Decreased exposure to saquinavir in HIV-1-infected patients after long-term antiretroviral therapy including ritonavir and saquinavir

Objective: To explore whether steady-state plasma pharmacokinetics of ritonavir and saquinavir change during long-term treatment in HIV-1-infected patients on antiretroviral treatment including ritonavir and saquinavir. Methods: The pharmacokinetics of ritonavir and saquinavir were assessed during an 8-h period on two occasions in six HIV-1 infected patients on stable twice daily treatment with ritonavir 400 mg, saquinavir 400 mg and stavudine 40 mg with or without lamivudine 150 mg twice daily. Results: The first study day was 4-12 months (median 7 months) after the start of the current regimen. The second study day was 9-15 months (median 10 months) later. No significant differences were observed for the ritonavir pharmacokinetics between the first and second study day. However, median change in plasma trough level of saquinavir between the two study days was -30% (range -79 to +11%; P = 0.06). Median change in maximum plasma concentration was -40% (range -62 to +34%; P = 0.09). The median change in area under the plasma concentration versus time curve over 0-8 h was -33% (range 53 to +21%; P = 0.06). Conclusion: The exposure to saquinavir decreased over time in HIV-infected patients on stable antiretroviral therapy. These data suggest that regular monitoring of plasma drug concentrations should become part of routine patient care even in apparently compliant patients. (C) 2000 Lippincott Williams and Wilkins

The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1-infected individuals

Objective: To investigate and to compare the steady-state plasma pharmacokinetics of nevirapine in a dosing regimen of 400 mg once daily versus 200 mg twice daily in HIV-1-infected individuals. Design: Open-label, randomized, cross-over study. Methods: Twenty HIV-1-infected individuals who already used nevirapine as part of their antiretroviral regimen were randomized to continue their current regimen (200 mg twice daily) or to switch to the alternate regimen (400 mg once daily). The steady-state plasma pharmacokinetics of nevirapine were assessed after 2 weeks during a 24-h period. Subsequently, patients were switched to the alternate regimen and the pharmacokinetics of nevirapine were assessed again after 2 weeks. Noncompartmental methods were used to calculate the area under the plasma concentration versus time curve (AUC([24 h])), and the maximal (C(max)) and minimal plasma concentration (C(min)), the time to C(max) (t(max)), the plasma elimination half-life (t(1/2)), the apparent oral clearance (Cl/F) and the apparent volume of distribution (V/F). Differences in these pharmacokinetic parameters for the two dosing regimens were tested using ANOVA. Results: The exposure to nevirapine, as measured by the AUC([24 h]), was not significantly different between the 400 mg once daily and 200 mg twice daily dosing regimen (P = 0.60). Furthermore, the values for t(max), t(1/2) Cl/F and V/F were not significantly different between the two dosing regimens (P ≥ 0.08). However, C(max) and C(min) were higher and lower, respectively, when nevirapine was used in the once daily regimen as compared with the twice daily regimen. The median values for C(max) and C(min) as measured for the once daily and twice daily regimens were 6.69 and 5.74 μg/ml, respectively (P = 0.03), and 2.88 and 3.73 μg/ml, respectively (P < 0.01). Conclusion: These data show that the daily exposure to nevirapine, as measured by the plasma AUC([24 h]), is not different between a 400 mg once daily and a 200 mg twice daily dosing regimen. However, C(max) and C(min) are higher and lower, respectively, for the once daily regimen as compared with the twice daily regimen. The clinical implications of these differences remain to be established. (C) 2000 Lippincott Williams and Wilkins

Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor

Inhibitors of HIV protease have been shown to have antiapoptotic effects in vitro, yet whether these effects are seen in vivo remains controversial. In this study, we have evaluated the impact of the HIV protease inhibitor (PI) nelfinavir, boosted with ritonavir, in models of nonviral disease associated with excessive apoptosis. In mice with Fas-induced fatal hepatitis, Staphylococcal enterotoxin B–induced shock, and middle cerebral artery occlusion–induced stroke, we demonstrate that PIs significantly reduce apoptosis and improve histology, function, and/or behavioral recovery in each of these models. Further, we demonstrate that both in vitro and in vivo, PIs block apoptosis through the preservation of mitochondrial integrity and that in vitro PIs act to prevent pore function of the adenine nucleotide translocator (ANT) subunit of the mitochondrial permeability transition pore complex