Session: Poster Session: HIV Pharmacokinetics/Dynamics
Sunday, October 26, 2008: 12:00 AM
Room: Hall C
Background: BVM is a novel HIV-1 maturation inhibitor in Phase II development that targets the capsid SP-1 cleavage site of Gag. Recent analysis has shown that the antiviral activity of BVM is attenuated by the presence of baseline polymorphisms in the SP1 region of Gag; specifically, amino acid residues 369, 370, and 371. Our purpose was to characterize the PK/PD of BVM when administered as functional monotherapy. Methods: 46 HIV infected adults received 14 days of BVM QD at 400 mg (tablet) 250, 300, 350, or 400 mg (liquid doses). Plasma viral load and BVM concentrations were determined frequently over the dosing period. BVM PK parameters were determined by noncompartmental methods. Linear and nonlinear regression was used to evaluate the relationship between antiviral effect and BVM trough concentrations (mean of Day 14 and Day 15 troughs). Results: BVM exhibited predictable and linear PK. The mean log10 viral load change from baseline on Day 15 for patients without changes at positions 369-371 was -0.98, -1.14, -1.57, -0.60, and -1.01 for the 400 mg (tablet) 250, 300, 350, or 400 mg (liquid doses), respectively. The maximum antiviral effect of BVM was observed with an estimate for Emax of -1.48 log10. The 50% effective trough concentration (EC50) was estimated to be 22.4 µg/mL. When individual patients were examined, 92% of responders (>0.5 log10) had trough concentrations >20 µg/mL while 67% of non-responders (<0.5 log10) had trough concentrations <20 µg/mL. Conclusions: The maximum antiviral effect of BVM was observed at doses <400 mg/day. Patients without polymorphisms at Gag residues 369-371 that achieved trough concentrations >20 µg/mL were more likely to respond. This is consistent with the estimated EC50. These concentrations were achievable in all patients at doses >250 mg/day.