Affiliation:
1. University at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York
2. Roswell Park Cancer Institute, Buffalo, New York
3. Emprexe Analytical, LLC, Buffalo, New York
4. Panacos Pharmaceuticals, Gaithersburg, Maryland
Abstract
ABSTRACT
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 (
r
2
, 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 (
r
2
, 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 log
10
, with individual patients having reductions of greater than 0.7 log
10
. No bevirimat resistance mutations were detected during the course of the study.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference17 articles.
1. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2005
2. Dixit, N. M., and A. S. Perelson. 2004. Complex patterns of viral load decay under antiretroviral therapy: influence of pharmacokinetics and intracellular delay. J. Theor. Biol226:95-109.
3. Eshleman, S. H., L. A. Guay, A. Mwatha, S. P. Cunningham, E. R. Brown, P. Musoke, F. Mmiro, and J. B. Jackson. 2004. Comparison of nevirapine (NVP) resistance in Ugandan women 7 days vs. 6-8 weeks after single-dose nvp prophylaxis: HIVNET 012. AIDS Res. Hum. Retrovir.20:595-599.
4. Eshleman, S. H., and J. B. Jackson. 2002. Nevirapine resistance after single dose prophylaxis. AIDS Rev.4:59-63.
5. Hurvich, C. M., and C. L. Tsai. 1989. Regression and time series model selection in small samples. Biometrika76:297-307.
Cited by
166 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献