• Tipranavir/Ritonavir: Derivation of Doses That Achieve Effective Plasma Concentrations Above the IC50 for Multiple PI-Resistant HIV-1 Viruses (TuPeB4437)
  Authored by S. McCallister, V. Kohlbrenner, D. Mayers
  View the original abstract

Scott McCallister and colleagues from Boehringer-Ingelheim analyzed the results from several trials to establish the maximum tolerated dose of the protease inhibitor tipranavir (TPV) with an acceptable adverse-event profile and effective IC50 concentrations. There is considerable interest in tipranavir due to its different structure and activity in the setting of considerable protease resistance.

Three studies were reviewed by a panel of expert consultants that included doses of tipranavir 500/ritonavir 100 mg BID, tipranavir 500/ritonavir 200 mg BID, and tipranavir 750/ritonavir 200 mg BID. The morning Cmin levels after 21 days of treatment were available, as was the adverse-event profile and degree of virologic suppression. To be considered for further development, a Cmin level of 20µM was established as the minimum target level. Doses of tipranavir above 1,000 mg had an unacceptable adverse-event profile, so doses less than 1,000 mg were recommended.

Review of the data led to a recommendation to not develop the tipranavir 750/ritonavir 200 mg dose any further because the tipranavir 500/ritonavir 200 mg dose had a similar pharmacokinetic profile and less gastrointestinal side effects.

The result of this review supports the use of tipranavir 500/ritonavir 200 or 100 mg BID which are the doses now being evaluated in a phase IIB trial to further identify an optimal dose for phase III trials.