This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Purkins, L.
Right arrow Articles by Kleinermans, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Purkins, L.
Right arrow Articles by Kleinermans, D.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, August 2002, p. 2546-2553, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2546-2553.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics and Safety of Voriconazole following Intravenous- to Oral-Dose Escalation Regimens

L. Purkins,1 N. Wood,1* P. Ghahramani,1 K. Greenhalgh,1 M. J. Allen,1 and D. Kleinermans2

Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, United Kingdom,1 Pfizer Clinical Research Unit, Hôpital Erasme, B-1070 Brussels, Belgium2

Received 7 March 2002/ Accepted 19 April 2002

In this study, the safety, tolerability, and pharmacokinetics of intravenous (i.v.)- to oral-dose regimens of voriconazole were evaluated with a group of 42 healthy men, 41 of whom completed the study. Two cohorts of subjects participated in the study. Cohort 1 (n = 28) took part in two study periods, each consisting of 14 days separated by a minimum 7-day washout. In one of the periods, 14 subjects received 6 mg/kg i.v. twice a day (b.i.d.) on day 1 followed by 3 mg/kg i.v. b.i.d. on days 2 to 7 and were then switched to 200 mg orally b.i.d. for days 8 to 14. In the other period, subjects received 6 mg/kg i.v. b.i.d. on day 1 followed by 5 mg/kg i.v. b.i.d. on days 2 to 7and were then switched to 400 mg orally b.i.d. for days 8 to 14. The remaining 14 subjects in cohort 1 received a matching placebo throughout the study. In cohort 2 (n = 14), 7 subjects received 6 mg/kg i.v. b.i.d. on day 1 followed by 4 mg/kg i.v. b.i.d. on days 2 to 7 and were then switched to 300 mg orally b.i.d. for days 8 to 14. The remaining seven subjects in cohort 2 received a matching placebo. Blood samples were taken prior to dosing on days 1 to 6 and on days 8 to 13. Blood samples were drawn prior to dosing and at frequent intervals up to 12 h following the morning dose on days 7 and 14 of each study period. The samples were assayed for voriconazole by a high-performance liquid chromatography method. The maximum concentration in plasma (Cmax) occurred at the end of the 1-h i.v. infusion and between 1.4 and 1.8 h after oral administration. Voriconazole exhibited nonlinear pharmacokinetics, possibly due to saturable metabolism. For cohort 1, both Cmax and the area under the concentration-time curve within a dosage interval (AUC{tau}) increased disproportionately with dose for both i.v. and oral dosing. For i.v. dosing, a 1.7-fold increase in dose resulted in 2.4- and 3.1-fold increases in Cmax and AUC{tau}, respectively. Similarly, a 2-fold increase in oral dosing resulted in 2.8- and 3.9-fold increases in Cmax and AUC{tau}, respectively. The mean values for Cmax observed following oral dosing were lower than those obtained after i.v. administration, ranging from 62.7 to 89.6% of the i.v. value. After the switch from i.v. to oral dosing, most subjects achieved steady state by day 4, and mean minimum concentrations in plasma remained above clinically important MICs. The pharmacokinetic profiles for saliva followed a pattern similar to those observed for plasma; there was a highly significant correlation between plasma and saliva voriconazole concentrations (P < 0.0001). Voriconazole was well tolerated; the most commonly reported adverse events in voriconazole-treated subjects were mild to moderate headache, rash, and abnormal vision. Visual function tests detected no further abnormalities during voriconazole treatment.

* Corresponding author. Mailing address: Pfizer Global Research and Development, Ramsgate Rd., Sandwich, Kent CT13 9NJ, United Kingdom. Phone: 44 1304 643441. Fax: 44 1304 652590. E-mail: Nolan_Wood{at}sandwich.pfizer.com.

Antimicrobial Agents and Chemotherapy, August 2002, p. 2546-2553, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2546-2553.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Crandon, J. L., Banevicius, M. A., Fang, A. F., Crownover, P. H., Knauft, R. F., Pope, J. S., Russomanno, J. H., Shore, E., Nicolau, D. P., Kuti, J. L. (2009). Bronchopulmonary Disposition of Intravenous Voriconazole and Anidulafungin Given in Combination to Healthy Adults. Antimicrob. Agents Chemother. 53: 5102-5107 [Abstract] [Full Text]  
  • Bruggemann, R. J. M., Blijlevens, N. M. A., Burger, D. M., Franke, B., Troke, P. F., Donnelly, J. P. (2009). Pharmacokinetics and safety of 14 days intravenous voriconazole in allogeneic haematopoietic stem cell transplant recipients. J Antimicrob Chemother 0: dkp416v1-dkp416 [Abstract] [Full Text]  
  • van de Sande, W. W. J., Mathot, R. A. A., ten Kate, M. T., van Vianen, W., Tavakol, M., Rijnders, B. J. A., Bakker-Woudenberg, I. A. J. M. (2009). Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin. Antimicrob. Agents Chemother. 53: 2005-2013 [Abstract] [Full Text]  
  • Karlsson, M. O., Lutsar, I., Milligan, P. A. (2009). Population Pharmacokinetic Analysis of Voriconazole Plasma Concentration Data from Pediatric Studies. Antimicrob. Agents Chemother. 53: 935-944 [Abstract] [Full Text]  
  • Andes, D., Pascual, A., Marchetti, O. (2009). Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications. Antimicrob. Agents Chemother. 53: 24-34 [Full Text]  
  • Gencer, S., Ozer, S., Demirhan, G., Ak, O., Batirel, A. (2008). Angio-oedema as an unusual tolerable side effect of voriconazole therapy. J Med Microbiol 57: 1028-1031 [Abstract] [Full Text]  
  • Lignell, A., Lowdin, E., Cars, O., Sjolin, J. (2008). Characterization of the inhibitory effect of voriconazole on the fungicidal activity of amphotericin B against Candida albicans in an in vitro kinetic model. J Antimicrob Chemother 62: 142-148 [Abstract] [Full Text]  
  • Yanni, S. B., Annaert, P. P., Augustijns, P., Bridges, A., Gao, Y., Benjamin, D. K. Jr., Thakker, D. R. (2008). Role of Flavin-Containing Monooxygenase in Oxidative Metabolism of Voriconazole by Human Liver Microsomes. Drug Metab. Dispos. 36: 1119-1125 [Abstract] [Full Text]  
  • Troke, P., Aguirrebengoa, K., Arteaga, C., Ellis, D., Heath, C. H., Lutsar, I., Rovira, M., Nguyen, Q., Slavin, M., Chen, S. C. A., on behalf of the Global Scedosporium Study Group, (2008). Treatment of Scedosporiosis with Voriconazole: Clinical Experience with 107 Patients. Antimicrob. Agents Chemother. 52: 1743-1750 [Abstract] [Full Text]  
  • Stella, V. J., He, Q. (2008). Cyclodextrins. Toxicol Pathol 36: 30-42 [Abstract] [Full Text]  
  • Goodwin, M. L., Drew, R. H. (2008). Antifungal serum concentration monitoring: an update. J Antimicrob Chemother 61: 17-25 [Abstract] [Full Text]  
  • Levin, M.-D., den Hollander, J. G., van der Holt, B., Rijnders, B. J., van Vliet, M., Sonneveld, P., van Schaik, R. H. N. (2007). Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms. J Antimicrob Chemother 60: 1104-1107 [Abstract] [Full Text]  
  • Fuhrmann, V., Schenk, P., Jaeger, W., Miksits, M., Kneidinger, N., Warszawska, J., Holzinger, U., Kitzberger, R., Thalhammer, F. (2007). Pharmacokinetics of voriconazole during continuous venovenous haemodiafiltration. J Antimicrob Chemother 60: 1085-1090 [Abstract] [Full Text]  
  • Weiler, S., Zoller, H., Graziadei, I., Vogel, W., Bellmann-Weiler, R., Joannidis, M., Bellmann, R. (2007). Altered Pharmacokinetics of Voriconazole in a Patient with Liver Cirrhosis. Antimicrob. Agents Chemother. 51: 3459-3460 [Full Text]  
  • Eiden, C., Peyriere, H., Cociglio, M., Djezzar, S., Hansel, S., Blayac, J.-P., Hillaire-Buys, D., for the Network of the French Pharmacovigilance Ce, (2007). Adverse Effects of Voriconazole: Analysis of the French Pharmacovigilance Database. The Annals of Pharmacotherapy 41: 755-763 [Abstract] [Full Text]  
  • Pascual, A., Nieth, V., Calandra, T., Bille, J., Bolay, S., Decosterd, L. A., Buclin, T., Majcherczyk, P. A., Sanglard, D., Marchetti, O. (2007). Variability of Voriconazole Plasma Levels Measured by New High-Performance Liquid Chromatography and Bioassay Methods. Antimicrob. Agents Chemother. 51: 137-143 [Abstract] [Full Text]  
  • Meletiadis, J., Chanock, S., Walsh, T. J. (2006). Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy. Clin. Microbiol. Rev. 19: 763-787 [Abstract] [Full Text]  
  • Geist, M. J.P., Egerer, G., Burhenne, J., Mikus, G. (2006). Safety of Voriconazole in a Patient with CYP2C9*2/CYP2C9*2 Genotype.. Antimicrob. Agents Chemother. 50: 3227-3228 [Full Text]  
  • Smith, J., Safdar, N., Knasinski, V., Simmons, W., Bhavnani, S. M., Ambrose, P. G., Andes, D. (2006). Voriconazole therapeutic drug monitoring.. Antimicrob. Agents Chemother. 50: 1570-1572 [Abstract] [Full Text]  
  • Pfaller, M. A., Diekema, D. J., Rex, J. H., Espinel-Ingroff, A., Johnson, E. M., Andes, D., Chaturvedi, V., Ghannoum, M. A, Odds, F. C., Rinaldi, M. G., Sheehan, D. J., Troke, P., Walsh, T. J., Warnock, D. W. (2006). Correlation of MIC with Outcome for Candida Species Tested against Voriconazole: Analysis and Proposal for Interpretive Breakpoints.. J. Clin. Microbiol. 44: 819-826 [Abstract] [Full Text]  
  • Tan, K., Brayshaw, N., Tomaszewski, K., Troke, P., Wood, N. (2006). Investigation of the Potential Relationships Between Plasma Voriconazole Concentrations and Visual Adverse Events or Liver Function Test Abnormalities. J Clin Pharmacol 46: 235-243 [Abstract] [Full Text]  
  • Dowell, J. A., Schranz, J., Baruch, A., Foster, G. (2005). Safety and Pharmacokinetics of Coadministered Voriconazole and Anidulafungin. J Clin Pharmacol 45: 1373-1382 [Abstract] [Full Text]  
  • Bagg, J., Sweeney, M P., Davies, A. N, Jackson, M. S, Brailsford, S. (2005). Voriconazole susceptibility of yeasts isolated from the mouths of patients with advanced cancer. J Med Microbiol 54: 959-964 [Abstract] [Full Text]  
  • Canton, E., Peman, J., Gobernado, M., Viudes, A., Espinel-Ingroff, A. (2005). Synergistic Activities of Fluconazole and Voriconazole with Terbinafine against Four Candida Species Determined by Checkerboard, Time-Kill, and Etest Methods. Antimicrob. Agents Chemother. 49: 1593-1596 [Abstract] [Full Text]  
  • Burn, A. K., Fothergill, A. W., Kirkpatrick, W. R., Coco, B. J., Patterson, T. F., McCarthy, D. I., Rinaldi, M. G., Redding, S. W. (2004). Comparison of Antifungal Susceptibilities to Fluconazole and Voriconazole of Oral Candida glabrata Isolates from Head and Neck Radiation Patients. J. Clin. Microbiol. 42: 5846-5848 [Abstract] [Full Text]  
  • Krieter, P., Flannery, B., Musick, T., Gohdes, M., Martinho, M., Courtney, R. (2004). Disposition of Posaconazole following Single-Dose Oral Administration in Healthy Subjects. Antimicrob. Agents Chemother. 48: 3543-3551 [Abstract] [Full Text]  
  • Robatel, C., Rusca, M., Padoin, C., Marchetti, O., Liaudet, L., Buclin, T. (2004). Disposition of voriconazole during continuous veno-venous haemodiafiltration (CVVHDF) in a single patient. J Antimicrob Chemother 54: 269-270 [Abstract] [Full Text]  
  • Andes, D., Marchillo, K., Stamstad, T., Conklin, R. (2003). In Vivo Pharmacokinetics and Pharmacodynamics of a New Triazole, Voriconazole, in a Murine Candidiasis Model. Antimicrob. Agents Chemother. 47: 3165-3169 [Abstract] [Full Text]  
  • Martinez, V., Guillou, J.-L. L., Lamer, C., Jouan, M. L., Tod, M., Dromer, F. (2003). Serum Voriconazole Levels following Administration via Percutaneous Jejunostomy Tube. Antimicrob. Agents Chemother. 47: 3375-3375 [Full Text]  
  • Courtney, R., Pai, S., Laughlin, M., Lim, J., Batra, V. (2003). Pharmacokinetics, Safety, and Tolerability of Oral Posaconazole Administered in Single and Multiple Doses in Healthy Adults. Antimicrob. Agents Chemother. 47: 2788-2795 [Abstract] [Full Text]  
  • Roffey, S. J., Cole, S., Comby, P., Gibson, D., Jezequel, S. G., Nedderman, A. N. R., Smith, D. A., Walker, D. K., Wood, N. (2003). THE DISPOSITION OF VORICONAZOLE IN MOUSE, RAT, RABBIT, GUINEA PIG, DOG, AND HUMAN. Drug Metab. Dispos. 31: 731-741 [Abstract] [Full Text]  
  • Hyland, R., Jones, B. C., Smith, D. A. (2003). Identification of the Cytochrome P450 Enzymes Involved in the N-Oxidation of Voriconazole. Drug Metab. Dispos. 31: 540-547 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»