A Two-Period Open-Label, Single-Dose Crossover Study in Healthy Volunteers to Evaluate the Drug–Drug Interaction Between Cimetidine and Inhaled Extrafine CHF 5993

BACKGROUND AND OBJECTIVES: CHF 5993 is an extrafine ‘triple therapy’ combination of the long-acting muscarinic antagonist glycopyrronium bromide (GB), the long-acting β(2)-agonist formoterol fumarate (FF), and the inhaled corticosteroid beclometasone dipropionate (BDP). It is in development for chronic obstructive pulmonary disease and asthma delivered via pressurised metered-dose inhaler. METHODS: This two-period, open-label, crossover study examined the drug–drug interaction of CHF 5993 and cimetidine. In one period, subjects received cimetidine 800 mg twice daily for 6 days; on the fourth day they also received CHF 5993 (BDP/FF/GB 400/24/100 µg). In the other, they received CHF 5993 alone. Primary objective was to compare the area under the plasma concentration–time curve from time 0 to last quantifiable concentration (AUC(0–t)) of GB, with and without cimetidine. Secondary endpoints included GB AUC(0–12h), maximum concentration (C (max)), time to C (max) (t (max)), elimination half-life (t (½)) and urinary excretion. Pharmacokinetic parameters of BDP, beclometasone-17-monopropionate (B17MP; active metabolite of BDP) and formoterol were also evaluated. RESULTS: Twenty-six subjects were randomised; 25 completed. Co-administration of CHF 5993 and cimetidine resulted in small, statistically significant increases in GB AUC(0–t), AUC(0–12h) and C (max) vs CHF 5993 (ratios 1.16, 1.21 and 1.26, respectively); t (½), t (max) and urinary excretion were unaffected. There were small, statistically significant increases in formoterol AUC(0–t), AUC(0–24h) and t (½) following co-administration of cimetidine and CHF 5993; urinary excretion was unaffected. There were no significant differences for either BDP or B17MP. There were few adverse events (AEs), and no serious AEs. CONCLUSIONS: Overall, this study indicates that there is no clinically relevant drug–drug interaction between CHF 5993 and cimetidine. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13318-016-0345-2) contains supplementary material, which is available to authorized users.