Background: UK-427,857, an antagonist of the CCR5 receptor with potent anti-HIV activity in vitro, is being developed for the treatment of HIV infection. Studies in healthy volunteers were conducted to evaluate the pharmacokinetics, safety and toleration of the compound.

Methods: Healthy male volunteers received single and multiple oral doses of UK‑427,857 or placebo in two separate studies. Single doses ranged from 1–1,200 mg, multiple doses ranged from 3–300 mg bd, and 600 mg od for 12 days. The effect of food on the pharmacokinetics of UK-427,857 was also evaluated. Serial blood samples for determination of UK-427,857 plasma concentrations were collected at selected times throughout the dosing periods and for up to 72 hours following the last dose. Clinical safety evaluations, including laboratory safety tests, were performed throughout the studies.

Results: UK-427,857 is rapidly absorbed with maximum plasma concentrations being achieved in general between 0.5 and 4 hrs post-dose. For doses of 100mg and greater, the pharmacokinetics appear to be approximately proportional. The terminal half-life on multiple dosing is approximately 17 hrs and does not alter significantly with dose. A dose of 100mg twice a day achieves plasma concentrations in excess of the in vitro antiviral IC₉₀. Evaluation of the effect of food on the plasma concentration of UK-427,857 indicated that there is a significant reduction in the rate and extent of absorption when UK-427,857 is co-administered with food. UK-427,857 was well-tolerated in single and multiple oral doses up to 900mg and 600mg once a day, respectively. The most frequently recorded adverse events were postural hypotension (only at the highest doses in both studies), asthenia, light-headedness/dizziness, abnormal vision, and headache. No laboratory abnormalities or ECG findings were observed that would preclude further development.

Conclusions: Together these results indicate that further evaluation of UK-427,857 for the treatment of HIV infection is merited.