Advertisement

Clinical Pharmacokinetics

, Volume 45, Issue 7, pp 649–663 | Cite as

Pharmacokinetic/Pharmacodynamic Profile of Voriconazole

  • Ursula Theuretzbacher
  • Franziska Ihle
  • Hartmut Derendorf
Review Article

Abstract

Voriconazole is the first available second-generation triazole with potent activity against a broad spectrum of clinically significant fungal pathogens, including Aspergillus, Candida, Cryptococcus neoformans, and some less common moulds. Voriconazole is rapidly absorbed within 2 hours after oral administration and the oral bioavailability is over 90%, thus allowing switching between oral and intravenous formulations when clinically appropriate. Voriconazole shows nonlinear pharmacokinetics due to its capacity-limited elimination, and its pharmacokinetics are therefore dependent upon the administered dose. With increasing dose, voriconazole shows a superproportional increase in area under the plasma concentration-time curve (AUC). In doses used in children (age <12 years) voriconazole pharmacokinetics appear to be linear. Steady-state plasma concentrations are reached approximately 5 days after both intravenous and oral administration; however, steady state is reached within 24 hours with voriconazole administered as an intravenous loading dose. The volume of distribution of voriconazole is 2–4.6 L/kg, suggesting extensive distribution into extracellular and intracellular compartments. Voriconazole was measured in tissue samples of brain, liver, kidney, heart, lung as well as cerebrospinal fluid. The plasma protein binding is about 60% and independent of dose or plasma concentrations. Clearance is hepatic via N-oxidation by the hepatic cytochrome P450 (CYP) isoenzymes, CYP2C19, CYP2C9 and CYP3A4. The elimination half-life of voriconazole is approximately 6 hours, and approximately 80% of the total dose is recovered in the urine, almost completely as metabolites. As with other azole drugs, the potential for drug interactions is considerable.

Voriconazole shows time-dependent fungistatic activity against Candida species and time-dependent slow fungicidal activity against Aspergillus species. A short post-antifungal effect of voriconazole is evident only for Aspergillus species. The predictive pharmacokinetic/pharmacodynamic parameter for voriconazole treatment efficacy in Candida infections is the free drug AUC from 0 to 24 hour: minimum inhibitory concentration ratio.

Keywords

Fluconazole Triazole Voriconazole Posaconazole Rifabutin 
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 preparation of this article was supported by an educational grant from Pfizer.

References

  1. 1.
    Boucher HW, Groll AH, Chiou CC, et al. Newer systemic antifungal agents: pharmacokinetics, safety and efficacy. Drugs 2004; 64: 1997–20PubMedCrossRefGoogle Scholar
  2. 2.
    Patterson TF. Voriconazole: a viewpoint. Drugs 2002; 62: 2665–6CrossRefGoogle Scholar
  3. 3.
    Purkins L, Wood N, Ghahramani P, et al. Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother 2002; 46: 2546–53PubMedCrossRefGoogle Scholar
  4. 4.
    Purkins L, Wood N, Greenhalgh K, et al. Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety. Br J Clin Pharmacol 2003; 56 Suppl. 1: 10–6PubMedCrossRefGoogle Scholar
  5. 5.
    Purkins L, Wood N, Greenhalgh K, et al. The pharmacokinetics and safety of intravenous voriconazole: a novel wide-spectrum antifungal agent. Br J Clin Pharmacol 2003; 56 Suppl. 1: 2–9PubMedCrossRefGoogle Scholar
  6. 6.
    Lazarus HM, Blumer JL, Yanovich S, et al. Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study. J Clin Pharmacol 2002; 42: 395–402PubMedCrossRefGoogle Scholar
  7. 7.
    Jeu L, Piacenti FJ, Lyakhovetskiy AG, et al. Voriconazole. Clin Ther 2003; 25: 1321–81PubMedCrossRefGoogle Scholar
  8. 8.
    Pfizer Inc. Label: voriconazole for injection, tablets, oral suspension: LAB-0271-12; 2005 MarGoogle Scholar
  9. 9.
    Robatel C, Rusca M, Padoin C, et al. Disposition of voriconazole during continuous veno-venous haemodiafiltration (CVVHDF) in a single patient. J Antimicrob Chemother 2004; 54: 269–70PubMedCrossRefGoogle Scholar
  10. 10.
    Craig WA, Suh B. Protein binding and the antimircobial effects: methods for the determination of protein binding. In: Lorian V, editor. Antibiotics in laboratory medicine. Philadelphia (PA): Lippincott Williams & Wilkins, 1991: 367–402Google Scholar
  11. 11.
    Zhanel GG, Saunders DG, Hoban DJ, et al. Influence of human serum on antifungal pharmacodynamics with Candida albicans. Antimicrob Agents Chemother 2001; 45: 2018–22PubMedCrossRefGoogle Scholar
  12. 12.
    Andes D, Marchillo K, Conklin R, et al. Pharmacodynamics of a new triazole, posaconazole, in a murine model of disseminated candidiasis. Antimicrob Agents Chemother 2004; 48: 137–42PubMedCrossRefGoogle Scholar
  13. 13.
    Andes D, Marchillo K, Stamstad T, et al. In vivo pharmacodynamics of a new triazole, ravuconazole, in a murine candidiasis model. Antimicrob Agents Chemother 2003; 47: 1193–9PubMedCrossRefGoogle Scholar
  14. 14.
    Andes D, Marchillo K, Stamstad T, et al. In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model. Antimicrob Agents Chemother. 2003; 47: 3165–9PubMedCrossRefGoogle Scholar
  15. 15.
    Pearson MM, Rogers PD, Cleary JD, et al. Voriconazole: a new triazole antifungal agent. Ann Pharmacother 2003; 37: 420–32PubMedCrossRefGoogle Scholar
  16. 16.
    Groll A, Petraitiene R, Petraitis V, et al. Differential intrapulmonary distribution of voriconazole and liposomal amphotericin B in noninfected rabbits. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2003 Sep 14-17; Chicago (IL)Google Scholar
  17. 17.
    Lopes Bezerra LM, Filler SG. Interactions of Aspergillus fumigatus with endothelial cells: internalisation, injury and stimulation of tissue factor activity. Blood 2004; 103: 2143–9PubMedCrossRefGoogle Scholar
  18. 18.
    Luque IG, Hernández AP, Ballesta S, et al. Intracellular penetration and activity of voriconazole in human polymorphonuclear leukozytes. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2003 Sep 14-17; Chicago (IL)Google Scholar
  19. 19.
    Ballesta S, Garcia I, Perea EJ, et al. Uptake and intracellular activity of voriconazole in human polymorphonuclear leucocytes. J Antimicrob Chemother 2005; 55: 785–7PubMedCrossRefGoogle Scholar
  20. 20.
    Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos 2003; 31: 540–7PubMedCrossRefGoogle Scholar
  21. 21.
    Roffey SJ, Cole S, Comby P, et al. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. Drug Metab Dispos 2003; 31: 731–41PubMedCrossRefGoogle Scholar
  22. 22.
    Inoue K, Yamazaki H, Imiya K, et al. Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxylation and S-mephenytoin 4/t’-hydroxylation activities in livers of Japanese and Caucasian populations. Pharmacogenetics 1997; 7: 103–13PubMedCrossRefGoogle Scholar
  23. 23.
    Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis 2003; 36: 630–7PubMedCrossRefGoogle Scholar
  24. 24.
    Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994; 270: 414–23PubMedGoogle Scholar
  25. 25.
    Hoffman HL, Rathbun RC. Review of the safety and efficacy of voriconazole. Expert Opin Investig Drugs 2002; 11: 409–29PubMedCrossRefGoogle Scholar
  26. 26.
    Purkins L, Wood N, Kleinermans D, et al. Effect of food on the pharmacokinetics of multiple-dose oral voriconazole. Br J Clin Pharmacol 2003; 56 Suppl. 1: 17–23PubMedCrossRefGoogle Scholar
  27. 27.
    Donnelly JP, De Pauw BE. Voriconazole-a new therapeutic agent with an extended spectrum of antifungal activity. Clin Microbiol Infect 2004; 10 Suppl. 1: 107–17PubMedCrossRefGoogle Scholar
  28. 28.
    Wingard JR, Leather H. A new era of antifungal therapy. Biol Blood Marrow Transplant 2004; 10: 73–90PubMedCrossRefGoogle Scholar
  29. 29.
    Ally R, Schürmann D, Kreisel W, et al. Randomized, double blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophagteal candidiasis in immunocompromised patients. Clin Microbiol Infect Dis 2001; 33: 1447–54Google Scholar
  30. 30.
    Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002; 346: 225–34PubMedCrossRefGoogle Scholar
  31. 31.
    Vandecasteele SJ, Van Wijngaerden E, Peetermans WE. Two cases of severe phototoxic reactions related to long-term out-patient treatment with voriconazole. Eur J Clin Microbiol Infect Dis 2004; 23: 656–7PubMedCrossRefGoogle Scholar
  32. 32.
    Drusano GL. How does a patient maximally benefit from anti-infective chemotherapy? Clin Microbiol Infect Dis 2004; 39: 1245–6Google Scholar
  33. 33.
    Andes D. Clinical pharmacodynamics of antifungals. Infect Dis Clin North Am 2003; 17: 635–49PubMedCrossRefGoogle Scholar
  34. 34.
    Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]). Reference method for broth dilution antifungal susceptibility testing of yeasts: approved standard second edition M27-A2. Wayne (PA): NCCLS, 2002Google Scholar
  35. 35.
    Drago M, Scaltrito MM, Morace G. In vitro activity of voriconazole and other antifungal agents against clinical isolates of Candida glabrata and Candida krusei. Eur J Clin Microbiol Infect Dis 2004; 23: 619–24PubMedCrossRefGoogle Scholar
  36. 36.
    Pfaller MA, Messer SA, Boyken L, et al. Geographic variation in the susceptibilities of invasive isolates of Candida glabrata to seven systemically active antifungal agents: a global assessment from the ARTEMIS antifungal surveillance program conducted in 2001 and 2002. J Clin Microbiol 2004; 42: 3142–6PubMedCrossRefGoogle Scholar
  37. 37.
    Messer SA, Kirby JT, Sader HS, et al. Initial results from a longitudinal international surveillance programme for anidulafungin (2003). J Antimicrob Chemother 2004; 54: 1051–6PubMedCrossRefGoogle Scholar
  38. 38.
    Diekema DJ, Messer SA, Hollis RJ, et al. Activities of caspofungin, itraconazole, posaconazole, ravueonazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J Clin Microbiol 2003; 41: 3623–6PubMedCrossRefGoogle Scholar
  39. 39.
    Pfaller MA, Diekema DJ, Messer SA, et al. Activities of fluconazole and voriconazole against 1586 recent clinical isolates of Candida species determined by Broth microdilution, disk diffusion, and Etest methods: report from the ARTEMIS Global Antifungal Susceptibility Program, 2001. J Clin Microbiol 2003; 41: 1440–6PubMedCrossRefGoogle Scholar
  40. 40.
    Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]). Reference method for broth dilution antifungal susceptibility testing of filamentous fungi: approved standard M38-A. Standards Vol. 22 No. 16. Wayne (PA): NCCLS, 2002Google Scholar
  41. 41.
    Pfaller MA, Messer SA, Hollis RJ, et al. Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B 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
  42. 42.
    Gil-Lamaignere C, Hess R, Salvenmoser S. Effect of media composition and in vitro activity of posaconazole, caspofungin and voriconazole against zygomycetes. J Antimicrob Chemother 2005; 55: 1016–9PubMedCrossRefGoogle Scholar
  43. 43.
    Müller M, de la Pena A, Derendorf H. Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: kill curves versus MIC. Antimicrob Agents Chemother. 2004; 48: 369–77CrossRefGoogle Scholar
  44. 44.
    Burgess DS, Hastings RW, Summers KK, et al. Pharmacodynamics of fluconazole, itraconazole, and amphotericin B against Candida albicans. Diagn Microbiol Infect Dis 2000; 36: 13–8PubMedCrossRefGoogle Scholar
  45. 45.
    Klepser ME, Malone D, Lewis RE, et al. Evaluation of voriconazole pharmacodynamics using time-kill methodology. Antimicrob Agents Chemother 2000; 44: 1917–20PubMedCrossRefGoogle Scholar
  46. 46.
    Pfaller MA, Sheehan DJ, Rex JH. Determination of fungicidal activities against yeasts and molds: lessons learned from bactericidal testing and the need for standardization. Clin Microbiol Rev 2004; 17: 268–80PubMedCrossRefGoogle Scholar
  47. 47.
    Manavathu EK, Cutright JL, Chandrasekar PH. Organism-dependent fungicidal activities of azoles. Antimicrob Agents Chemother 1998; 42: 3018–21PubMedGoogle Scholar
  48. 48.
    Varanasi NL, Baskaran I, Alangaden GJ, et al. Novel effect of voriconazole on conidiation of Aspergillus species. Int J Antimicrob Agents 2004; 23: 72–9PubMedCrossRefGoogle Scholar
  49. 49.
    Chandrasekar PH, Cutright J, Manavathu E. Efficacy of voriconazole against invasive pulmonary aspergillosis in a guinea-pig model. J Antimicrob Chemother 2000; 45: 673–6PubMedCrossRefGoogle Scholar
  50. 50.
    Kirkpatrick WR, McAtee RK, Fothergill AW, et al. Efficacy of voriconazole in a guinea pig model of disseminated invasive Aspergillosis. Antimicrob Agents Chemother 2000; 44: 2865–8PubMedCrossRefGoogle Scholar
  51. 51.
    Murphy M, Bernard EM, Ishimaru T, et al. Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive aspergillosis. Antimicrob Agents Chemother 1997; 41: 696–8PubMedGoogle Scholar
  52. 52.
    George D, Miniter P, Andriole VT. Efficacdy of UK-109,496, a new azole antifungal agent, in an experimental model of invasive aspergillosis. Antimicrob Agents Chemother 1996; 40: 86–91PubMedGoogle Scholar
  53. 53.
    Ghannoum MA, Okogbule-Wonodi I, Bhat N, et al. Antifungal activity of voriconazole (UK-109,496), fluconazole and amphetericin B against hemtogenous Candida krusei infection in neutropenic guinea pig model. J Chemother 1999; 11: 34–9PubMedGoogle Scholar
  54. 54.
    Chryssanthou E, Sjolin J. Post-antifungal effect of amphotericin B and voriconazole against Aspergillus fumigatus analysed by an automated method based on fungal CO2 production: dependence on exposure time and drug concentration. J Antimicrob Chemother 2004; 54: 940–3PubMedCrossRefGoogle Scholar
  55. 55.
    Manavathu EK, Ramesh MS, Baskaran I, et al. A comparative study of the post-antifungal effect (PAFE) of amphotericin B, triazoles and echinocandins on Aspergillus fumigatus and Candida albicans. J Antimicrob Chemother 2004; 53: 386–9PubMedCrossRefGoogle Scholar
  56. 56.
    Garcia MT, Llorente MT, Lima JE, et al. Activity of voriconazole: post-antifungal effect, effects of low concentrations and of pretreatment on the susceptibility of Candida albicans to leucocytes. Scand J Infect Dis 1999; 31: 501–4PubMedCrossRefGoogle Scholar
  57. 57.
    Louie A, Drusano GL, Banerjee P, et al. Pharmacodynamics of fluconazole in a murine model of systemic candidiasis. Antimicrob Agents Chemother 1998; 42: 1105–9PubMedGoogle Scholar
  58. 58.
    Andes D, van Ogtrop M. Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model. Antimicrob Agents Chemother 1999; 43: 2116–20PubMedGoogle Scholar
  59. 59.
    Rex JH, Pfaller MA, Walsh TJ, et al. Antifungal susceptibility testing: practical aspects and current challenges. Clin Microbiol Rev 2001; 14: 643–58PubMedCrossRefGoogle Scholar
  60. 60.
    Lee SC, Fung CP, Huang JS, et al. Clinical correlates of antifungal macrodilution susceptibility test results for non-AIDS patients with severe Candida infections treated with fluconazole. Antimicrob Agents Chemother 2000; 44: 2715–8PubMedCrossRefGoogle Scholar
  61. 61.
    Craig WA. Pharmacokinetic/pharmacodynamic parameters: rational for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26: 1–12PubMedCrossRefGoogle Scholar
  62. 62.
    Kullberg B, Pappas P, Ruhnke M, et al. Voriconazole compared with a strategy of amphotericin B followed by fluconazole of candidaemia in non-neutropenic patients [abstract no. O245]. 14th European Congress of Microbiology and Infectious Diseases; 2004 May 1–4; PragueGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Ursula Theuretzbacher
    • 1
  • Franziska Ihle
    • 2
  • Hartmut Derendorf
    • 2
  1. 1.Center for Anti-Infective AgentsViennaAustria
  2. 2.Department of Pharmaceutics, College of PharmacyUniversity of FloridaGainesvilleUSA

Personalised recommendations