Objective: To identify an alternative inhaled corticosteroid to fluticasone propionate that can be safely coadministered with HIV protease inhibitors, the safety and pharmacokinetics of beclomethasone dipropionate (BDP) and its active metabolite, beclomethasone 17-monopropionate (17-BMP), in combination with ritonavir (RTV) and darunavir/ritonavir (DRV/r) were assessed.
Design: Open-label, prospective, randomized pharmacokinetic and pharmacodynamic study in healthy volunteers.
Methods: Thirty healthy volunteers received inhaled 160 μg bid BDP for 14 days and were then randomized (1:1:1) into 3 groups: group 1 (control) remained on BDP alone for 28 days, group 2 received 100 mg bid BDP + RTV for 28 days, and group 3 received 600/100 mg bid BDP + DRV/r 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% confidence interval) for 17-BMP area under the concentration–time curve in groups 1, 2, and 3, respectively, were 0.93 (0.81 to 1.06, P = 0.27), 2.08 (1.52 to 2.65, P = 0.006), and 0.89 (0.68 to 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, whereas 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 that BDP can be safely coadministered with DRV/r and likely other RTV-boosted protease inhibitors.
*Office of Safety and Epidemiology, US Food and Drug Administration, Silver Spring, MD;
†National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
‡Clinical Research Directorate/Clinical Monitoring Research Program, SAIC-Science Applications International Corporation Inc, Frederick National Laboratory for Cancer Research, Frederick, MD;
§Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD;
‖Clinical Center Pharmacy Department; and
¶Critical Care Medicine Department, Clinical Research Center, National Institutes of Health, Bethesda, MD.
Correspondence to: Sarita D. Boyd, PharmD, Office of Safety and Epidemiology, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993 (e-mail: firstname.lastname@example.org).
Study was completed at National Institutes of Health.
Supported by the Intramural research programs of the National Institutes of Health Clinical Center, the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract no. HHSN261200800001E.
The content of this publication neither necessarily reflects the views or policies of the Department of Health and Human Services nor mention of trade names, commercial products, or organizations implies endorsement by the US Government.
The authors have no conflicts of interest to disclose.
Presented in abstract form at the Conference on Retroviruses and Opportunistic Infections, March 2012, Seattle, WA (Poster 610, abstract N-139; Poster 611, abstract N-1001).
Received December 17, 2012
Accepted February 26, 2013