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.
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 E max 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.
A 2-compartment model was fitted to the drug concentration data. At week 2, a higher vicriviroc C min 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 C min > 54 ng/mL, the mean viral load decrease was 1.35 log10 copies/mL vs. 0.76 log10 with C min < 54 ng/mL (P = 0.003, Student t test). At this C min breakpoint, 70% of subjects with the higher C min had a >1 log drop in HIV RNA, compared with 44% with a lower C min (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.
There was a positive correlation between vicriviroc C min, 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.
From the *Department of Clinical Pharmacology, Johns Hopkins University, Baltimore, MD; †Department of Clinical Pharmacokinetics/Pharmacodynamics, Merch/Schering-Plough Research Institute, Kenilworth, NJ; ‡Center for Biostatistics in AIDS Research, Harvard University School of Public Health, Boston, MA; §Section on Retroviral Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and ‖Division of Infections Diseases, Weill Medical College of Cornell University, New York, NY.
Received for publication June 1, 2009; accepted October 26, 2009.
Correspondence to: Keith W. Crawford, PhD, RPh, Johns Hopkins University, School of Medicine, 1830 Monument Street, Suite 8074, Baltimore, Maryland 21287 (e-mail: email@example.com; firstname.lastname@example.org).