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

Abstract

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.