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  8th International Workshop on Pharmacology of HIV Therapy
Budapest
April 16-18, 2007
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Vicriviroc Levels Predict Early Salvage Response
 
 
  8th International Workshop on Pharmacology of HIV Therapy
April 16-18, 2007, Budapest
 
Mark Mascolini
 
Trough concentrations (Cmin) of the CCR5 antagonist vicriviroc measured after 2 weeks predicted virologic response in people who went on to build a salvage regimen around the drug in ACTG study 5211 [1]. Two-week area under the concentration-time curve (AUC) also correlated with 2-week response.
 
ACTG 5211 enrolled people with CCR5-tropic virus and randomized them to 5, 10, or 15 mg of vicriviroc once daily or placebo for 2 weeks while continuing a failing regimen [2]. Everyone had three-class antiretroviral experience and a current viral load above 5000 copies while taking a ritonavir-boosted protease inhibitor. After 2 weeks study participants kept vicriviroc or placebo but traded their failing regimen for a fresh one planned for maximal control of their resistant virus. All vicriviroc doses lowered viral load better than placebo after 24 weeks, though the 5-mg arm was closed.
 
Charles Flexner (Johns Hopkins University, Baltimore) reported dose-related vicriviroc concentrations in 86 study participants, with Cmins averaging 42.3 ng/mL with the 5-mg dose, 90.9 ng/mL with 10 mg, and 121 ng/mL with 15 mg. Maximum concentrations averaged 62.5 ng/mL with 5 mg, 130 ng/mL with 10 mg, and 181 ng/mL with 15 mg. These values did not differ much from week 2 to week 8.
 
To develop a pharmacokinetic model, Flexner combined data from these patients with results from intensive drug level monitoring in 110 healthy volunteers enrolled in five early studies of the CCR5 antagonist. The model set the 50% effective concentration at 20.9 ng/mL.
 
After 2 weeks of what amounted to vicriviroc monotherapy in ACTG 5211, 70% of people with a vicriviroc Cmin at or above 53.7 ng/mL had at least a 10-fold (1-log) drop in viral load compared with 44% who had a lower Cmin (Table). The average viral load fell 1.35 log copies/mL in people with a Cmin at or above 53.7 ng/mL and 0.76 log in those with a lower Cmin.
 

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A vicriviroc AUC breakpoint of 1460 ng/hour/mL also discriminated between good and poor responders at week 2. After 16 to 24 weeks of vicriviroc therapy, however, Flexner found no correlation between vicriviroc levels and virologic response, perhaps, he surmised, because responses at later points also depended on the antiretrovirals added at week 2.
 
An estimated 90% effective concentration (EC90) of 56 ng/mL lay just above the 54-ng/mL cutoff. Most people taking 10 mg of vicriviroc and everyone taking 15 mg had an EC90 at or above 56 ng/mL.
 
This analysis turned up no links between race, gender, or age and virologic response at weeks 2, 16, and 24.
 
References
1. Flexner C, Keung A, Li C, et al. Pharmacokinetic/pharmacodynamic modeling of the antiretroviral activity of the CCR5 antagonist vicriviroc in treatment experienced HIV-infected patients (ACTG 5211). 8th International Workshop on Pharmacology of HIV Therapy. April 16-18, 2007. Budapest. Abstract 15.
2. Gulick RM, Su Z, Flexner C, et al. ACTG 5211: phase II study of the safety and efficacy of vicriviroc in HIV-infected treatment-experienced subjects. XVI International AIDS Conference. August 13-18, 2006. Toronto. Abstract THLB0217.