July 14, 2003
Many patients with HIV infection have multi-drug resistant virus and/or medication intolerances, and because of this have few viable treatment options. One new agent being studied and hopefully coming closer to approval is the protease inhibitor (PI) tipranavir (TPV) boosted with low-dose ritonavir (RTV, Norvir).
Previous work has shown that tipranavir/ritonavir (TPV/r) possesses good antiviral activity against viruses resistant to all currently available PIs. The study reported here was funded by the maker of TPV/r, Boehringer-Ingelheim, and was presented by one of their senior scientists.
Interactions between antiretroviral agents are common and play an important role in HIV management. The interaction between tipranavir and ritonavir has actually allowed tipranavir to proceed in clinical development. If not for the higher drug levels of tipranavir produced by ritonavir there would not be adequate antiviral activity. Boosting various PI drug levels with ritonavir has become a key tactic in HIV treatment.
With that said, interaction studies are performed to determine if medications may be co-administered and if dose adjustments are necessary. This study was carried out in healthy volunteers without HIV infection. It examined the interactions of TPV/r with AZT (zidovudine, Retrovir), ddI (didanosine, Videx), tenofovir (TDF, Viread) and efavirenz (EFV, Sustiva, Stocrin). For all of the studies presented herein, the dose range of TPV/r was either 500 mg/100 mg, 500 mg/200 mg or 750 mg/200 mg, as in the phase II trials.
The efavirenz interaction studies were done with 68 subjects and showed no significant effect of TPV/r on efavirenz drug levels. There was some reduction of tipranavir levels with the 500-mg/100-mg dose, but not with the 500-mg/200-mg dose that is being carried forward in phase III trials. There was no effect of TPV/r on efavirenz plasma levels.
The AZT interaction studies were done with 60 subjects and showed that TPV/r reduced the Cmax (maximum serum concentration) and AUC (area under the curve) for AZT by approximately 60 percent and 40 percent respectively. The reduction in AZT concentrations was thought to be related to a non-Phase II metabolic induction pathway. Since plasma concentrations of AZT are not directly related to intracellular phosphorylated levels, the reductions of AZT were not felt to be clinically relevant. There was no effect of AZT on TPV/r plasma levels.
The tenofovir interaction studies were performed with 49 subjects and showed no significant interactions between TPV/r and tenofovir.
The ddI EC interaction studies were performed with 23 subjects and no significant effects were noted in serum concentrations of either agent. However, in a physical compatibility study, there was an interaction with the SEDDS coating used for TPV/r. This suggests that ddI EC and TPV/r should be dosed at least four hours apart.
It is also worth mentioning the side effect information regarding TPV/r that was reported in this poster. Approximately 50 percent of these healthy adults complained of nausea, diarrhea and loose stools. Headache and abdominal pain were reported by about 25 percent of subjects and overall side effects were more common with the higher dose of 750 mg/200 mg. These side effect data derived in healthy subjects represent high estimates of side effects and TPV/r was better tolerated in phase II trials in HIV-infected subjects.
In summary, TPV/r has non-significant interactions with AZT, tenofovir and efavirenz. Because of the physical incompatibility between the coating of TPV/r and ddI EC, these medications should have dosing separated by at least four hours.
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