Comparison of the systemic bioavailability of mometasone furoate after oral inhalation from a mometasone furoate/formoterol fumarate metered-dose inhaler versus a mometasone furoate dry-powder inhaler in patients with chronic obstructive pulmonary disease

Teddy Kosoglou,¹ James Hubbell,² Fengjuan Xuan,³ David L Cutler,¹ Alan G Meehan,⁴ Bhavna Kantesaria,⁵ Bret A Wittmer<sup>6,†

1</sup>Clinical Pharmacology, ²Exploratory Drug Metabolism, ³Early Development Statistics, ⁴Medical Communications, ⁵Drug Metabolism/Pharmacokinetics, Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USA; ⁶Commonwealth Biomedical Research, LLC, Madisonville, KY, USA

^†Dr Bret A Wittmer passed away on May 9, 2012.

Background: Coadministration of mometasone furoate (MF) and formoterol fumarate (F) produces additive effects for improving symptoms and lung function and reduces exacerbations in patients with asthma and chronic obstructive pulmonary disease (COPD). The present study assessed the relative systemic exposure to MF and characterized the pharmacokinetics of MF and formoterol in patients with COPD.
Methods: This was a single-center, randomized, open-label, multiple-dose, three-period, three-treatment crossover study. The following three treatments were self-administered by patients (n = 14) with moderate-to-severe COPD: MF 400 µg/F 10 µg via a metered-dose inhaler (MF/F MDI; DULERA^®/ZENHALE^®) without a spacer device, MF/F MDI with a spacer, or MF 400 µg via a dry-powder inhaler (DPI; ASMANEX^® TWISTHALER^®) twice daily for 5 days. Plasma samples for MF and formoterol assay were obtained predose and at prespecified time points after the last (morning) dose on day 5 of each period of the crossover. The geometric mean ratio (GMR) as a percent and the corresponding 90% confidence intervals (CI) were calculated for treatment comparisons.
Results: Systemic MF exposure was lower (GMR 77%; 90% CI 58, 102) following administration by MF/F MDI compared to MF DPI. Additionally, least squares geometric mean systemic exposures of MF and formoterol were lower (GMR 72%; 90% CI 61, 84) and (GMR 62%; 90% CI 52, 74), respectively, following administration by MF/F MDI in conjunction with a spacer compared to MF/F MDI without a spacer. MF/F MDI had a similar adverse experience profile as that seen with MF DPI. All adverse experiences were either mild or moderate in severity; no serious adverse experience was reported.
Conclusion: Systemic MF exposures were lower following administration by MF/F MDI compared with MF DPI. Additionally, systemic MF and formoterol exposures were lower following administration by MF/F MDI with a spacer versus without a spacer. The magnitude of these differences with respect to systemic exposure was not clinically relevant.

Keywords: mometasone furoate, chronic obstructive pulmonary disease, pharmacokinetics, systemic exposure, metered-dose inhaler, dry-powder inhaler