February 6, 2006
For HIV-infected patients with protease inhibitor (PI) resistance, there has been a lot of good news of late with the advent of PIs such as tipranavir (TPV, Aptivus) and TMC114. There also remains continued interest in the use of dual PIs for the treatment of patients with PI resistance. However, significant liabilities for dual-PI use exist; they include the need for pharmacokinetic boosting with ritonavir (RTV, Norvir) and the complex potential for two- or three-way drug-drug interactions.
The finding that the PI atazanavir (ATV, Reyataz) has the potential to inhibit cytochrome P450 has raised the possibility that atazanavir could be exploited to simultaneously treat HIV and boost the levels of other PIs. This later point is attractive, given ritonavir's cost, side effects and toxicities.
This poster presentation by pharmacologist Patrick Clay from Kansas City University of Medicine and collaborators in Denver and Buffalo explored the pharmacology of once-daily administered fosamprenavir (FPV, 908, Lexiva, Telzir) 1,400 mg + atazanavir 400 mg in 21 HIV-uninfected study patients.
This detailed study was a three-way, crossover design, in which each patient served as his/her own control and received fosamprenavir, atazanavir or the combination of both for 14 days.
Overall, the combination of fosamprenavir + atazanavir was well tolerated, with minimal side effects or toxicity. The study showed that atazanavir modestly boosts amprenavir (APV, Agenerase) exposure (amprenavir is the active metabolite of fosamprenavir). Increases in AUC, Cmax and Cmin were 78%, 36% and 283%, respectively, but levels of atazanavir were reduced by 33%, 30% and 57%. By comparison with historical controls, fosamprenavir dosed once daily with atazanavir achieves levels that are similar to unboosted fosamprenavir, dosed twice-daily -- though importantly, the Cmin levels are lower.
Because of the significant decrease in atazanavir levels and the lower fosamprenavir trough levels, this dosing scheme should not be used. Patients currently in need of a potent PI (or multiple PIs) to construct combination therapy should probably receive better-tested combinations, rather than risk suboptimal drug levels (and insufficiently potent drugs).
Nonetheless, the study does prove the feasibility of atazanavir boosting, although atazanavir boosting is less potent than ritonavir boosting. And even though the currently studied doses don't meet the requirements of maintaining all drug levels at target levels, this study should provide the intellectual basis for exploring other dosing possibilities for single- or double-boosted PIs.