Influence of Low-Dose Ritonavir With and Without Darunavir on the Pharmacokinetics and Pharmacodynamics of Inhaled Beclomethasone

Abstract

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.

HIV-associated obstructive lung diseases: insights and implications for the clinician

“…62–67 Most case reports describe interactions between fluticasone and protease inhibitors, but the clinician should be aware that other inhaled corticosteroids including budesonide and, to a lesser extent, beclomethasone, can lead to hypercortisolism symptoms if they are given concomitantly with protease inhibitors. 68–70 The 2013 update of the antiretroviral treatment guidelines 71 advised clinicians to avoid co-administration of ritonavir-based ART with inhaled budesonide or fluticasone, unless the benefits clearly outweighed the risks; however, inhaled beclomethasone was not included in this advice. The adverse side-effects of inhaled budesonide or fluticasone combined with ART seem reversible with cessation of the inhaled corticosteroid.…”

Unexpected rapid weight gain in a patient with HIV and anorexia

“…There is some evidence that inhaled or intranasal beclometasone is a relatively safe option in patients receiving protease inhibitors or cobicistat. 8 In this case, it was not necessary to alter the antiretroviral therapy to prevent the interaction. However, when longer acting steroids are used, such as intra-articular or epidural triamcinolone injections, 6 9 it may been necessary to remove the ongoing interaction by switching from ritonavir to a different antiretroviral therapy regimen.…”

Hypothalamic–pituitary–adrenal axis suppression by inhaled or nasal corticosteroids in HIV-infected patients

“…One study of healthy volunteers showed that beclomethasone in combination with ritonavir does not lead to adrenal suppression tested by an ACTH-stimulation test [7]. This study and pharmacokinetic evidence has resulted in the general advice to change the inhalation corticosteroid fluticasone to beclomethasone if a patient also uses a CYP3A4 inhibitor [3,4] This advice was already actively implemented in the involved hospitals.…”