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Vicriviroc Is a Novel, Potent CCR5 Inhibitor With Outstanding Pharmaceutic, Pharmacokinetic and PharmaCodynamic (PK/PD) Properties

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The CCR5 chemokine receptor is a promising target for antiretroviral therapy because of its role as a coreceptor for HIV entry and propagation of infection. Vicriviroc, a small molecule CCR5 inhibitor being studied in clinical trials, has shown potent in vitro activity against HIV (IC90<13 nM). In addition, the pharmaceutic and PK/PD properties of vicriviroc appear to distinguish it from other compounds in clinical development.

Vicriviroc is highly water-soluble and demonstrates oral bioavailability of >89% in rats and monkeys. The compound is modestly human plasma protein-bound (≈ 84%) and widely distributed in the extra vascular space. Absorption and exposure in humans are linear and dose-proportional, with a terminal phase half-life >24 hours supportive of once daily dosing. Variability in absorption is modest (20–40%). Exposure to vicriviroc, a substrate for CYP3A4, is "boosted" by CYP3A4 inhibition with ritonavir (RTV), without being affected by other metabolizing enzymes or pGp. Because of the high oral bioavailability and highly predictable exposure, particularly when boosted with as little as 100 mg RTV, potent HIV suppression of 1.5 log10 is anticipated with as little as 10 mg vicriviroc daily with RTV. Dosage adjustments are not expected in combination regimens.

Vicriviroc shows particular promise as an HIV therapeutic due to pharmaceutic, PK/PD properties that support its potent activity and convenient once daily dosing.

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Correspondence to Lisa Dunkle.

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  • Chemokine Receptor
  • Ritonavir
  • Oral Bioavailability
  • Terminal Phase
  • CYP3A4 Inhibition