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The exhalation delivery system with fluticasone propionate (Xhance®) has been shown to deliver drug substantially more broadly in the nasal cavity (particularly into superior/posterior regions), with less off-target loss of drug to drip-out and swallowing, than conventional nasal sprays. This open-label study evaluated the systemic bioavailability of Xhance® by comparing the pharmacokinetic (PK) properties of a single dose of fluticasone from 3 products administering the drug using 3 different devices: Xhance®, Flonase® (fluticasone propionate inhalational nasal spray), and Flovent® HFA (fluticasone propionate inhalational aerosol). This open-label study was conducted in 2 parts. Study part 1 compared systemic exposure with a single dose of Xhance® 186 or 372 μg versus Flonase® 400 μg (3-way, 3-treatment, 3-sequence, randomized crossover in healthy subjects; n = 90). A separate study, part 2, under the same umbrella protocol, compared systemic exposure with Xhance® 372 μg versus Flovent® HFA 440 μg (2-way, 2-treatment, 2-sequence, randomized crossover in patients with mild to moderate asthma; n = 30). With Xhance® 186 μg, the geometric least squares mean (LSM) C max was higher than with Flonase® 400 μg (16.02 vs 11.66 pg/mL, respectively; geometric mean ratio [GMR], 137.42%) and the geometric LSM AUC 0–∞ values were similar (97.30 vs 99.61 pg · h/mL; GMR, 97.78%). With Xhance® 372 μg, the geometric LSM C max and AUC 0–∞ were higher than with Flonase® 400 μg (C max , 23.50 vs 11.66 pg/mL [GMR, 201.53%]; AUC 0–∞ , 146.61 vs 99.61 pg · h/mL [GMR, 147.19%]). In part 2, the geometric LSM C max and AUC 0–∞ values were lower with Xhance® 372 μg than with Flovent® HFA 440 μg (C max , 25.28 vs 40.02 pg/mL [GMR, 63.18%]; AUC 0–∞ , 205.78 vs 415.16 pg · h/mL [GMR, 49.57%]). Similar intranasal doses of Xhance® (372 μg) and Flonase® (400 μg) are clearly not bioequivalent. Systemic exposure is very low with all products. Systemic exposure is higher with Xhance® than with Flonase® and substantially lower than with Flovent® HFA 440 μg and, based on dose normalization, Flovent® HFA 220 μg. ClincalTrials.gov identifier: NCT02266927. [ABSTRACT FROM AUTHOR]

The nose offers an attractive noninvasive alternative for drug delivery. Nasal anatomy, with a large mucosal surface area and high vascularity, allows for rapid systemic absorption and other potential benefits. However, the complex nasal geometry, including the narrow anterior valve, poses a serious challenge to efficient drug delivery. This barrier, plus the inherent limitations of traditional nasal delivery mechanisms, has precluded achievement of the full potential of nasal delivery. Breath Powered bi-directional delivery, a simple but novel nasal delivery mechanism, overcomes these barriers. This innovative mechanism has now been applied to the delivery of sumatriptan. Multiple studies of drug deposition, including comparisons of traditional nasal sprays to Breath Powered delivery, demonstrate significantly improved deposition to superior and posterior intranasal target sites beyond the nasal valve. Pharmacokinetic studies in both healthy subjects and migraineurs suggest that improved deposition of sumatriptan translates into improved absorption and pharmacokinetics. Importantly, the absorption profile is shifted toward a more pronounced early peak, representing nasal absorption, with a reduced late peak, representing predominantly gastrointestinal ( GI) absorption. The flattening and 'spreading out' of the GI peak appears more pronounced in migraine sufferers than healthy volunteers, likely reflecting impaired GI absorption described in migraineurs. In replicated clinical trials, Breath Powered delivery of low-dose sumatriptan was well accepted and well tolerated by patients, and onset of pain relief was faster than generally reported in previous trials with noninjectable triptans. Interestingly, Breath Powered delivery also allows for the potential of headache-targeted medications to be better delivered to the trigeminal nerve and the sphenopalatine ganglion, potentially improving treatment of various types of headache. In brief, Breath Powered bi-directional intranasal delivery offers a new and more efficient mechanism for nasal drug delivery, providing an attractive option for improved treatment of headaches by enabling or enhancing the benefits of current and future headache therapies. [ABSTRACT FROM AUTHOR]

Background: Inadequate efficacy of current intranasal steroids in chronic rhinosinusitis (CRS) is attributable to ineffective and/or inconsistent drug delivery to target anatomic sites. A new exhalation delivery system with fluticasone (EDS‐FLU) may improve outcomes by significantly increasing superior/posterior corticosteroid delivery. A study was conducted to assess the long‐term efficacy and safety outcomes of EDS‐FLU in individuals with CRS. Methods: This was a 12‐month, multicenter, single‐arm study evaluating the safety and efficacy of EDS‐FLU 372 μg twice daily in CRS patients (with [n = 34] or without [n = 189] nasal polyps [NP]). Efficacy assessments by serial nasal endoscopy and patient report included: 22‐item Sino‐Nasal Outcome Test (SNOT‐22), NP grade, standardized surgical indicator assessment, Lund‐Kennedy score, and Patient Global Impression of Change. Adverse event (AE) evaluations included nasal endoscopy. Additional safety and efficacy outcomes were assessed. Results: Of 223 patients who received EDS‐FLU, 96% reported prior corticosteroid use and 29% prior sinus surgery. The EDS‐FLU AE profile was similar to conventional intranasal steroids studied in similar populations. Most patients (87%) reported symptom improvement. Through 12 months, mean SNOT‐22 scores improved by −21.5 and −21.1 for CRS with and without NP, respectively. Among patients with NP, 54.2% had polyp elimination in at least 1 nostril and 83.3% had ≥1‐point improvement in polyp grade. Conclusion: Over 1 year of treatment in CRS with and without NP, EDS‐FLU 372 μg twice daily was well tolerated and produced improvements across a broad range of objective and subjective measures. EDS‐FLU may be a desirable new option for patients with this condition. [ABSTRACT FROM AUTHOR]

Computational fluid dynamics (CFD) has been used to investigate the intranasal deposition of corticosteroid sprays. CFD Lagrangian tracking models terminate particle motion once particles come into contact with a surface ("trap" boundary condition) and disregard the liquid film buildup on the mucosal surfaces of the sinonasal cavity walls. However, the interaction between spray droplets and the mucosal surface is critical for corticosteroid delivery using the exhalation delivery system (EDS) nasal spray device. Droplets coalesce on sinonasal walls, forming a thin "wall-film" on which droplets spread along the surface, splash, and/or break into secondary particles, depending on impact energy. To advance nasal drug delivery modeling, three CFD models of fluticasone propionate deposition using the EDS device in a Draf III post-surgical geometry were developed: (1) using traditional "trap" boundary conditions; (2) using "wall-film" boundary conditions and one-way coupling; and (3) using "wall-film" boundary conditions with two-way coupling (to account for the high-mass loading in the near-nozzle spray field). Contour plots and data sets for each CFD model were qualitatively compared with physical models in the same geometry (visualized in a 3D-printed sinonasal cast). The CFD simulations showed that EDS delivers fluticasone to all sinonasal regions, including areas superiorly and posteriorly in the sinonasal cavity. In addition, deposition improved and more closely correlated with physical experiments as the CFD model complexity evolved. "Wall-film" modeling of EDS delivery demonstrated increased surface coverage compared to the "trap" model. The "wall-film/two-way coupling" model demonstrated substantially higher deposition in the remote frontal and maxillary sinuses, agreeing with physical cast experiments. In conclusion, CFD simulation of EDS delivery using the "wall-film" boundary/two-way coupling model appears to most accurately represent observations from physical model experiments in the same geometry. • We created CFD models of drug deposition with the exhalation delivery system (EDS). • An iterative process improved CFD model simulation of deposition in nasal casts. • The most accurate CFD model used "Wall-film" conditions and two-way coupling. • CFD simulations and cast studies suggest EDS delivers drug to all sinonasal regions. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is often associated with multiple comorbidities and subsequent polypharmacy. Treatment of AD with acetylcholinesterase (AChE) inhibitors can carry a risk of drug interaction with multiple medications often prescribed for other co-existing illnesses. Rivastigmine is an AChE inhibitor that is enzymatically cleaved by AChE, minimally metabolized by cytochrome P450 enzymes, has low protein binding, has a short plasma half-life, and a relatively short duration of action. Such properties make it ideal for use in this patient population. A pharmacodynamic analysis of rivastigmine administered concomitantly with other medications (22 different therapeutic classes) did not reveal any significant pattern of increase in adverse events that would indicate a drug interaction. In summary, rivastigmine was well tolerated and safely administered to a population receiving multiple medications for ‘real-world’ comorbidities. Copyright © 2000 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Inasmuch as this limited evidence raised corticosteroid irrigation to a "strong recommendation", surely the Grade A evidence in NAVIGATE I/II should earn EDS-FLU a "strong recommendation" for use as a component of appropriate medical treatment, particularly after inadequate response to standard INCS treatment. Corticosteroid use, irrigations, medical therapy for chronic rhinosinusitis, rhinosinusitis, sinusitis, topical therapies for chronic rhinosinusitis Keywords: corticosteroid use; irrigations; medical therapy for chronic rhinosinusitis; rhinosinusitis; sinusitis; topical therapies for chronic rhinosinusitis EN corticosteroid use irrigations medical therapy for chronic rhinosinusitis rhinosinusitis sinusitis topical therapies for chronic rhinosinusitis 893 895 3 05/17/22 20220601 NES 220601 The International Consensus Statement on Allergy and Rhinology: Rhinosinusitis 2021 (ICAR-RS-2021) provides important updates on new therapies that have become available since 2016.1 As authors of the NAVIGATE I and II studies, we bring to your attention an apparent misunderstanding regarding controlled clinical trials that evaluated the efficacy and safety of the exhalation delivery system with fluticasone (EDS-FLU; XHANCE SP ® sp ) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). [Extracted from the article]