title: 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.
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.
authors.affiliation: Hoffman-La Roche Inc, Clinical Pharmacology, Nutley, NJ 07110-1199, USA. Patrick.smith@roche.com
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Abayomi
authors.initials: A
authors.lastname: Ogundele
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.forename: John
authors.initials: J
authors.lastname: Wilton
authors.forename: Karl
authors.initials: K
authors.lastname: Salzwedel
authors.forename: Judy
authors.initials: J
authors.lastname: Doto
authors.forename: Graham P
authors.initials: GP
authors.lastname: Allaway
authors.forename: David E
authors.initials: DE
authors.lastname: Martin
mesh_terms: D000328:Adult; D000465:Algorithms; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001499:Bayes Theorem; D018791:CD4 Lymphocyte Count; D002138:Calibration; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D008297:Male; D015233:Models, Statistical; D012367:RNA, Viral / Q000097:blood; D013386:Succinates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014315:Triterpenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects; D053978:Pentacyclic Triterpenes
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D013386:Succinates; D014315:Triterpenes; C479935:bevirimat; D053978:Pentacyclic Triterpenes