title: Pharmacokinetic/pharmacodynamic modeling of the antiretroviral activity of the CCR5 antagonist Vicriviroc in treatment experienced HIV-infected subjects (ACTG protocol 5211).
abstract: OBJECTIVE
  This substudy of AIDS Clinical Trials Group (ACTG) Protocol 5211 explored the relationship between antiretroviral effect and plasma concentrations of vicriviroc, an investigational CCR5 antagonist for HIV infection.
  
  
  METHODS
  Eighty-six treatment-experienced subjects failing their current antiretroviral regimens were randomized to add vicriviroc 5, 10, or 15 mg once daily or placebo for 2 weeks. Beyond week 2, subjects were changed to optimized background antiretroviral treatment while continuing vicriviroc or placebo. Plasma samples collected at weeks 2 and 8 were assayed for vicriviroc concentrations and combined with vicriviroc concentration data from 110 seronegatives enrolled in 5 phase 1 studies. An inhibitory Emax model was used to assess pharmacokinetic (PK)/pharmacodynamic relationships and recursive partitioning was applied to determine the breakpoint in vicriviroc PK parameters associated with virologic suppression.
  
  
  RESULTS
  A 2-compartment model was fitted to the drug concentration data. At week 2, a higher vicriviroc Cmin was associated with a greater mean drop in HIV RNA (viral load) and a higher percentage of subjects experiencing a >1 log10 copies/mL drop in viral load. In subjects with Cmin > 54 ng/mL, the mean viral load decrease was 1.35 log10 copies/mL vs. 0.76 log10 with Cmin < 54 ng/mL (P = 0.003, Student t test). At this Cmin breakpoint, 70% of subjects with the higher Cmin had a >1 log drop in HIV RNA, compared with 44% with a lower Cmin (P = 0.048, Fisher exact test). Similar results were seen with an area under the curve breakpoint of 1460 ng h/mL. At weeks 16 and 24, all vicriviroc-treated subjects experienced better viral load responses than placebo recipients, but there was no apparent relationship between PK and change in viral load among these vicriviroc-treated subjects.
  
  
  CONCLUSIONS
  There was a positive correlation between vicriviroc Cmin, area under the curve, and viral load changes at week 2 in treatment-experienced HIV-infected subjects receiving no other new active antiretroviral drugs. This correlation did not persist beyond week 16, probably because treatment response at that point also depended on having other active drugs in the regimen.
authors.affiliation: Department of Clinical Pharmacology, Johns Hopkins University, Baltimore, MD 21287, USA. kwcrawford@jhmi.edu
authors.forename: Keith W
authors.initials: KW
authors.lastname: Crawford
authors.forename: Chonghua
authors.initials: C
authors.lastname: Li
authors.forename: Anther
authors.initials: A
authors.lastname: Keung
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Su
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hughes
authors.forename: Wayne
authors.initials: W
authors.lastname: Greaves
authors.forename: Daniel
authors.initials: D
authors.lastname: Kuritzkes
authors.forename: Roy
authors.initials: R
authors.lastname: Gulick
authors.forename: Charles
authors.initials: C
authors.lastname: Flexner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D065100:CCR5 Receptor Antagonists; D004311:Double-Blind Method; D005260:Female; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010879:Piperazines; D011743:Pyrimidines; D012367:RNA, Viral; C486781:vicriviroc