Bioavailability and disposition of azelastine and fluticasone propionate when delivered by MP29-02, a novel aqueous nasal spray.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • The topical second generation anti-histamine azelastine hydrochloride (AZE) and the potent corticosteroid fluticasone propionate (FP) are well established first-line treatments in allergic rhinitis (AR). • MP29-02, a novel intranasal AZE and FP formulation, has been shown to control AR symptoms faster and better than standard intranasal AZE or FP. • The systemic bioavailabilities of marketed AZE and FP nasal spray products have been established at about 40% and 1% only, respectively. • For new combination medicinal products such as MP29-02, the determination of possible pharmacokinetic (PK) drug-drug interactions between both active components and formulation-based bioavailability alterations is essential. WHAT THIS STUDY ADDS: • This paper provides for the first time information on potential drug-drug interactions, AZE and FP bioavailability and disposition characteristics of each component administered by the novel nasal spray formulation MP29-02. • The studies employed highly sensitive FP and AZE LC-MS/MS assays and could therefore be conducted with recommended therapeutic doses, thereby circumventing previously recognized draw-backs that required nasal bioavailability studies to be conducted using supra-therapeutic doses. • No significant PK drug-drug interaction between the active components AZE and FP was noted for MP29-02. • AZE bioavailabilty was equivalent when MP29-02 data were compared with MP29-02-AZE-mono and Astelin®. • Increased FP exposure was observed with MP29-02-based products compared with FP-BI. FP serum concentrations were generally very low with all investigational products suggesting no clinically meaningful pharmacodynamic differences in terms of systemic safety. AIM(S): To determine azelastine hydrochloride (AZE) and fluticasone propionate (FP) bioavailabilities of the novel nasal spray combination product MP 29-02, compared with MP29-02-based products containing only AZE (MP29-02-AZE-mono), FP (MP29-02-FP-mono), marketed AZE and FP single entity products (Astelin® and FP Boehringer-Ingelheim; FP-BI).
METHODS: Two randomized, three period, six sequence, three treatment crossover studies were conducted in healthy subjects. Study 1 administered 200 µg FP as MP29-02, MP29-02-FP-mono or FP-BI. Study 2 administered 548 µg AZE as MP29-02, MP29-02-AZE-mono or Astelin®. Each dose consisted of two sprays/nostril. Serum FP and plasma AZE were followed over 24 (FP) and 120 h (AZE) and quantified by LC-MS/MS. Peak (C(max) ) and total exposures AUC(0,t(last) ) were compared between the treatments by anova.
RESULTS: Study 1: Average FP C(max) was very low with all products (≤ 10 pg ml(-1) ). FP AUC(0,t(last) ) point estimates (90% CIs) for MP29-02 : MP29-02-FP-mono and MP29-02 : FP-BI ratios (%) were 93.6 (83.6, 104.7) and 161.1 (137.1, 189.3). Corresponding ratios for C(max) were 91.0 (82.5, 100.4) and 157.4 (132.5, 187.1). Study 2: AZE AUC(0,t(last) ) point estimates (90% CIs) for MP29-02 : MP29-02-AZE-mono and MP29-02 : Astelin® ratios (%) were 98.8 (91.0, 107.4) and 105.5 (95.6, 116.4). Corresponding outcomes for C(max) were 102.7 (92.1, 114.4) and 107.3 (92.6, 124.3).
CONCLUSIONS: No interactions of AZE and FP were found with the MP29-02 formulation. Azelastine bioavailability was similar for MP29-02 and Astelin®. Maximum and total FP exposure was higher for MP29-02-based products compared with FP-BI. FP concentrations were generally very low with all investigational products and did not suggest clinically meaningful differences concerning systemic safety.

RCT Entities:   Population Interventions Outcomes