A Multiple Dose Study To Determine Safety, Tolerability, and Pharmacokinetics Of PF-04634817 In Healthy Adult Subjects

• Adverse events, supine and standing vital sign measurements, 12-lead ECGs, blood and urine safety tests. [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]
• Plasma PK Day 1: Cmax, Tmax, AUClast, AUCtau at all dose levels. Plasma PK Day 14: Cmax, Tmax, AUClast, AUCtau, AUCinf, t½, CL/F and Vss/F at all dose levels. [ Time Frame: 14 days ] [ Designated as safety issue: No ]
• AUCtau (Day 14) vs. AUCtau (Day 1) - estimate of accumulation ratio; Cmax (Day 14) vs. Cmax (Day 1); Tmax (Day 14) vs. Tmax (Day 1). [ Time Frame: 14 days ] [ Designated as safety issue: No ]
• Urinary PK: Aet (amount excreted in urine); Aet% at all doses of PF-04634817 where t = 24 hours on Day 1 and 14; CLr at all doses on Day 14. [ Time Frame: 14 days ] [ Designated as safety issue: No ]
• Pharmacodynamic: MCP-1 change from baseline. [ Time Frame: 14 days ] [ Designated as safety issue: No ]

• Pharmacodynamic: p-ERK Inhibition in human monocytes: percent inhibition of monocyte p-ERK activity relative to the pre-dose baseline value [ Time Frame: 14 days ] [ Designated as safety issue: No ]
• MIP-1β stimulated CCR5 receptor internalization: percent inhibition of internalization relative to the pre-dose baseline value [ Time Frame: 14 days ] [ Designated as safety issue: No ]
• Absolute and percent change in circulating monocytes; Absolute and percent change in CD14+CD16+ monocytes. [ Time Frame: 14 days ] [ Designated as safety issue: No ]

• Pharmacodynamic: p-ERK Inhibition in human monocytes: percent inhibition of monocyte p-ERK activity relative to the pre-dose baseline value; [ Time Frame: 14 days ] [ Designated as safety issue: No ]
• MIP-1β stimulated CCR5 receptor internalization: percent inhibition of internalization relative to the pre-dose baseline value [ Time Frame: 14 days ] [ Designated as safety issue: No ]
• Absolute and percent change in circulating monocytes; Absolute and percent change in CD14+CD16+ monocytes. [ Time Frame: 14 days ] [ Designated as safety issue: No ]

The goals of this study are to evaluate the safety and tolerability of multiple ascending doses of PF-04634817 administered orally to healthy adult subjects. In additional, the plasma and urinary pharmacokinetics of multiple ascending doses of PF-04634817 administered orally to healthy adult subjects will be evaluated. Finally, the effect of multiple doses of PF-04634817 on circulating monocytes will be explored.

• Drug: PF-04634817
  Oral solution of PF-04634817 at 3 mg will be given once daily for 14 days.
• Drug: PF-04634817
  Oral solution of PF-04634817 at 30 mg will be given once daily for 14 days.
• Drug: PF-04634817
  Oral solution of PF-04634817 at 100 mg will be given once daily for 14 days.
• Drug: PF-04634817
  Oral solution of PF-04634817 at 300 mg will be given once daily for 14 days.
• Drug: PF-04634817
  Cohort will only be dosed if necessary. Dose selected for this cohort may be a repeat of a previous cohort or intermediate dose not to exceed 300 mg.

• Experimental: Cohort 1 (N=10)
  Placebo-controlled, multiple doses of PF-04634817 at 3 mg per day for 14 days. (2 placebo: 8 active)
  Intervention: Drug: PF-04634817
• Experimental: Cohort 2 (N=10)
  Placebo-controlled, multiple doses of PF-04634817 at 3 mg per day for 14 days. (2 placebo: 8 active)
  Intervention: Drug: PF-04634817
• Experimental: Cohort 3 (N=10)
  Placebo-controlled, multiple doses of PF-04634817 at 30 mg per day for 14 days. (2 placebo: 8 active)
  Intervention: Drug: PF-04634817
• Experimental: Cohort 4 (N=10)
  Placebo-controlled, multiple doses of PF-04634817 at 100 mg per day for 14 days. (2 placebo: 8 active)
  Intervention: Drug: PF-04634817
• Experimental: Cohort 5 (N=10)
  Placebo-controlled, multiple doses of PF-04634817 at 300 mg per day for 14 days. (2 placebo: 8 active)
  Intervention: Drug: PF-04634817
• Experimental: Cohort 6 (N=10) Optional cohort
  Placebo-controlled, multiple doses of PF-04634817 up to 300 mg per day for 14 days. (2 placebo: 8 active)
  Intervention: Drug: PF-04634817

Inclusion Criteria:

• Healthy male and female (of non-childbearing potential) subjects between the ages of 18 and 55 years, inclusive.
• Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs).

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease;
• Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication;
• Use of tobacco- or nicotine-containing products in excess of the equivalent of 5 cigarettes per day;
• Nursing females;
• Females of childbearing potential.