ABSTRACT
A fixed-dose combination (FDC) containing mometasone furoate (MF) and formoterol fumarate (F) in a pressurized metered dose inhaler (MDI) is approved for asthma and is being developed for COPD. This randomized, open-label, 4-period crossover study compared single-dose pharmacokinetics of MF 800 µg; F 20 µg; MF 800 µg + F 20 µg coadministered (MF + F); and MF 800 µg/F 20 µg (MF/F) FDC in healthy subjects. MF, F, and MF + F were administered from single-ingredient MDI devices. MF and formoterol plasma samples were obtained predose and up to 48 hours post dose for estimation of AUC0-tf (primary endpoint) and Cmax . Treatments were deemed comparable if the 90% CIs for the geometric mean ratios (GMRs) fell within 70-143%. MF AUC0-tf was comparable following treatment with MF + F versus MF (GMR 98%; 90% CI 85-113%) and MF/F versus MF + F (GMR 95%; 90% CI 82-109%). Similarly, formoterol AUC0-tf was comparable following treatment with MF + F versus F (GMR 98%; 90% CI 77-124%) and MF/F versus MF + F (GMR 108%; 90% CI 85-136%). The 90% CIs for MF and formoterol Cmax fell within the prespecified comparability bounds for all comparisons. Systemic exposures to MF and formoterol were similar following treatment with the FDC MDI device versus individual or concomitant use of single-ingredient MDI devices.
Subject(s)
Adrenergic beta-2 Receptor Agonists/pharmacokinetics , Anti-Inflammatory Agents/pharmacokinetics , Bronchodilator Agents/pharmacokinetics , Metered Dose Inhalers , Mometasone Furoate, Formoterol Fumarate Drug Combination/pharmacokinetics , Administration, Inhalation , Adolescent , Adrenergic beta-2 Receptor Agonists/administration & dosage , Adrenergic beta-2 Receptor Agonists/adverse effects , Adult , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/adverse effects , Area Under Curve , Bronchodilator Agents/administration & dosage , Bronchodilator Agents/adverse effects , Cross-Over Studies , Drug Monitoring , Female , Half-Life , Humans , Male , Metabolic Clearance Rate , Middle Aged , Mometasone Furoate, Formoterol Fumarate Drug Combination/administration & dosage , Mometasone Furoate, Formoterol Fumarate Drug Combination/adverse effects , Young AdultABSTRACT
PURPOSE: This randomized, open-label, multiple-dose, two-period, crossover study compared the systemic bioavailability of mometasone furoate (MF) administered from a metered-dose inhaler containing MF and formoterol fumarate (F) (MF/F-MDI) versus MF administered from a single-ingredient dry-powder inhaler (MF-DPI). METHODS: Healthy, non-smoking adults, 18-65 years with body mass index 18-29 kg/m(2) (N = 12) received MF 800 µg/F 20 µg via MF/F-MDI or MF 800 µg via MF-DPI twice daily for 5 days separated by a 7-day period. MF pharmacokinetics (AUC(0-12 hour) , Cmax , and Tmax ) were measured at Day 1 and 5 after each treatment. Safety and tolerability were assessed. RESULTS: Systemic exposure to MF based on AUC(0-12 hour) was â¼25% lower following MDI versus DPI administration. The Day 5 geometric mean ratio (MDI/DPI) estimates (90% confidence intervals [CI]) for AUC(0-12 hour) and Cmax were 0.747 (0.61, 0.91) and 0.606 (0.49, 0.75), respectively. The accumulation index (R) value for MF was higher following MDI (3.81-fold) versus DPI administration (2.34-fold) indicative of prolonged absorption. The most common adverse events were tremor, headache, and catheter site pain. CONCLUSIONS: Systemic exposure to MF was lower following multiple-dose MF/F-MDI administration versus MF-DPI administration. The magnitude of this difference is not considered to be clinically important. MF/F-MDI was safe and generally well tolerated.
