Background: Tipranavir (TPV)-based therapy, has demonstrated a uniquely robust resistance profile with sustained viral load response during up to 48 wks of treatment in single and multiple Protease Inhibitor (PI)-experienced patients (pts). The preliminary target median plasma concentration for TPV has been set at 10X the protein adjusted IC₉₀ in multiple PI resistant HIV-1. The study presented here, conducted in highly treatment-experienced pts, allows for further characterization of the plasma concentration profile of this novel non-peptidic protease inhibitor (NPPI).

Methods: BI 1182.52 was a multicenter, international, randomized, blinded trial of 3 doses of TPV/r (500 mg/100 mg; 500 mg/200 mg; and 750 mg/200 mg). Plasma concentrations of TPV were measured 8–16 hrs following the last drug administration on days 7 and 14.

Results: A total 216 pts with a median baseline viral load of 4.5 log₁₀ copies/mL and CD4⁺ cell count of 153 cells/mm³ were randomized and received treatment. The median trough plasma concentrations of TPV exceeded the target value in all arms. TPV/r plasma concentrations on days 7 and 14 were 21.8 mM and 20.1 mM, 32.1 mM and 29.11 mM, and 52.2 mM and 42.6 mM for the 500/100, 500/200, and 750/200 doses, respectively. Seventy-eight percent (78%) and 77% of pts in the 500/200 and 750/200 arms, respectively, achieved the target plasma concentration, as compared with 48% in the 500/100 arm. There was greater variability of plasma levels in the 750 mg/200 mg arm. The median change in viral load for patients with TPV C_mins of ≤2, 2–5, 5–10, 10–15, 15–20 and > 20 mM was -0.32 log₁₀, -0.62 log₁₀, -1.11 log₁₀, -0.40 log₁₀, -1.14 log₁₀, and -1.10 log₁₀, respectively.

Conclusions: The consistency of plasma trough levels from days 7 to 14 indicate that steady state is reached within the first 7 days of treatment in these highly treatment experienced pts (switched from PI). These results indicate that a consistently robust viral load response was achieved in pts achieving trough plasma concentrations > 15 mM; more pts in the 500/200 and 750/200 arms of the study achieved this concentration than in the 500/100 arm. All doses of TPV/r studied achieved the preliminary target plasma levels, reaching a median plasma concentration well in excess of 10X the IC₉₀ for PI resistant virus.