Role of nasal casts for in vitro evaluation of nasal drug delivery and quantitative evaluation of various nasal casts.

Background: Nasal casts may characterize intranasal drug deposition. Methodology: The Koken cast, described as 'anatomically correct', and the Optinose cast, derived from MRI of a healthy male during velum closure, were dimensionally compared and assessed for deposition assessment suitability. Results: Smallest vertical cross-sectional areas (valve region) for Koken and Optinose right/left: 2.55/2.75 and 1.18/1.18 cm2, respectively, versus a 'normative' mean (range) of 0.85 cm2 (0.2-1.6 cm2). Intranasal volumes differed (computed tomography/water fill): Koken, 35.8/38.6 cm3 and Optinose, 24.1/25.0 cm3, versus a 'normative' mean (range) of 26.4 cm3 (20.9-31.1 cm3). Conclusion: Koken cast dimensions are larger than the normal range and the Optinose cast. The validity of casts for regulatory drug deposition studies is suspect.

A Randomized Comparison of the Pharmacokinetics and Bioavailability of Fluticasone Propionate Delivered via Xhance Exhalation Delivery System Versus Flonase Nasal Spray and Flovent HFA Inhalational Aerosol.

PURPOSE: 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). METHODS: 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). FINDINGS: With Xhance® 186 µg, the geometric least squares mean (LSM) Cmax 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 AUC0-∞ values were similar (97.30 vs 99.61 pg · h/mL; GMR, 97.78%). With Xhance® 372 µg, the geometric LSM Cmax and AUC0-∞ were higher than with Flonase® 400 µg (Cmax, 23.50 vs 11.66 pg/mL [GMR, 201.53%]; AUC0-∞, 146.61 vs 99.61 pg · h/mL [GMR, 147.19%]). In part 2, the geometric LSM Cmax and AUC0-∞ values were lower with Xhance® 372 µg than with Flovent® HFA 440 µg (Cmax, 25.28 vs 40.02 pg/mL [GMR, 63.18%]; AUC0-∞, 205.78 vs 415.16 pg · h/mL [GMR, 49.57%]). IMPLICATIONS: 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.

NAVIGATE I: Randomized, Placebo-Controlled, Double-Blind Trial of the Exhalation Delivery System With Fluticasone for Chronic Rhinosinusitis With Nasal Polyps.

BACKGROUND: Chronic rhinosinusitis is a common, high-morbidity chronic inflammatory disease, and patients often experience suboptimal outcomes with current medical treatment. The exhalation delivery system with fluticasone (EDS-FLU) may improve care by increasing superior/posterior intranasal corticosteroid deposition. OBJECTIVE: To evaluate the efficacy and safety of EDS-FLU versus EDS-placebo in patients with nasal polyps (NP). Coprimary end points were change in nasal congestion and polyp grade. Key secondary end points were Sino-Nasal Outcome Test-22 (SNOT-22) and Medical Outcomes Study Sleep Scale-Revised (MOS Sleep-R). Other prespecified end points included all 4 cardinal symptoms of NP, 36-Item Short Form Health Survey (SF-36), Patient Global Impression of Change (PGIC), Rhinosinusitis Disability Index (RSDI), and key indicators for surgical intervention. DESIGN: Randomized, double-blind, EDS-placebo-controlled, multicenter study. METHODS: Three hundred twenty-three subjects with NP and moderate-severe congestion/obstruction, most with history of corticosteroid use (94.4%) and/or prior surgery (60.4%), were randomized to EDS-FLU 93 µg, 186 µg, or 372 µg or EDS-placebo twice daily (BID) for 24 weeks (16 double-blind + 8 single-arm extension with EDS-FLU 372 µg BID). RESULTS: All EDS-FLU doses produced significant improvement in both coprimary end points ( P < .05) and in SNOT-22 total score ( P ≤ .005). EDS-FLU significantly improved all 4 cardinal symptoms of NP ( P < .05), including congestion/obstruction, facial pain/pressure, rhinorrhea/post-nasal drip, and hyposmia/anosmia. Approximately 80% of subjects reported improvement with EDS-FLU, with 65% reporting "much" or "very much" improvement by week 16. Adverse events were generally local in nature and similar to other intranasal steroids studied for similar durations in similar populations, with the most common being epistaxis. CONCLUSIONS: In patients with chronic rhinosinusitis with NP (CRSwNP) who were symptomatic despite high rates of prior intranasal steroid use and/or surgery, EDS-FLU produced statistically significant and clinically meaningful improvements compared to EDS-placebo in multiple subjective and objective outcomes (symptoms, SNOT-22, RSDI, SF-36, PGIC, and NP grade), including all 4 cardinal symptoms of CRSwNP.

A cross-sectional, population-based survey of U.S. adults with symptoms of chronic rhinosinusitis.

Background: Chronic rhinosinusitis (CRS) is believed to create a substantial population-level disease burden in the United States due to its high prevalence and significant disease morbidity, but many studies of CRS epidemiology are based on administrative or historical record sources rather than primary population sources. Objective: To characterize CRS symptoms, burden, and patient characteristics by using a primary U.S. population-based representative sample. Methods: A demographically and geographically representative sample of 10,336 U.S. adults recruited from a general panel of 4.3 million were obtained by using three-stage randomization. Data collected included a range of respondent-reported CRS symptoms, symptom impact and severity, symptom duration, and treatment. Results: Approximately 11.5% of the respondents (n = 1189) reported defining symptom and duration criteria for CRS. A previous diagnosis of nasal polyps was reported by ∼10% of this population. The remaining respondents reported severe (7.3%) or moderate (3.1%) symptom severity. The most frequently reported defining symptoms were nasal congestion and/or obstruction (94-97%) and drainage (89-92%). CRS participants reported a high average degree of symptom burden (e.g., on a 0-10 scale, 8.2 for CRS with nasal polyps, 8.4 for CRS without nasal polyps with severe symptoms, and 6.4 for CRS without nasal polyps with moderate symptoms). The participants with CRS reported high health-care use for CRS, adverse effects of CRS symptoms on multiple areas of daily life, and high dissatisfaction with currently available treatments. Conclusion: More than 10% of the general U.S. adult population have CRS symptoms. Most report severe symptoms, lack of satisfaction with current treatment options, and a substantial adverse impact on daily functioning.

NAVIGATE II: Randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis.

BACKGROUND: Chronic rhinosinusitis is common and sometimes complicated by nasal polyps (NPs). Corticosteroid nasal sprays are often unsatisfactory because they are ineffective at delivering medication to high/deep sites of inflammation. OBJECTIVE: We sought to assess whether an exhalation delivery system with fluticasone (EDS-FLU) capable of high/deep drug deposition improves outcomes. METHODS: Patients (n = 323) 18 years and older with moderate-to-severe congestion and NPs were randomized to twice-daily EDS-FLU (93, 186, or 372 µg) or exhalation delivery system (EDS)-placebo for 24 weeks (16 double-blind plus 8 open-label when all received 372 µg). Coprimary end points were change in nasal congestion/obstruction at 4 weeks and summed bilateral polyp grade at 16 weeks. Secondary end points included symptoms, polyp elimination, and functioning. RESULTS: EDS-FLU was superior on both coprimary end points (P < .001 vs EDS-placebo, all doses). Mean polyp grade improved continuously through week 24 (P < .009, all comparisons), with polyps eliminated on at least 1 side in approximately 25% of patients at week 24 versus 8.7% with EDS-placebo (P ≤ .014, all comparisons). Sino-Nasal Outcomes Test scores also improved significantly versus those in patients receiving EDS-placebo (-21.1 to -21.4 vs -11.7 at week 16, P < .05 all doses). At the end of the double-blind period, EDS-FLU (all doses) significantly improved all 4 defining disease symptoms. In most patients (68%), those receiving EDS-FLU reported "much" or "very much" improvement. The number of patients eligible for surgery decreased by 62%-67%. The safety profile was similar to that reported in prior trials evaluating conventional corticosteroid nasal sprays in comparable populations. CONCLUSION: EDS-FLU produces clinically and statistically significant improvement in all 4 diagnostically defining disease symptoms, polyp grade, and quality of life in patients with chronic rhinosinusitis with NPs.

EXHANCE-12: 1-year study of the exhalation delivery system with fluticasone (EDS-FLU) in chronic rhinosinusitis.

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.

The nasal approach to delivering treatment for brain diseases: an anatomic, physiologic, and delivery technology overview.

The intricate pathophysiology of brain disorders, difficult access to the brain, and the complexity and high risks and costs of drug development represent major hurdles for improving therapies. Nose-to-brain drug transport offers an attractive alternative or addition to formulation-only strategies attempting to enhance drug penetration into the CNS. Although still a matter of controversy, many studies in animals claim direct nose-to-brain transport along the olfactory and trigeminal nerves, circumventing the traditional barriers to CNS entry. Some clinical trials in man also suggest nose-to-brain drug delivery, although definitive proof in man is lacking. This review focuses on new nasal delivery technologies designed to overcome inherent anatomical and physiological challenges and facilitate more efficient and targeted drug delivery for CNS disorders.

Breath powered nasal delivery: a new route to rapid headache relief.

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.