Session: Slide Session: Antiretroviral Therapy
Sunday, October 26, 2008: 12:00 AM
Room: Independence A (Grand Hyatt)
Background: RDEA806 is a novel NNRTI in development for the treatment of HIV infection. Preclinical testing has shown RDEA806 has a better resistance profile than other NNRTIs, and was safe and well tolerated with single or multiple doses in phase 1 trials. A phase 2a study was conducted to evaluate the pharmacokinetics (PK) of RDEA806 and its relationship with pharmacodynamic (PD) response (viral load reduction) after RDEA806 monotherapy in näive HIV patients. In addition, secondary PD evaluation included the effect of RDEA806 on uric acid and β-hydroxycortisol/cortisol ratio. Methods: A Phase 2a, randomized, double-blind, placebo-controlled, proof-of-concept trial was conducted in two cohorts of 12 näive HIV patients each (9 active and 3 placebo); patients either received RDEA806 400 mg twice daily (BID), or 600 mg once daily (QD), for 7 days and a single morning dose on Day 8 for PK determination. Blood and urine samples were collected to assess viral load, β-hydroxycortisol/cortisol ratio, uric acid, and RDEA806 plasma levels. Results: RDEA806 was readily absorbed with a mean Tmax of 2.1 hr in both cohorts. Mean Ctrough at steady state were 407 and 112 nM for the BID and QD groups, respectively, and were well above the anti-HIV EC50wt (3 nM) and EC50K103N (2.3 nM). There was no correlation between the 1.5 - 2.0 log viral load reduction and AUC or Cmax, although a trend was seen with Ctrough. Significant dose-related reduction in uric acid levels was observed. β-hydroxycortisol/cortisol ratio was not significantly changed, indicating a lack of CYP450 3A4 induction. Conclusions: RDEA806 exhibits favorable PK parameters with positive outcomes for both viral load and serum uric acid reduction. Studies with additional cohorts to evaluate higher once daily doses with an enteric coated tablet formulation are underway.