Objective To identify an alternative inhaled corticosteroid to fluticasone propionate that can be safely coadministered with HIV protease inhibitors (PIs), we assessed the safety and pharmacokinetics of beclomethasone dipropionate (BDP) and its active metabolite, 17-monopropionate (17-BMP), in combination with ritonavir (RTV) and darunavir/ritonavir (DRV/r). Design Open label, prospective, randomized pharmacokinetic and pharmacodynamic study in healthy volunteers. Methods Thirty healthy volunteers received inhaled BDP 160 mcg BID for 14 days and were then randomized (1:1:1) into three groups: Group 1 (control) remained on BDP alone for 28 days; Group 2 received BDP + RTV 100 mg BID for 28 days, and Group 3 received BDP + DRV/r 600/100 mg BID for 28 days. Pharmacokinetic sampling for 17-BMP was performed on days 14 and 28, and pharmacokinetic parameter values were compared within patients and between groups. Cortisol stimulation testing was also performed on days 1, 14, 28, and 42 and compared within and between groups. Results Geometric mean ratios (day 28:day 14) (90% CI) for 17-BMP area under the concentration-time curve in groups 1, 2, and 3, respectively, were 0.93 (0.81–1.06, p=0.27), 2.08 (1.52–2.65; p=0.006), and 0.89 (0.68–1.09; p=0.61). There were no significant reductions in serum cortisol levels within or between groups (p>0.05). Conclusions DRV/r did not increase 17-BMP exposure, while RTV alone produced a statistically significant but clinically inconsequential 2-fold increase in 17-BMP exposure. Adrenal suppression was not observed in any of the study groups. These data suggest BDP can be safely coadministered with DRV/r and likely other RTV-boosted PIs.

Study Objective As we previously observed a significant 41% reduction in gemfibrozil exposure after 2 weeks of lopinavir-ritonavir administration, we sought to determine the influence of lopinavir-ritonavir and ritonavir alone on the pharmacokinetics of fenofibric acid, an alternative to gemfibrozil for the treatment of elevated triglyceride levels. Design Open-label, single-sequence pharmacokinetic study. Setting Clinical Research Center at the National Institutes of Health. Subjects Thirteen healthy adult volunteers. Intervention Subjects received a single oral dose of fenofibrate 145 mg during three study phases: before ritonavir administration, after 2 weeks of administration of ritonavir 100 mg twice daily, and after 2 weeks of administration of lopinavir 400 mg–ritonavir 100 mg twice daily. Measurements and Main Results Serial blood samples were collected over 120 hours for determination of fenofibric acid concentrations. Fenofibric acid pharmacokinetic parameter values were compared before and after concomitant ritonavir or lopinavir-ritonavir administration. The geometric mean ratios (90% confidence intervals) for fenofibric acid area under the plasma concentration–time curve were 0.89 (0.77–1.01) after 14 days of ritonavir alone compared with baseline (p>0.05) and 0.87 (0.69–1.05) after 14 days of lopinavir-ritonavir compared with baseline (p>0.05). Study drugs were generally well tolerated; all adverse events were mild or moderate, transient, and resolved without intervention. Conclusion In contrast to a significant interaction between gemfibrozil and lopinavir-ritonavir, neither lopinavir-ritonavir nor ritonavir alone altered the pharmacokinetics of fenofibric acid in healthy volunteers. These data suggest that fenofibrate remains an important option in human immunodeficiency virus–infected patients receiving common ritonavir-boosted therapy.

Study Objective Panax ginseng has been shown in pre-clinical studies to modulate cytochrome P450 (CYP) enzymes involved in the metabolism of HIV protease inhibitors. Therefore, the purpose of this study was to determine the influence of Panax ginseng on the pharmacokinetics of the HIV protease inhibitor combination lopinavir/ritonavir (LPV/r) in healthy volunteers. Design Single sequence, open-label, single-center pharmacokinetic investigation. Setting Government healthcare facility. Subjects Twelve healthy human volunteers. Measurements and Main Results Thirteen healthy volunteers received LPV/r (400/100 mg) twice daily for 29.5 days. On day 15 of LPV/r administration, serial blood samples were collected over 12 hrs for determination of lopinavir and ritonavir concentrations. On study day 16, subjects began taking Panax ginseng 500 mg twice daily, which they continued for 2 weeks in combination with LPV/r. On day 30 of LPV/r administration, serial blood samples were again collected over 12 hrs for determination of lopinavir and ritonavir concentrations. Lopinavir and ritonavir pharmacokinetic parameter values were determined using noncompartmental methods and compared pre- and post-ginseng administration using a student’s t-test, where P < 0.05 was accepted as statistically significant. Conclusion Neither lopinavir nor ritonavir steady-state pharmacokinetics were altered by two weeks of Panax ginseng administration to healthy human volunteers. Thus, a clinically significant interaction between Panax ginseng and LPV/r is unlikely to occur in HIV-infected patients who choose to take these agents concurrently. It is also unlikely that Panax ginseng will interact with other ritonavir-boosted protease inhibitor combinations, although confirmatory data are necessary.

NCT01479361.