Background:  RDEA806 is a novel NNRTI being developed for the treatment of HIV-1 infection. Preclinical testing has shown a better resistance profile of RDEA806 over current NNRTI against multiple HIV reverse transcriptase (RT) mutations, including the most common mutation K103N and the double mutation K103N/L100I. Many NNRTI bind to serum proteins, effectively reducing the amount of drug available for antiviral activity. To predict a therapeutically effective concentration of RDEA806, in vitro antiviral activity was measured in the presence of human serum or serum proteins.
Methods:  The antiviral activities of RDEA806 and other NNRTI were determined using vesicular stomatitis virus (VSV) -g pseudotyped HIV-1 containing wild type and NNRTI-resistant RT sequences in the absence or presence of human serum, human serum albumin (HSA), or a1 acid glycoprotein (AAG). The EC₅₀ values were determined by nonlinear regression analysis, and the EC₅₀ shift in the presence of serum proteins was compared to that of other NNRTI. The RDEA806 serum-adjusted EC₅₀ values were compared with the mean C_t and C_max values from individuals receiving 400 mg every 12 hours of RDEA806 to evaluate the likelihood of achieving effective concentrations of RDEA806.
Results:  The fold-change in the EC₅₀ value of RDEA806 against wild type HIV-1 in 50% human serum is 14, and is lower than the 40 fold-change observed for efavirenz (EFV), 53 fold-change for TMC125, and 161 fold-change for TMC278. The EC₅₀ of RDEA806 shifts 11-fold in the presence of physiologic concentrations of HSA and 1.3-fold in the presence of AAG. RDEA806 also compares favorably with other NNRTI in the presence of human serum against the most prevalent NNRTI-resistant mutation, K103N. The EC₅₀ of RDEA806 against K103N in 50% human serum is 53 nM, compared with 134 nM and 40 nM for EFV and TMC-278, respectively. After 10 days of  400 mg every 12 hours of RDEA806, the mean C_max of 5560 ng/mL and C_t of 228 ng/mL are well above the 22 ng/mL serum-adjusted RDEA806 EC₅₀ value against wild type  HIV-1.
Conclusions:  The RDEA806 anti-HIV-1 activity is reduced in the presence of human serum proteins, an effect due predominantly to HSA. The antiviral activity of RDEA806 is less affected by human serum proteins than that of EFV, TMC125, and TMC278 against a prevalent NNRTI-resistant virus. The RDEA806 inhibitory quotient, the ratio of plasma level to serum-adjusted EC₅₀ is 10 to 252, suggesting that therapeutically effective concentrations of RDEA806 are achieved.