Tipranavir and ritonavir trough levels significantly increased in presence of enfuvirtide (Fuzeon)

By Mark Mascolini

February 07, 2006

Analysis of tipranavir and ritonavir plasma levels in 39 HIV-infected patients receiving concomitant enfuvirtide found trough levels of the PIs to be higher than expected. Although the mechanism of this interaction remains unclear, Daniel Gonzalez de Requena reported at the 13th Conference on Retroviruses and Opportunistic Infections, it may involve the volume of distribution and elimination half-lives of the PIs.

Dr. Gonzalez de Requena of the University of Turin in Italy and colleagues measured tipranavir and ritonavir troughs in 71 samples from 20 patients taking enfuvirtide and in 62 samples from 19 patients who were not taking the fusion inhibitor. Tipranavir troughs (± standard deviation) averaged 40,666 ± 20,230 ng/mL with enfuvirtide and 26,522 ± 16,907 ng/mL without enfuvirtide (P = .024). Respective average ritonavir troughs measured 410 ± 379 ng/mL and 265 ± 144 ng/mL (P = .012).

Modeling all plasma samples with a first-order absorption and elimination single-compartment model, the investigators confirmed that tipranavir and ritonavir trough levels were higher in the presence of enfuvirtide (42.770 vs 28.195 µg/mL for tipranavir and 0.400 vs 0.138 µg/mL for ritonavir).

Peak concentrations, areas under the concentration-time curve, and clearance of PIs did not differ with or without enfuvirtide in the modeling study. However, volume of distribution and elimination half-life for both tipranavir and ritonavir proved higher with enfuvirtide. In the modeling analysis, tipranavir elimination half-life measured 9.57 hours with enfuvirtide and 4.10 hours without it. For ritonavir, the half-lives were 4.32 hours vs 2.65 hours.

In 3 closely studied individuals taking tipranavir/ritonavir, stopping enfuvirtide or adding it to the regimen changed tipranavir trough concentrations in the direction predicted by the group results noted across the study.

Dr. Gonzalez de Requena and colleagues urged further study to examine potential clinical consequences of their findings.

Reference

Gonzalez de Requena D, Calcagno A, Bonora S, et al. Unexpected drug-drug interaction between tipranavir/ritonavir and enfuvirtide. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 579.