scholar
  3. 3.
    Dannaoui E, Meletiadis J, Mouton JW, et al. In vitro susceptibilities of Zygomycetes to conventional and new antifungals. J Antimicrob Chemother 2003; 51: 45–52PubMedCrossRefGoogle Scholar
  4. 4.
    Gonzalez GM, Sutton DA, Thompson E, et al. In vitro activities of approved and investigational antifungal agents against 44 clinical isolates of basidiomycetous fungi. Antimicrob Agents Chemother 2001; 45: 633–5PubMedCrossRefGoogle Scholar
  5. 5.
    Lutz JE, Clemons KV, Aristizabal BH, et al. Activity of the triazole SCH 56592 against disseminated murine coccidioidomycosis. Antimicrob Agents Chemother 1997; 41: 1558–61PubMedGoogle Scholar
  6. 6.
    Manavathu EK, Cutright JL, Loebenberg D, et al. A comparative study of the in vitro susceptibilities of clinical and laboratory-selected resistant isolates of Aspergillus spp. to amphotericin itraconazole, voriconazole and posaconazole (SCH 56592). J Antimicrob Chemother 2000; 46: 229–34PubMedCrossRefGoogle Scholar
  7. 7.
    Perfect JR, Cox GM, Dodge RK, et al. In vitro and in vivo efficacies of the azole SCH56592 against Cryptococcus neoformans. Antimicrob Agents Chemother 1996; 40: 1910–3PubMedGoogle Scholar
  8. 8.
    Pfaller MA, Messer SA, Hollis RJ, et al. Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin against 239 clinical isolates of Aspergillus spp. and other filamentous fungi: report from SENTRY Antimicrobial Surveillance Program, 2000. Antimicrob Agents Chemother 2002; 46: 1032–7PubMedCrossRefGoogle Scholar
  9. 9.
    Sugar AM, Liu XP. In vitro and in vivo activities of SCH 56592 against Blastomyces dermatitidis. Antimicrob Agents Chemother 1996; 40: 1314–6PubMedGoogle Scholar
  10. 10.
    Uchida K, Yokota N, Yamaguchi H. In vitro antifungal activity of posaconazole against various pathogenic fungi. Int J Antimicrob Agents 2001; 18: 167–72PubMedCrossRefGoogle Scholar
  11. 11.
    Laverdiere M, Hoban D, Restieri C, et al. In vitro activity of three new triazoles and one echinocandin against Candida bloodstream isolates from cancer patients. J Antimicrob Chemother 2002; 50: 119–23PubMedCrossRefGoogle Scholar
  12. 12.
    Fothergill AW. Identification of dematiaceous fungi and their role in human disease. Clin Infect Dis 1996; 22 Suppl. 2: S179–84PubMedCrossRefGoogle Scholar
  13. 13.
    Cacciapuoti A, Loebenberg D, Corcoran E, et al. In vitro and in vivo activities of SCH 56592 (posaconazole), a new triazole antifungal agent, against Aspergillus and Candida. Antimicrob Agents Chemother 2000; 44: 2017–22PubMedCrossRefGoogle Scholar
  14. 14.
    Manavathu EK, Abraham OC, Chandrasekar PH. Isolation and in vitro susceptibility to amphotericin itraconazole and posaconazole of voriconazole-resistant laboratory isolates of Aspergillus fumigatus. Clin Microbiol Infect 2001; 7: 130–7PubMedCrossRefGoogle Scholar
  15. 15.
    Petraitiene R, Petraitis V, Groll AH, et al. Antifungal activity and pharmacokinetics of posaconazole (SCH 56592) in treatment and prevention of experimental invasive pulmonary aspergillosis: correlation with galactomannan antigenemia. Antimicrob Agents Chemother 2001; 45: 857–69PubMedCrossRefGoogle Scholar
  16. 16.
    Heimark L, Shipkova P, Greene J, et al. Mechanism of azole antifungal activity as determined by liquid chromatographic/mass spectrometric monitoring of ergosterol biosynthesis. J Mass Spectrom 2002; 37: 265–9PubMedCrossRefGoogle Scholar
  17. 17.
    Chiller TM, Stevens DA. Treatment strategies for Aspergillus infections. Drug Resist Updat 2000; 3: 89–97PubMedCrossRefGoogle Scholar
  18. 18.
    Graybill JR. Changing strategies for treatment of systemic mycoses. Braz J Infect Dis 2000; 4: 47–54PubMedGoogle Scholar
  19. 19.
    Woo SB, Sonis ST, Monopoli MM, et al. A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients. Cancer 1993; 72: 1612–7PubMedCrossRefGoogle Scholar
  20. 20.
    Arikan S, Rex JH. New agents for treatment of systemic fungal infections. Opin Emerg Drugs 2000; 5: 135–60CrossRefGoogle Scholar
  21. 21.
    Marr KA, Carter RA, Crippa F, et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34: 909–17PubMedCrossRefGoogle Scholar
  22. 22.
    Oakley KL, Morrisey G, Denning DW. Efficacy of SCH-56592 in a temporarily neutropenic murine model of invasive aspergillosis with an itraconzaole-susceptible and an itraconazole-resistant isolate of Aspergillus fumigatus. Antimicrob Agents Chemother 1997; 41: 1504–7PubMedGoogle Scholar
  23. 23.
    Courtney R, Pai S, Laughlin M, et al. Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother 2003; 47: 2788–95PubMedCrossRefGoogle Scholar
  24. 24.
    Courtney R, Wexler D, Radwanski E, et al. Effect of food on the relative bioavailability of two oral fomulations of posaconazole in healthy adults. Br J Clin Pharmacol 2004; 57: 218–22PubMedCrossRefGoogle Scholar
  25. 25.
    Saha P, Kou J. Effect of solubilizing excipients on permeation of poorly water-soluble compounds across Caco-2 monolayers. Eur J Pharm Biopharm 2000; 50: 403–11PubMedCrossRefGoogle Scholar
  26. 26.
    Nomeir AA, Kumari P, Hilbert MJ, et al. Pharmacokinetics of SCH 56592, a new azole broad-spectrum antifungal agent, in mice, rats, rabbits, dogs, and cynomolgus monkeys. Antimicrob Agents Chemother 2000; 44: 727–31PubMedCrossRefGoogle Scholar
  27. 27.
    Ezzet F, Wexler D, Courtney R, et al. The pharmacokinetics of posaconazole in neutropenic oncology patients [abstract no. A26]. Interscience Conference on Antimicrobial Agents and Chemotherapy; 2001 Dec 16–19; Chicago, 4Google Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Farkad Ezzet
    • 1
  • David Wexler
    • 1
  • Rachel Courtney
    • 1
  • Gopal Krishna
    • 1
  • Josephine Lim
    • 1
  • Mark Laughlin
    • 1
  1. 1.Schering-Plough Research InstituteKenilworthUSA

Personalised recommendations