Pharmacokinetics and Safety of Two Voriconazole Formulations after Intravenous Infusion in Healthy Korean Volunteers

Sang Heon Cho, Cheol Woo Kim, Moon Suk Nam, Sang Heon Cho, Cheol Woo Kim, Moon Suk Nam

Abstract

Background: Voriconazole, a triazole antifungal agent exhibits broad-spectrum antifungal activity. It is used to treat severe, invasive fungal infections, including invasive aspergillosis and candidemia. The aim of this study was to assess the pharmacokinetic equivalence of a test formulation (Vorico® Injection) and reference formulation (Vfend® IV) of voriconazole.

Materials and methods: This was a randomized, open-label, single-dose, three-group, two-treatment, two-sequence, two-period, crossover phase I trial with 7-day washout periods (ClinicalTrials.gov identifier NCT02631954). Twenty-four healthy Korean male subjects were recruited. In each group, eight subjects were randomized in a 1:1 manner to receive a single dose of 200 mg test or reference formulation intravenously over 1.5 h. Blood samples were collected over 24 h post-dose, and plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined using a non-compartmental analysis, and safety was evaluated.

Results: Twenty-three subjects completed the study. The geometric mean ratio (90% confidence interval) of the test formulation to reference formulation was 0.9570 (0.8178 - 1.1199) for the maximum plasma concentration (Cmax) and 1.0720 (1.0262 - 1.1198) for the area under the concentration-time curve from dosing to the last quantifiable concentration (AUClast). The mean plasma concentration-time profiles, pharmacokinetic parameters, and safety were comparable between the two formulations.

Conclusion: Equivalent pharmacokinetic characteristics that satisfied the criteria of bioequivalence and similar safety profiles were observed for both test and reference formulations of voriconazole.

Keywords: Bioequivalence; Pharmacokinetics; Safety; Voriconazole.

Conflict of interest statement

No conflicts of interest.

Copyright © 2020 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.

Figures

Figure 1. Mean (± standard deviation) plasma…
Figure 1. Mean (± standard deviation) plasma voriconazole concentration against time, following a single intravenous dose of the reference or test formulation for 1.5 h in healthy male subjects (pharmacokinetic population): (A) linear scale, (B) semi-logarithmic scale.
aVorico® Injection 200 mg. bVfend® IV 200 mg.

References

    1. Chiou CC, Groll AH, Walsh TJ. New drugs and novel targets for treatment of invasive fungal infections in patients with cancer. Oncologist. 2000;5:120–135.
    1. Koltin Y, Hitchcock CA. The search for new triazole antifungal agents. Curr Opin Chem Biol. 1997;1:176–182.
    1. Donnelly JP, De Pauw BE. Voriconazole-a new therapeutic agent with an extended spectrum of antifungal activity. Clin Microbiol Infect. 2004;10(Suppl 1):107–117.
    1. Sandherr M, Maschmeyer G. Pharmacology and metabolism of voriconazole and posaconazole in the treatment of invasive aspergillosis-review of the literature. Eur J Med Res. 2011;16:139–144.
    1. Vehreschild JJ, Böhme A, Reichert D, Kiehl MG, Arenz D, Pankraz K, Kochanek M, Ullmann AJ, Cornely OA. Treatment of invasive fungal infections in clinical practice: a multi-centre survey on customary dosing, treatment indications, efficacy and safety of voriconazole. Int J Hematol. 2008;87:126–131.
    1. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA, van Burik JA, Wingard JR, Patterson TF Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327–360.
    1. Medicines Evaluation Board. Medicine Information Bank. Public assessment report scientific discussion. Voriconazol Synthon 50 mg and 200 mg, film-coated tablets. Voriconazol Synthon 200 mg, powder for solution for infusion (voriconazole). NL/H/2709/001-003/DC. 2014. [Accessed 1 March 2020]. Available at: .
    1. Scholz I, Oberwittler H, Riedel KD, Burhenne J, Weiss J, Haefeli WE, Mikus G. Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype. Br J Clin Pharmacol. 2009;68:906–915.
    1. Wang G, Lei HP, Li Z, Tan ZR, Guo D, Fan L, Chen Y, Hu DL, Wang D, Zhou HH. The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers. Eur J Clin Pharmacol. 2009;65:281–285.
    1. Weiss J, Ten Hoevel MM, Burhenne J, Walter-Sack I, Hoffmann MM, Rengelshausen J, Haefeli WE, Mikus G. CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J Clin Pharmacol. 2009;49:196–204.
    1. Ikeda Y, Umemura K, Kondo K, Sekiguchi K, Miyoshi S, Nakashima M. Pharmacokinetics of voriconazole and cytochrome P450 2C19 genetic status. Clin Pharmacol Ther. 2004;75:587–588.
    1. Chung H, Lee H, Han HK, An H, Lim KS, Lee YJ, Cho JY, Yoon SH, Jang IJ, Yu KS. A pharmacokinetic comparison of two voriconazole formulations and the effect of CYP2C19 polymorphism on their pharmacokinetic profiles. Drug Des Devel Ther. 2015;9:2609–2616.
    1. Lee S, Kim BH, Nam WS, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS. Effect of CYP2C19 polymorphism on the pharmacokinetics of voriconazole after single and multiple doses in healthy volunteers. J Clin Pharmacol. 2012;52:195–203.
    1. Denning DW, Ribaud P, Milpied N, Caillot D, Herbrecht R, Thiel E, Haas A, Ruhnke M, Lode H. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis. 2002;34:563–571.
    1. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubin RH, Wingard JR, Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH, Hodges MR, Schlamm HT, Troke PF, De Pauw B Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408–415.
    1. Howard A, Hoffman J, Sheth A. Clinical application of voriconazole concentrations in the treatment of invasive aspergillosis. Ann Pharmacother. 2008;42:1859–1864.
    1. Zrenner E, Tomaszewski K, Hamlin J, Layton G, Wood N. Effects of multiple doses of voriconazole on the vision of healthy volunteers: a double-blind, placebo-controlled study. Ophthalmic Res. 2014;52:43–52.

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