Pharmacokinetic Evidence of Steady and Sustained Drug Release from Long-Acting Implantable Corticosteroid Matrices for Chronic Rhinosinusitis.

BACKGROUND: The efficacy of topical corticosteroids is limited in chronic rhinosinusitis (CRS) due to rapid clearance from the nasal cavity and insufficient drug delivery to inflamed sinonasal passages. LYR-210 is an implantable corticosteroid matrix designed to provide up to 24 weeks of treatment to patients with CRS by locally delivering mometasone furoate (MF) to the sinonasal mucosa. In a randomized, controlled, dose-ranging LANTERN study, LYR-210 (7500 µg) achieved clinically relevant improvement in CRS cardinal symptom composite scores, the 22-item Sinonasal Outcome Test (SNOT-22), ethmoid opacification, and the need for rescue treatment at 24 weeks. OBJECTIVE: As the plasma MF concentrations of LYR-210 (2500 µg) and LYR-210 (7500 µg) were evaluated at weeks 4, 12, and 24 in the LANTERN study (data on file at Lyra Therapeutics, Inc.), this study aims to characterize the pharmacokinetic profiles of both doses of LYR-210 at earlier timepoints post-placement in patients with CRS. METHODS: Twenty-four surgically naïve adult patients with CRS were enrolled in an open-label, multicenter study and underwent in-office bilateral administration of LYR-210 (2500 µg) (n = 12 patients) or LYR-210 (7500 µg) (n = 12 patients) into the middle meatus. Plasma MF concentrations were determined pre-placement and 1-h post-placement (day 1), and on days 2, 3, 7, 14, 21, 28, 42, and 56 by liquid chromatography-tandem mass spectrometry. RESULTS: Both LYR-210 doses were well-tolerated with no serious adverse events. Systemic MF levels were dose-dependent and lower than reported values of other respiratory MF products. Plasma MF concentrations showed steady drug release from LYR-210 (2500 µg) and LYR-210 (7500 µg) that persisted through day 56. CONCLUSION: LYR-210 achieved dose-dependent, continuous local MF delivery at a steady rate with low systemic exposure for months.

Exposure-Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy.

Exposure-response relationships of vamorolone, a novel dissociative steroidal anti-inflammatory drug, were investigated in clinical trials in boys with Duchenne muscular dystrophy. Variables were clinical outcome measures, Fridericia-corrected QT (QTcF) duration, and pharmacodynamic (PD) biomarkers. Exposure metrics were area under the plasma concentration time curve (AUC) and maximum plasma concentration (Cmax ), with a sigmoid Emax model applied. Significant improvement in clinical efficacy outcomes was observed after 24 weeks of daily dosing. The primary outcome, time to stand from supine velocity, exhibited the highest sensitivity to vamorolone, with the lowest AUC value providing 50% of maximum effect (E50  = 186 ng·h/mL), followed by time to climb 4 stairs (E50  = 478 ng·h/mL), time to run/walk 10 m (E50  = 1220 ng·h/mL), and 6-minute walk test (E50  = 1770 ng·h/mL). Week 2 changes of proinflammatory PD biomarkers showed exposure-dependent decreases. The E50 was 260 ng·h/mL for insulin-like growth factor-binding protein 2, 1200 ng·h/mL for matrix metalloproteinase 12, 1260 ng·h/mL for lymphotoxin α1/ß2, 1340 ng·h/mL for CD23, 1420 ng·h/mL for interleukin-22-binding protein, and 1600 ng·h/mL for macrophage-derived chemokine/C-C motif chemokine 22. No relationship was found between QTcF interval changes from baseline and Cmax in week 2 or 24. This analysis showed that improvements in clinical efficacy end points in week 24 and PD biomarkers in week 2 were achieved at typical vamorolone exposure of 2 mg/kg daily dose with a median AUC dose of 6 mg/kg (3651 ng·h/mL), corresponding to approximately 95% of maximum effects for most response variables.

Population Pharmacokinetics of Vamorolone (VBP15) in Healthy Men and Boys With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder occurring in boys and caused by mutations in the dystrophin gene. Vamorolone is a first-generation delta-9,11 compound that has favorable efficacy and side effect profiles relative to classical glucocorticoids. The pharmacokinetics (PK) of oral vamorolone were assessed in parallel-group studies in healthy men (phase 1, n = 86) and boys with DMD (phase 2a, n = 48) during 14 days of once-daily dosing with a range of doses. Vamorolone exhibited moderate variability in PK, with the maximum plasma concentration usually occurring at 2-4 hours and a half-life of approximately 2 hours for all doses and days examined. Population PK modeling of all data together indicated that the PK of vamorolone can be well described by a 1-compartment model with zero-order absorption. Both men and boys showed a dose-linearity of PK parameters for the doses examined, with no accumulation of the drug during daily dosing. Ingestion with food resulted in markedly enhanced absorption of the drug, as tested in healthy men. There were similar PK of vamorolone in healthy men and DMD boys with apparent clearance averaging 2.0 L/h/kg in men and 1.7 L/h/kg in boys. Overall, vamorolone exhibited well-behaved linear PK, with similar profiles in healthy men and boys with DMD, moderate variability in PK parameters, and absorption and disposition profiles similar to those of classical glucocorticoids.

Lung Delivery of Indacaterol and Mometasone Furoate Following Inhalation of QMF149 in Healthy Volunteers.

This single-dose, 4-period crossover study evaluated the pharmacokinetics (PK) of the ß2 -agonist indacaterol maleate and the corticosteroid mometasone furoate (MF) after inhalation of a fixed-dose combination (QMF149, indacaterol maleate/MF, 500/400 µg) via the Twisthaler (TH) device with and without activated charcoal and postdose mouth rinsing in healthy volunteers. The PK of indacaterol maleate 300 µg inhaled via the Breezhaler (BRZ) device was also characterized. Relative bioavailability of indacaterol and MF for inhalation with versus without charcoal, based on AUClast, was 0.25 (90% confidence interval [CI], 0.18-0.35) and 0.70 (90%CI, 0.52-0.93), respectively. Thus, 25% and 70% of systemic exposure of indacaterol and MF, respectively was due to pulmonary absorption and 75% and 30%, respectively, was due to gastrointestinal absorption. Mouth rinsing reduced the systemic exposure of indacaterol by approximately 35% but had no relevant effect on the exposure of MF. Dose-normalized AUClast for indacaterol inhaled via the BRZ device was 2.3-fold higher than QMF149 via the TH device. All treatments had a good safety profile and were well tolerated. Data from this study and comparison with inhalation of indacaterol via the BRZ device suggest that the latter was more efficient than the TH device regarding lung delivery of indacaterol.

Pharmacokinetics of indacaterol and mometasone furoate delivered alone or in a free or fixed dose combination in healthy subjects.

PURPOSE: QMF149 is a fixed-dose combination of the long-acting ß2 agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler(®) device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects. METHODS: In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 µg, mometasone furoate 320 µg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 µg/mometasone furoate 320 µg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose. RESULTS: Indacaterol AUC0-24h,ss and Cmax,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC0-24h,ss and Cmax,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC0-24h,ss and Cmax,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for Cmax,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. CONCLUSIONS: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC0-24h,ss and Cmax,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment.

Pharmacokinetics of QMF149 in Japanese versus Caucasian subjects: an open-label, randomized phase I study.

OBJECTIVES: This study aimed to evaluate influence of ethnic factors on the pharmacokinetics of orally inhaled QMF149, a novel combination of an approved longacting ß2-agonist, indacaterol (Onbrez® Breezhaler® for COPD), and an approved inhaled corticosteroid, mometasone furoate (MF), (Asmanex® Twisthaler® for asthma), following multiple dose administration of QMF149 (indacaterol acetate/MF) 150/80 µg and 150/320 µg via the Breezhaler® device in healthy Japanese and Caucasian subjects. METHODS: This was a single-center, openlabel, multiple-dose, two-period, complete crossover study that randomized healthy Japanese and, age and weight matched Caucasian subjects to QMF149 150/80 µg or 150/320 µg once daily (o.d.) for 14 days in each period. Pharmacokinetics (PK) were assessed up to 24 hours on days 1 and 14. RESULTS: 24 Japanese and 24 Caucasian healthy subjects were enrolled. Indacaterol and MF had similar PK profiles across both the doses and both ethnic groups. The maximum geometric mean ratios (90% confidence interval (CI)) for Japanese vs. Caucasian subjects for Cmax were 1.23 (1.11 - 1.38) and 1.24 (1.11 - 1.38) for indacaterol and MF, respectively. For AUC, the maximum ratios were 1.22 (1.09 - 1.36) and 1.30 (1.18 - 1.44) for indacaterol and MF, respectively. The mild trend towards higher exposure in Japanese subjects could be explained by the fact that the mean body weight was 14% higher for Caucasians compared to their Japanese counterparts. No serious adverse events or discontinuations related to study medication were reported. CONCLUSION: The study demonstrated increase of mean exposure parameters in Japanese subjects vs. Caucasian subjects, which ranged between 19 - 23% and 17 - 30%, for indacaterol and MF components, respectively. Multiple doses of both the QMF149 dose levels were safe and well-tolerated in all subjects. Body weight was considered a key contributory factor for the observed difference in exposure. These results suggest no dose adjustment for QMF149 is required in Asian populations.

Regional deposition of mometasone furoate nasal spray suspension in humans.

Nasal deposition studies can demonstrate whether nasal sprays treating allergic rhinitis and polyposis reach the ciliated posterior nasal cavity, where turbinate inflammation and other pathology occurs. However, quantifying nasal deposition is challenging, because in vitro tests do not correlate to human nasal deposition; gamma scintigraphy studies are thus used. For valid data, the radiolabel must distribute, as the drug, into different-sized droplets, remain associated with the drug in the formulation after administration, and not alter its deposition. Some nasal deposition studies have demonstrated this using homogenous solutions. However, most commercial nasal sprays are heterogeneous suspensions. Using mometasone furoate nasal suspension (MFS), we developed a technique to validate radiolabel deposition as a surrogate for nasal cavity drug deposition and characterized regional deposition and nasal clearance in humans. Mometasone furoate (MF) formulation was spiked with diethylene triamine pentacaetic acid. Both unlabeled and radiolabeled formulations (n = 3) were sprayed into a regionally divided nasal cast. Drug deposition was quantified by high pressure liquid chromatography within each region; radiolabel deposition was determined by gamma camera. Healthy subjects (n = 12) were dosed and imaged for six hours. Scintigraphic images were coregistered with magnetic resonance imaging scans to quantify anterior and posterior nasal cavity deposition and mucociliary clearance. The ratio of radiolabel to unlabeled drug was 1.05 in the nasal cast and regionally appeared to match, indicating that in vivo radiolabel deposition could represent drug deposition. In humans, MFS delivered 86% (9.2) of metered dose to the nasal cavity, approximately 60% (9.1) of metered dose to the posterior nasal cavity. After 15 minutes, mucociliary clearance removed 59% of the initial radiolabel in the nasal cavity, consistent with clearance rates from the ciliated posterior surface. MFS deposited significant drug into the posterior nasal cavity. Both nasal cast validation and mucociliary clearance confirm the radiolabel deposition distribution method accurately represented corticosteroid nasal deposition.

Steroid-eluting sinus implant for in-office treatment of recurrent polyposis: a pharmacokinetic study.

BACKGROUND: Long-term use of systemic glucocorticoid therapy has been associated with hypothalamic-pituitary-adrenal axis suppression and other systemic adverse events. This pharmacokinetic study evaluated the systemic safety and performance of a bioabsorbable sinus implant that gradually releases 1350 µg of mometasone furoate directly to the sinus mucosa. METHODS: A prospective, single-center study treating 5 adult patients with recurrent polyposis after bilateral total ethmoidectomy. Each patient received 2 steroid-releasing implants in-office under local/topical anesthesia. Plasma concentrations of mometasone furoate and cortisol were determined before placement and through 30-day follow-up, which also included endoscopic grading and patient-reported outcomes. RESULTS: Five patients (mean age 46.2 ± 9.2 standard deviation [SD] years; 60% male) underwent successful placement in all 10 ethmoid sinuses. There were no serious adverse events. The plasma concentrations of mometasone furoate were generally below the lower limit of quantification (LLOQ) of the assay (30 pg/mL). Cortisol concentrations at follow-up ranged from 3.9 to 5.7 mg/dL compared to 4.7 mg/dL at baseline. At 1 month, there was a significant improvement in bilateral polyp grade (p = 0.037), nasal obstruction score (p = 0.002), and 22-item Sino-Nasal Outcome Test (SNOT-22) (p = 0.010) compared to baseline. CONCLUSION: The reported 100% placement success, negligible systemic exposure to mometasone furoate released over time, lack of adrenal suppression, and the absence of serious adverse events suggest that the implant provides a valid and safe option for the in-office treatment of recurrent polyposis. Randomized, controlled, blinded clinical studies are underway to provide further evidence of safety and efficacy.

Nanoencapsulation in lipid-core nanocapsules controls mometasone furoate skin permeability rate and its penetration to the deeper skin layers.

AIMS: The influence of nanoencapsulation of mometasone furoate (MF) in poly(ε-caprolactone) lipid-core nanocapsules (LNC) on its in vitro human skin permeation and penetration was evaluated. METHODS: Semisolid formulations were prepared by increasing the viscosity of LNC using a carbomer (Carbopol(®) Ultrez at 0.5% w/v). Two complementary techniques (the static Franz diffusion cell model and the Saarbrücken penetration model) were used to evaluate skin permeation/penetration. RESULTS: The drug release rate was decreased by nanoencapsulation. The skin permeability of MF was controlled by the nanoencapsulation as well as by increasing the viscosity. Furthermore, the formulation containing the nanoencapsulated MF controlled the amount of drug reaching the deeper skin layers without changing its accumulation in the stratum corneum. CONCLUSION: This formulation is suitable for prolonged treatment of skin disorders which should avoid systemic absorption.

Nasal deposition of ciclesonide nasal aerosol and mometasone aqueous nasal spray in allergic rhinitis patients.

BACKGROUND: Sensory attributes of intranasal corticosteroids, such as rundown to the back of the throat, may influence patient treatment preferences. This study compares the nasal deposition and nasal retention of a radiolabeled solution of ciclesonide nasal aerosol (CIC-hydrofluoroalkane [HFA]) with a radiolabeled suspension of mometasone furoate monohydrate aqueous nasal spray (MFNS) in subjects with either perennial allergic rhinitis (AR) or seasonal AR. METHODS: In this open-label, single-dose, randomized, crossover scintigraphy study, 14 subjects with symptomatic AR received a single dose of radiolabeled 74-µg CIC-HFA (37 µg/spray, 1 spray/each nostril) via a nasal metered-dose inhaler or a single dose of radiolabeled 200-µg MFNS (50 µg/spray, 2 sprays/each nostril), with a minimum 5-day washout period between treatments. Initial deposition (2 minutes postdose) of radiolabeled CIC-HFA and MFNS in the nasal cavity, nasopharynx, and on nasal wipes, and retention of radioactivity in the nasal cavity and nasal run-out on nasal wipes at 2, 4, 6, 8, and 10 minutes postdose were quantified with scintigraphy. RESULTS: At 2 and 10 minutes postdose, deposition of radiolabeled CIC-HFA was significantly higher in the nasal cavity versus radiolabeled MFNS (99.42% versus 86.50% at 2 minutes, p = 0.0046; and 81.10% versus 54.31% at 10 minutes, p < 0.0001, respectively; p values unadjusted for multiplicity). Deposition of radioactivity on nasal wipes was significantly higher with MFNS versus CIC-HFA at all five time points, and posterior losses of radiolabeled formulation were significantly higher with MFNS at 6, 8, and 10 minutes postdose. CONCLUSION: In this scintigraphic study, significantly higher nasal deposition and retention of radiolabeled aerosol CIC-HFA were observed versus radiolabeled aqueous MFNS in subjects with AR.

Mometasone furoate hydrogel for scalp use: in vitro and in vivo evaluation.

Dermatological inflammatory diseases often affect the scalp and the eyebrows. Common dosage forms available on the market for those situations are lotions; however, the presence of hair limits their use. Gels, for their consistency and adhesiveness, are a suitable alternative to the lotions in these situations. The aim of this study was to develop a new stable gel containing mometasone furoate (MF), with anti-inflammatory activity and a controlled delivery, to improve topical treatment of scalp dermatitis. Pharmaceutical development, physical and chemical characterization, stability, in vitro release and permeation studies and in vivo anti-inflammatory activity were performed. The gel presented an acidic pH and an apparent viscosity of 35 Pa.s. The microbiological analysis showed that the results were within the established specification limits. The release and the permeation profiles suggest that the drug is mainly retained in the upper skin layers. MF gel was tested in an animal model of cutaneous inflammation and presented similar anti-inflammatory activity compared to a commercially available MF dosage form. The gel was chemically, physically and microbiologically stable. The results suggest that the developed hydrogel formulation containing MF can be of actual value for improving the clinical effectiveness in the treatment of scalp dermatitis.

Microdialysis as a tool to determine the skin concentration of mometason furoate in rats.

The objective of this study was to investigate the feasibility of microdialysis as a tool to determine the skin concentration of mometason furoate (MF), a lipophilic and highly protein-bound compound. The relative recovery (RR) of mometasone furoate was determined by an in vitro no-net-flux method using three different perfusates (40% PEG400, 5% fat emulsion, and 20% fat emulsion) and four flow rates (0.5, 1, 2, and 4 µL x min(-1)). With the increasing of flow rate, the relative recovery was decreased from 48.8% to 3.1%. The in vitro recovery was increased to 23.71%, 42.76% and 56.21% when 40% PEG400, 5% fat emulsion or 20% fat emulsion was used as microdialysis perfusates, respectively. Fat emulsion (5%) was chosen as the perfusate to evaluate the in vivo recovery by a retrodialysis method, in which mometasone furoate concentration in different tissues was determined. The result showed that concentrations of mometasone furoate in the dermis was greater than that in the subcutaneous or muscle tissue. It was concluded that a recovery enhancer could be used in microdialysis technique, especially for determining skin concentrations of lipophilic and high protein-bounds.

Comparison of the systemic bioavailability of mometasone furoate after oral inhalation from a mometasone furoate/formoterol fumarate metered-dose inhaler versus a mometasone furoate dry-powder inhaler in patients with chronic obstructive pulmonary disease.

BACKGROUND: Coadministration of mometasone furoate (MF) and formoterol fumarate (F) produces additive effects for improving symptoms and lung function and reduces exacerbations in patients with asthma and chronic obstructive pulmonary disease (COPD). The present study assessed the relative systemic exposure to MF and characterized the pharmacokinetics of MF and formoterol in patients with COPD. METHODS: This was a single-center, randomized, open-label, multiple-dose, three-period, three-treatment crossover study. The following three treatments were self-administered by patients (n = 14) with moderate-to-severe COPD: MF 400 µg/F 10 µg via a metered-dose inhaler (MF/F MDI; DULERA(®)/ZENHALE(®)) without a spacer device, MF/F MDI with a spacer, or MF 400 µg via a dry-powder inhaler (DPI; ASMANEX(®) TWISTHALER(®)) twice daily for 5 days. Plasma samples for MF and formoterol assay were obtained predose and at prespecified time points after the last (morning) dose on day 5 of each period of the crossover. The geometric mean ratio (GMR) as a percent and the corresponding 90% confidence intervals (CI) were calculated for treatment comparisons. RESULTS: Systemic MF exposure was lower (GMR 77%; 90% CI 58, 102) following administration by MF/F MDI compared to MF DPI. Additionally, least squares geometric mean systemic exposures of MF and formoterol were lower (GMR 72%; 90% CI 61, 84) and (GMR 62%; 90% CI 52, 74), respectively, following administration by MF/F MDI in conjunction with a spacer compared to MF/F MDI without a spacer. MF/F MDI had a similar adverse experience profile as that seen with MF DPI. All adverse experiences were either mild or moderate in severity; no serious adverse experience was reported. CONCLUSION: Systemic MF exposures were lower following administration by MF/F MDI compared with MF DPI. Additionally, systemic MF and formoterol exposures were lower following administration by MF/F MDI with a spacer versus without a spacer. The magnitude of these differences with respect to systemic exposure was not clinically relevant.

Bioavailability, antipsoriatic efficacy and tolerability of a new light cream with mometasone furoate 0.1%.

Mometasone furoate, a potent glucocorticoid (class III) with a favorable benefit/risk ratio, has emerged as a standard medication for the treatment of inflammatory skin disorders. The purpose of the investigation presented here was to determine the noninferiority of a topical mometasone formulation, a light cream (O/W 60/40 emulsion) with mometasone furoate 0.1% (water content of 33%) versus marketed comparators. Using the vasoconstrictor assay, a strong blanching effect of the new cream (called Mometasone cream) comparable to that of a mometasone comparator, a fatty cream with mometasone furoate 0.1%, could be demonstrated. Thus, the topical bioavailability of the active ingredient mometasone furoate (0.1%) was regarded to be similar for Mometasone cream and the mometasone comparator. Using the psoriasis plaque test, a strong antipsoriatic effect comparable to that of the mometasone comparator was found for Mometasone cream after 12 days of occlusive treatment. A nearly identical reduction in the mean infiltrate thickness and similar mean AUC values were noted with both formulations confirmed by clinical assessment data. The noninferiority of Mometasone cream to its active comparator with respect to the AUC of change to baseline in infiltrate thickness was demonstrated. Both medications were well tolerated. Overall, Mometasone cream and the mometasone comparator showed similar efficacy and tolerability. Mometasone cream, in addition to its high potency and good tolerability, provides the properties of a light cream, which might make this new medication particularly suitable for application on acutely inflamed and sensitive skin.

Use of mometasone furoate administered via a dry powder inhaler in the treatment of asthma.

BACKGROUND: Inhaled corticosteroids (ICSs) are effective controller medications that treat the chronic inflammation of asthma. The goal of asthma treatment is to improve lung function, symptoms, and the ability to perform daily activities, while decreasing the risk of exacerbations. Mometasone furoate delivered via a dry powder inhaler (MF-DPI) is indicated for once-daily maintenance treatment of asthma in patients as young as 4 years old. OBJECTIVE: To review the quality of evidence for the clinical efficacy and safety of MF-DPI in both adults and children in the context of grading systems for guideline recommendations. Publications were identified by searching PubMed (MEDLINE) for 'mometasone furoate AND dry powder inhaler AND asthma' in any field with search limits for publications from 1 January 1995 to 1 August 2008. FINDINGS: MF-DPI has been evaluated in 21 randomized, double-blind, active- or placebo-controlled trials in adults with asthma. Clinical trials investigating the efficacy in patients previously treated with only short-acting beta(2)-agonists, other ICSs, or oral corticosteroids revealed that MF-DPI is efficacious in these populations. The results of a pooled analysis of ten trials and individual results of three long-term safety trials indicate that MF-DPI is well-tolerated with minimal adverse events. Six clinical trials of MF-DPI have been completed in children. Studies of pediatric patients treated with approved doses of MF-DPI indicate that children previously maintained on twice-daily treatment of other ICSs showed improvements in lung function, health-related quality of life, and rescue medication use. In addition, there is no effect on growth velocity or the hypothalamic-pituitary-adrenal axis. In both adults and children, once-daily dosing of MF-DPI has been demonstrated to be as efficacious as twice-daily dosing. CONCLUSION: The findings of this single-database review are that once-daily MF-DPI is efficacious and safe in both adults and children with asthma.

Different approaches for improving skin accumulation of topical corticosteroids.

The aim of this paper was to evaluate the effect of vehicle, chemical enhancer and iontophoresis on the skin accumulation of clobetasol propionate (CP) and mometasone furoate (MF). In vitro permeation experiments were performed using pig ear skin as barrier and HPLC as quantification method. The formulations tested were chitosan gels, sodium-deoxycholate gels and commercial creams of CP and MF. The results obtained indicate that Na-DOC gel had an enhancing effect on the skin accumulation of both active agents. This effect was more evident with CP especially in the stratum corneum and epidermis which are the target sites of topical steroidal treatment. Two terpene derivatives (D-limonene and nerolidol) and Transcutol P were evaluated as chemical penetration enhancers. Nerolidol produced considerable increase in the amount of CP and MF accumulated without any permeation across the skin. The application of electric current (anodal iontophoresis) to the gels improved the accumulation of MF while it did not effect the accumulation of CP. Due to the best accumulation results of nerolidol, the enhancement effect in combination with iontophoresis was also investigated. It was shown that, the combination of anodal iontophoresis and chemical enhancer (nerolidol) produced no further enhancement for both active agents.

Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications.

Intranasal corticosteroids (INSs) are effective treatments for allergic rhinitis, rhinosinusitis, and nasal polyposis. In recent years, increased understanding of corticosteroid and glucocorticoid receptor pharmacology has enabled the development of molecules designed specifically to achieve potent, localized activity with minimal risk of systemic exposure. Pharmacologic potency studies using affinity and other assessments have produced similar rank orders of potency, with the most potent being mometasone furoate, fluticasone propionate, and its modification, fluticasone furoate. The furoate and propionate ester side chains render these agents highly lipophilic, which may facilitate their absorption through nasal mucosa and uptake across phospholipid cell membranes. These compounds demonstrate negligible systemic absorption. Systemic absorption rates are higher among the older corticosteroids (flunisolide, beclomethasone dipropionate, triamcinolone acetonide, and budesonide), which have bioavailabilities in the range of 34-49%. Studies, including 1-year studies with mometasone furoate, fluticasone propionate, and budesonide that evaluated potential systemic effects of INSs in children have generally found no adverse effects on hypothalamic-pituitary-adrenal axis function or growth. Clinical data suggest no significant differences in efficacy between the INSs. Theoretically, newer agents with lower systemic availability may be preferable, and may come closer to the pharmacokinetic/pharmacologic criteria for the ideal therapeutic choice.

Mometasone furoate: a review of its intranasal use in allergic rhinitis.

Mometasone furoate (Nasonex) is a high-potency intranasal corticosteroid available for the treatment and/or prophylaxis of the nasal symptoms of seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). In the EU, it is approved for use in patients aged > or =6 years and, in the US, it is approved as a treatment in patients aged > or =2 years and as prophylaxis in those > or =12 years of age.Extensive experience in both clinical trials and the clinical practice setting has firmly established the efficacy and good tolerability profile of intranasal mometasone furoate in children and adults with PAR or SAR. Thus, intranasal mometasone furoate is a useful first-line option for the treatment and prophylactic management of these conditions, including in children as young as 2 years of age in some countries and 6 years of age in others.