February 12, 2003
Tipranavir is a protease inhibitor (PI) in the final stages of clinical testing. It has been touted as having activity against multi-PI-resistant strains of virus and is being studied as a twice-daily-administered drug. To accomplish this dosing frequency and a reduced pill burden, tipranavir must be co-administered with ritonavir (RTV, Norvir).
A series of presentations at this conference report the results of the BI 1182.52 trial, a multi-centered, international, randomized and blinded study of three dosing strategies of tipranavir/RTV: 500 mg/100 mg BID, 500 mg/200 mg BID and 750 mg/200 mg BID.
A total of 216 subjects enrolled and were required to be treatment experienced with agents from all three antiretroviral drug classes, including at least two PIs, and have at least one of a specified list of primary PI mutations but not have more than one of the following: 82L/T, 84V, 90M.
In other words, they had to be PI resistant but not too PI resistant. The screening HIV RNA PCR level had to be >1,000 copies/mL but any CD4 cell count was permitted.
Subjects entering the study replaced their pre-entry PI with one of the three tipranavir/RTV doses but maintained their other antiretrovirals for 14 days after which optimization of the regimen was allowed. Complete efficacy data will be presented on Friday but information regarding the correlation between plasma levels of tipranavir in each study arm and viral response was reported today.
At baseline, median CD4 cell count was 153 cells/mm3 and median HIV viral load was 4.53 log10 copies/mL. More than 75 percent of the subjects were white and over 80 percent were male. Data on the degree of resistance seen at baseline were not included but may be forthcoming at Friday's oral presentation. Mean trough plasma concentration of tipranavir at days seven and 14 were above a threshold of 20 µM, which is ten times the protein adjusted IC90 for PI-resistant HIV, in 48 percent of the 500/100 group, 79 percent of the 500/200 group and 77 percent of the 750/200 group. Importantly, 9 percent of the 500/200-assigned subjects and 15 percent of those randomized to 750/200 had trough concentrations less than 15 µM -- well below the target concentration. How much of this represents individual variability in absorbing and metabolizing this drug or poor adherence is not known.
Further, greater variability in tipranavir concentrations were seen in the two extreme doses while the 500/200 dose provided the tightest concentrations among the 68 subjects participating in an intensive pharmacokinetics sub-study. The variability in the 750/200 arm was thought to be possibly due to increased toxicity and subsequent reduced adherence with this dosing strategy but no adherence data were included.
The median drop in HIV RNA PCR levels from baseline among the proportion of subjects achieving the desired tipranavir concentration above 20 µM was only 0.79 log10 copies/mL in the 500/100 arm compared to a 1.16 log10 copies/mL and a 1.11 log10 copies/mL drop in the 500/200 and the 750/200 arms, respectively. Thus, even when concentrations of the drug exceeded the target, in the 500/100 arm, viral response appeared muted. The declines in viral load in the two higher dose strategies are impressive when one considers that these patients were treatment experienced and failing their pre-entry regimen.
More information about the entry resistance patterns will help place these declines in context. Given these data and the tolerability (or intolerability) of the 750/200 BID dosing of tipranavir/RTV, Boehringer Ingelheim Pharmaceuticals, the company that is developing tipranavir, has opted to pursue the 500/200 BID strategy in the next phase of clinical trials. Hopefully, more data regarding the concerning degree of variability seen in trough plasma concentrations even at this dose will be obtained.