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 Smith, P. F.
Right arrow Articles by Martin, D. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Smith, P. F.
Right arrow Articles by Martin, D. E.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, October 2007, p. 3574-3581, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00152-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Phase I and II Study of the Safety, Virologic Effect, and Pharmacokinetics/Pharmacodynamics of Single-Dose 3-O-(3',3'-Dimethylsuccinyl)Betulinic Acid (Bevirimat) against Human Immunodeficiency Virus Infection{triangledown}

Patrick F. Smith,1,2* Abayomi Ogundele,1,2 Alan Forrest,1 John Wilton,3 Karl Salzwedel,4 Judy Doto,4 Graham P. Allaway,4 and David E. Martin4

University at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York,1 Roswell Park Cancer Institute, Buffalo, New York,2 Emprexe Analytical, LLC, Buffalo, New York,3 Panacos Pharmaceuticals, Gaithersburg, Maryland4

Received 1 February 2007/ Returned for modification 13 May 2007/ Accepted 8 July 2007

Bevirimat [3-O-(3',3'-dimethylsuccinyl)betulinic acid] is the first in a new class of anti-human immunodeficiency virus (HIV) drugs that inhibit viral maturation by specifically blocking cleavage of the Gag capsid (CA) precursor, CA-SP1, to mature CA protein, resulting in defective core condensation and release of immature noninfectious virions. Four cohorts of six HIV-infected adults, with CD4 counts of >200 and plasma viral loads of 5,000 to 250,000 transcripts/ml and not currently receiving antiretroviral therapy, were randomized to receive a single oral dose of placebo, 75, 150, or 250 mg of bevirimat. Thirty blood samples for drug concentrations and 20 HIV RNA measures were collected from each subject over a 20-day period. Candidate pharmacokinetic/pharmacodynamic models were fit to individual subjects by maximum likelihood followed by Bayesian estimation; model discrimination was by corrected Akaike's Information Criterion. The bevirimat pharmacokinetics was well described by an oral two-compartment linear model (r2, 0.98), with a mean (percent coefficient of variation) half-life of 60.3 (13.6) h and apparent oral clearance of bevirimat from the plasma compartment of 0.17 (18) liters/h. HIV RNA was modeled as being produced in infected CD4 cells, with bevirimat inhibiting infection of new CD4 cells thru a Hill-type function (r2, 0.87). Single oral doses of bevirimat were well tolerated and demonstrated a dose-dependent reduction in viral load. The average maximum reduction from baseline following the 150- and 250-mg doses was greater than 0.45 log10, with individual patients having reductions of greater than 0.7 log10. No bevirimat resistance mutations were detected during the course of the study.

* Corresponding author. Mailing address: Hoffman-La Roche, Inc., Clinical Pharmacology, 340 Kingsland Street, Nutley, NJ 07110-1199. Phone: (973) 562-2890. Fax: (973) 562-3411. E-mail: Patrick.smith{at}roche.com

{triangledown} Published ahead of print on 16 July 2007.

Antimicrobial Agents and Chemotherapy, October 2007, p. 3574-3581, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00152-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Blair, W. S., Cao, J., Fok-Seang, J., Griffin, P., Isaacson, J., Jackson, R. L., Murray, E., Patick, A. K., Peng, Q., Perros, M., Pickford, C., Wu, H., Butler, S. L. (2009). New Small-Molecule Inhibitor Class Targeting Human Immunodeficiency Virus Type 1 Virion Maturation. Antimicrob. Agents Chemother. 53: 5080-5087 [Abstract] [Full Text]  
  • Adamson, C. S., Waki, K., Ablan, S. D., Salzwedel, K., Freed, E. O. (2009). Impact of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Evolution of Resistance to the Maturation Inhibitor Bevirimat (PA-457). J. Virol. 83: 4884-4894 [Abstract] [Full Text]  
  • Van Baelen, K., Salzwedel, K., Rondelez, E., Van Eygen, V., De Vos, S., Verheyen, A., Steegen, K., Verlinden, Y., Allaway, G. P., Stuyver, L. J. (2009). Susceptibility of Human Immunodeficiency Virus Type 1 to the Maturation Inhibitor Bevirimat Is Modulated by Baseline Polymorphisms in Gag Spacer Peptide 1. Antimicrob. Agents Chemother. 53: 2185-2188 [Abstract] [Full Text]  
  • Purdy, J. G., Flanagan, J. M., Ropson, I. J., Rennoll-Bankert, K. E., Craven, R. C. (2008). Critical Role of Conserved Hydrophobic Residues within the Major Homology Region in Mature Retroviral Capsid Assembly. J. Virol. 82: 5951-5961 [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»