The pharmacokinetics, safety, and tolerability of single, high-strength doses of fluticasone propionate and fluticasone propionate/salmeterol delivered via a novel multidose dry powder inhaler in adolescents and adults with persistent asthma

ABSTRACT

Objective: Characterize fluticasone propionate (Fp) and combination fluticasone propionate and salmeterol (FS) pharmacokinetic and safety profiles, delivered via a novel, inhalation-driven, multidose dry powder inhaler (MDPI). Methods: This multicenter, open-label, four-period crossover, single-dose study randomized patients aged ≥12 years with persistent asthma to Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, Fp dry powder inhaler (DPI) 500 mcg (250 mcg × 2 inhalations), or FS DPI 500/50 mcg. Blood samples for determination of Fp and salmeterol pharmacokinetic parameters including C_max, AUC_0–t, AUC_0–inf, t_max, and t_½ were collected predose through 36 h postdose (14 time points). Safety assessments comprised adverse events, vital signs, and physical examinations. The institutional review board approved the study protocol. Results: The pharmacokinetic analysis set and safety population each included 40 patients. Fp systemic exposure (C_max, AUC_0–t, and AUC_0–inf) was highest for Fp DPI 500 mcg and similar for Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, and FS DPI 500/50 mcg. Fp geometric mean t_½ values were similar across treatments. Salmeterol C_max was 20% lower and AUC_0–t and AUC_0–inf were approximately 50% lower with FS MDPI versus FS DPI. Median t_max and geometric mean t_½ were similar between FS MDPI and FS DPI. Adverse events were similar across treatments with no relevant changes in vital signs, physical examinations, or hematology test results. Conclusions: Fp MDPI and FS MDPI produced similar or lower systemic exposure to Fp and salmeterol, despite lower doses, versus conventional DPI devices, suggesting improved efficiency due to formulation and device differences.

KEYWORDS:

• Adverse events
• delivery device
• inhaled corticosteroid
• long-acting beta-2 agonists
• tolerability

Acknowledgments

The authors wish to thank the clinical personnel and the patients who participated in this study, and Dimitry Golubovsky, clinical programmer, Ave Beatty, data management, and Steve Gorman, bioanalytical of DMPK, all of whom are employees of Teva Pharmaceutical Industries, Frazer, PA, USA. The authors gratefully acknowledge Paul H. Ratner, MD, MBA, for his contribution.

Declaration of interest

This study was sponsored by Teva Branded Pharmaceutical Products R&D, Inc. Medical writing assistance was provided by Lisa Feder, PhD, of Peloton Advantage and was funded by Teva Branded Pharmaceutical Products R&D, Inc. Teva provided a full review of the article. Gloria Yiu, Courtney Nugent, and Sharon Song are employees of Teva Pharmaceutical Industries, Frazer, PA, USA. Cynthia Caracta was an employee of Teva Pharmaceutical Industries, Frazer, PA, USA, at the time of study conduct and manuscript preparation.