All protease inhibitors (PIs) are substrates, as well as inducers or inhibitors, of the CYP3A4 system. Combining PIs can either increase or decrease the concentration of each drug. While ritonavir (RTV, Norvir), a potent CYP3A4 inhibitor, is widely used to boost other PIs, the combination of certain PIs, such as amprenavir (APV, Agenerase) and lopinavir (LPV), may have a negative effect, with decreased levels of both drugs. Tipranavir (TPV, PNU-140690), a novel non-peptidic PI with activity against multiple PI-resistant HIV, is a CYP3A4 inducer.

Study BI 1182.51 is an open-label safety and pharmacokinetics study of tipranavir plus ritonavir (TPV/r) alone or in combination with a second boosted PI in highly treatment-experienced patients with >3 PI mutations at codons 33, 82, 84 and 90. Patients were randomized to receive twice a day either:

1. tipranavir and ritonavir (500 mg/200 mg) -- the control group;
2. tipranavir, saquinavir (SQV, Fortovase, Invirase) and ritonavir (500 mg/1,000 mg/200 mg);
3. tipranavir, amprenavir and ritonavir (500 mg/600 mg/200 mg); or
4. tipranavir, lopinavir and ritonavir (500 mg/400 mg/100 mg).

All patients received a preselected, investigator-defined, optimized background regimen. For the first 2 weeks, all patients received a ritonavir-boosted single PI regimen. After 2 weeks of single PI treatment, tipranavir was added to the dual-boosted PI arms.

Overall, the combination of tipranavir with other PIs was well tolerated, with the same adverse event incidence in all arms. The most common adverse event was diarrhea (5-15%), followed by nausea (4-13%). Most gastrointestinal side effects improved after the second week. The incidence of laboratory abnormalities was similar in all arms, with elevated triglycerides as the most common one.

The efficacy of tipranavir plus ritonavir alone in the first 2 weeks was better than that of the other boosted PIs, with a 1.15-log drop in viral load compared to only about a 0.2-0.3-log drop in the other boosted-PI arms. When tipranavir was added to other boosted PIs, there was further viral load reduction of about 1 log. After week 4, however, the viral load started to return to baseline. As for drug levels, when tipranavir was combined with either amprenavir or lopinavir, there was a slight increase in tipranavir levels. Unfortunately, tipranavir decreased the levels of other PIs significantly. The minimum concentration of drug in plasma (Cmin) values for amprenavir, lopinavir and saquinavir were reduced by 51%, 45% and 84%, respectively.

In summary, tipranavir plus ritonavir alone or in combination with other PIs seems to be well tolerated. However, the efficacy of tipranavir plus ritonavir alone or in combination in this HIV treatment-experienced group was not that great after 4 weeks. This cannot be explained only by the negative drug-drug interactions shown here. It is also possible that most patients in this trial were preselected to have at least 3 out of 4 protease-associated mutations (33, 82, 84 and 90), which can cause up to a 2.2-fold change in the half-maximal inhibitory concentration of tipranavir (phenotypic cutoff = 2). It is very likely that when tipranavir is approved, it will be used in salvage therapy where double-boosted PIs are commonly used. Given the negative pharmacokinetics seen with amprenavir plus ritonavir, saquinavir plus ritonavir and lopinavir plus ritonavir, further studies need to be done to determine the optimal dosing of these combinations.