Boehringer-Ingelheim has announced that its new experimental protease inhibitor tipranavir is to be made available to a wider number of patients in the United Kingdom.
The company announced this week that previous requirements for a CD4 cell count below 100 cells/mm3 and virologic failure will be relaxed in order to make the drug available to anyone who has experience of at least two prior protease inhibitor-containing regimens.
The company has also relaxed restrictions on the use of tipranavir alongside other protease inhibitors.
In practice the new eligibility criteria will make it easier to combine tipranavir with the fusion inhibitor T-20 (enfuvirtide or Fuzeon) before serious immune suppression develops on failing treatment, but the company warns that if doctors want to offer a double boosted protease inhibitor-containing regimen to patients,they must be fully informed of the potential risks and benefits of such a regimen.
In particular doctors and patients need to know that tipranavir appears to reduce levels of the three protease inhibitors likely to be combined with tipranavir.
However, no one can currently advise on how doses of the protease inhibitors could be adjusted to counteract the tipranavir effect because studies still need to be done - an urgent priority for Boehringer-Ingelheim if it is to get tipranavir approved in Europe and the United States in 2005, as the company hopes.
What's the problem?
At the recent International Workshop on Clinical Pharmacology of HIV Therapy Boehirnger-Ingelheim reported on the interaction between tipranavir/ritonavir and other protease inhibitors observed in the BI 1182.51 study. This study recruited patients with experience of all three antiretroviral classes and who had experience of at least two PI-containing regimens who showed evidence of at least three protease mutations from codons 33, 82, 84 and 90 (universal protease-associated mutations, or UPAMs). Participants had median viral load of almost 100,000 copies/ml and a median CD4 cell count of 140 cells/mm3 – exactly the group of patients now likely to be eligible for double-boosting.
In BI 1182.51 participants were randomised to receive either:
tipranavir/ritonavir (500/200mg) twice daily
- amprenavir/ritonavir (600/100mg twice daily)
- saquinavir/ritonavir (1000/100mg twice daily)
- lopinavir/ritonavir (400/100mg twice daily)
All participants received a background regimen optimnised through resistance testing. Use of T-20 was limited: 18% in the TPV/r arm, 12% in the TPV/r/amprenavir arm, 11% in the TPV/r/saquinavir arm, and 14% in the TPV/r/lopinavir/r arm.
After two weeks all participants not already receiving tipranavir added it to their regimen, together with 100mg of ritonavir twice daily (final ritonavir dose: 200mg twice daily).
The study recruited 296 patients of whom 134 patients were included in an intensive pharmacokinetic sub-study. PK data were available on 86 patients who had been evaluated at two separate visits.
By week 2 viral load had fallen a median of -1.2 log10 copies in the tipranavir/ritonavir treated patients, compared to declines of -0.2 log10 copies in the amprenavir/ritonavir, 0.3log10 copies in the saquinavir/ritonavir group and 0.4 log10 copies in the lopinavir/ritonavir group.
After the addition of tipranavir the median viral load fell to -1.2log10 copies below baseline in the amprenavir, saquinavir and lopinavir groups, but had rebounded in all groups to between -0.4 log10 copies below baseline (in the original tipranavir group) and -0.8 log10 copies below baseline (in the amprenavir group) by week 8.
Although Boehringer-Ingelheim has argued that the rebound towards baseline was attributable to lack of new background drugs, the effect of tipranavir itself on other protease inhibitors in the regimen also contributed to the disappointing response. Unusually for a protease inhibitor tipranavir appears to have acted as an inducer of CYP 3A4, the enzyme inhibited by ritonavir, despite evidence from a healthy volunteers study of its potent inhibitory action against CYP 3A4.
After the addition of tipranavir at week 2 levels of the protease inhibitors fell sharply. When PK parameters for each of the protease inhibitors after the addition of tipranavir are expressed as a ratio of the pre-tipranavir levels the extent of the effect is clear:
- Amprenavir: AUC and Cmin 0.5, Cmax 0.6
- Lopinavir: AUC 0.5, Cmax 0.6, Cmin 0.4
- Saquinavir: AUC 0.3, Cmax 0.3, Cmin 0.2
In each case the 90% confidence interval lay substantially below 1, indicating that all reductions were statistically significant.
24 week results from this study are due to be presented at the World AIDS Conference in Bangkok in July.
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