Presentation on theme: "Impact of Allergic Rhinitis (AR) Symptoms on Quality of Life"— Presentation transcript:
1 Impact of Allergic Rhinitis (AR) Symptoms on Quality of Life Moderate-to-severe allergic rhinitis symptoms are associated withFatigue and daytime somnolence1–3Daily activity impairment4,5Reduced work productivity4–8Disturbed cognitive functions9Reduced learning abilities10,11Adverse effects on adolescent behaviour61. Borres MP et al. Ann Allergy Asthma Immunol 1997; 78: 29–34; 2. Craig TJ et al. J Allergy Clin Immunol 2005; 116: 1264–1266; 3. Young T et al. J Allergy Clin Immunol 1997; 99: S757–S762; 4. Reilly MC et al. Clin Drug Invest 1996; 11: 278–288; 5. Tanner et al. Am J Manag Care 1999; 5(Suppl 4): S235–S247; 6. Juniper EF et al. J Allergy Clin Immunol 1994; 93: 413–423; 7. Corey JP et al. Otolaryngol Head Neck Surg 2000; 122: 681–685; 8. Blanc PD et al. J Clin Epidemiol 2001; 54: 610–618; 9. Marshall PS and Colon EA. Ann Allergy 1993; 71: 251–258; 10. Vuurman EF et al. Ann Allergy Asthma Immunol 1996; 76: 247–252; 11. Walker S et al. Eur Respir J 2005; 26(Suppl 49): 134s.
2 Epidemiology Of Allergic Rhinitis Allergic rhinitis was reported the second most prevalent chronic condition in the United States in 1994Affects 40 to 50 million peopleIncidence highest in people ages yearsPrevalence of Allergic Rhinitis is IncreasingNational Rhinitis Classification Task Force survey of 975 patients entering an allergist’s office complaining of chronic rhinitis. 43% had pure allergic rhinitis, 23% pure non allergic, and 34% had mixed rhinitis. 57% presented with non allergic rhinitis. Non allergic rhinitis may be a bigger problem than allergic rhinitis. When reviewing the literature there are literall thousands of articles on allergic rhinitis, only a few dedicated to non allergic rhinitis, and rarely does one find and article on mixed rhinitis. (Data presented at the National Allergy Advisory Council meeting:The Broad Spectrum of Rhinitis, Etiology, Diagnosis, and Advances in Treatment. St Thomas, US Virgin Islands. October 16, 1999)
3 Despite Available Treatment Nasal Symptom Burden Remains High A population-based cross-sectional survey was carried out to assess the symptom burden of patients with rhinitis symptoms during an allergy seasonA total of 7069 individuals with complete data were analysedThis survey showed that AR symptom sufferers, during an allergy season, have a large nasal symptom burden despite the availability of over-the-counter (OTC) and prescription medication treatmentsNathan, R.A., Meltzer, E., Derebery, J., Stang, P., Campbell, U., & Stanford, R “Rhinitis symptom sufferers report a significant symptom burden during an allergy season”, AAAAI, Poster.During an allergy season AR symptom sufferers have a large nasal symptom burden despite the availability of over-the-counter and prescription treatmentsNathan RA et al. AAAAI 2006.
4 Hay Fever Symptoms Have a Significant Impact on Exam Performance A case-control study in UK students sitting national exams in three subjects (May–June 2004)36% (673/1862) dropped at least one grade in at least one subject compared with winter examCases (dropped at least one grade) (n=673)Controls (n=1189)Mean diff (95% Cl)Hay fever symptoms, n (%)389 (59.9%)623 (53.9%)5.4%*( )*P=0.001Walker S et al. Eur Respir J 2005; 26(Suppl 49): 134s.
5 Očesni simptomi so pomembni pri zdravljenju alergijskega rinitisa 71% bolnikov trpi zaradi očesnih simptomov50% jemlje več zdravil za ARThese ocular symptoms are important as they are very prevalentCurrently AR is treated by symptoms. INS for the nose and eye drops or AH for the eyesPolypharmacy means patients are not fully satisfiedMajority of these still not satisfied with treatmentAnti-histamines are not effective enough on nasal symptomsCurrent INSs do not work on eye symptoms
6 Systemic availability of INS Systemic availability via swallowed portionInfluenced by:INS bioavailabilityDegree of first-pass inactivation in liverSystemic availability via lungsNoseLiver Hepatic inactivation (first-pass metabolism)PharynxStomachOesophagusLungsKey message:Intranasally administered drugs can be systemically absorbed. Therefore, it is important to have attributes that minimise the systemic availability.Key points of information:A Phase I pharmacokinetic study (FFR10008) using an oral solution of radiolabelled drug demonstrated that at least 30% of FF is absorbed and the oral bioavailability is, on average, 1.26%.1This is indicative of extensive first-pass metabolism of FF.Although the contribution of direct nasal absorption to the overall bioavailability has not been determined, it is expected to be negligible.Clearance of FF is primarily by metabolism; FF is rapidly cleared (average total plasma clearance of 57.5 L/h) from the systemic circulation principally by hydrolysis in the liver by the cytochrome P450 enzyme CYP3A4 to a pharmacologically inactive 17 -carboxylic metabolite.2References:GSK, data on file.Veramyst (fluticasone furoate) label information; Last accessed 16/05/07.Brand PL. Eur Respir J 2001;17:287–94.Daley-Yates PT, Richards DH. Clin Ther 2004;26:1905–19.Brand PL. Eur Resp J 2001;287–94.Daley-Yates PT, Richards DH. Clin Ther 2004;26:1905–19.
7 Nazalno okularni živčni refleks 1. FF ima visoko afiniteto do glukokortikoidnega receptorja1-32. To lahko povzroči boljšo inhibicijo nasalno okularnega refleksnega mehanizma3. Sproščanje mediatorjev, ki povzročajo okularne simptome je zmanjšanoKey message:FF consistently demonstrates efficacy against the ocular symptoms of AR.Key points of information:The mechanism of action of FF on the ocular symptoms of AR has yet to be established.A systemic effect is unlikely due to the low bioavailability, rapid first-pass metabolism, and low systemic concentration of FF; in addition, safety analyses show no evidence of ocular adverse events in patients.Evidence suggests a neural mechanism (portrayed visually in the diagram above):Bilateral nasal secretions occur post unilateral allergen exposure.1Increased symptom scores on the side contralateral to allergen challenge have been observed.1–6In a nasal challenge study, authors reported that approximately 20% of AR sufferers experienced ocular symptoms during nasal provocation with grass pollen.7These data suggest that allergic ocular symptoms can occur without direct allergen contact to the conjunctiva.Additional point of information:The enhanced affinity for the GR, greater GR selectivity, longer duration of action compared with other INS are possibly the reasons why FF has consistent efficacy for the ocular symptoms of AR.References:Konno A, Togawa K. Ann Otol Rhinol Laryngol 1979;88:258–66.Wagenmann M et al. Clin Exp Allergy 1996;26:371–8.Malmberg H et al. Acta Otolarygol 1989;107:446–9.Raphael GD et al. J Allergy Clin Immunol 1991;88:33–42.Baroody FM et al. Am J Respir Crit Care Med 1998;157:899–906.Sheahan P et al. Clin Exp Allergy 2005;35:45–51.Lebel B et al. J Allergy Clin Immunol 1988;82:869–77.
8 Fluticasone furoate: glukokortikoid z večjo afiniteto do receptorjev 300025002000Relative receptor affinity (RRA)15001000500Fluticasone furoateMometasone furoateFluticasone propionateBeclometha- sone-17- monopropionateCiclesonide active principleDexamethasoneBudesonideValotis A, Högger P. EAACI 2006, Abstract 780.
9 Fluticasone furoate: a novel molecule SCH2FCH2CIOOOOSCH2FOCOCH2CH3OOHOHOOOCOHO17FOCIFOOFFMometasone furoate (MF)Fluticasone furoateFluticasone propionate (FP)Key message:The chemical structure of FF differs significantly from FP and mometasone furoate (MF), the key difference being its 17-α furoate ester and steroid backbone.Key points of information:FF:Has the combination of a furoate ester group at the 17-α position with the metabolically labile fluoromethylthioester group at the 17-β position on the fluticasone backbone.1,2,3Differs from FP due to its 17-α furoate ester.1,2,3Differs from MF due to its different steroid backbone.4Additional points of information:FF is only active in the body as the intact molecule and is, therefore, neither a pro-drug, like beclomethasone dipropionate and ciclesonide, nor an alternative salt of FP.1,2,3FF is rapidly metabolised and inactivated by the liver after it enters the systemic circulation by removal of the 17-β fluoromethylthioester.1,2,3Rapid inactivation ensures that systemic glucocorticoid-mediated side effects are minimised.1,2,3At no point does fluticasone exist alone during corticosteroid metabolism, therefore, FF and FP have no metabolites in common.1,2,3A mode of action video demonstrating the difference between the chemical structures of FF and FP and the potential implications of this is available and could be shown at this point.References:USAN. USP Dictionary of USAN and International Drug Names 2006 USP Dictionary Supplement 3. Pharmacopeial Forum 2006;32:1393–605.Biggadike K et al. Presented at the XXV Congress of the European Academy of Allergology and Clinical Immunology, Vienna, Austria, June 10–14, 2006; Abstract 783.Biggadike K et al. J Med Chem 2008;51:3349–52.Sahasranaman S et al Drug Metab Dispos 2006;34:225–33.Fluticasone furoate is a different active chemical entity from fluticasone propionate or mometasone furoateBiggadike K et al. EAACI 2006, Abstract 783.Biggadike K et al. J Med Chem 2008;51:3349–52.9Key slide
10 Fluticasone furoate tissue retention in human lung epithelial cells Fluticasone propionate (10-10M)Fluticasone furoate (10-10M)4 hKey message:FF binds more effectively to human lung epithelial cells than other clinically used glucocorticoids, thereby enhancing its duration of action.Key points of information:Please note this slide is based on in vitro data.Previous slides have shown that FF binds to the GR with a long half-life and shows sustained anti-inflammatory activity in vitro with prolonged incubation.An additional way that FF may increase its duration of action in vivo is through its high affinity for respiratory tissue.The slide above shows that FF binds for longer to human lung epithelial cells than FP.1,2Experiments with BEAS 2B human lung epithelial cells show that FF remains bound to the fluorescently labelled GR in the nucleus for up to 30 hours.1,2The very high association of FF with tissue will increase the likelihood that sufficient FF will be contained in the tissue to maintain full anti-inflammatory activity over 24 hours.Additional points of information:This phenomenon has also been seen with nasal epithelia.Furthermore, studies with the isolated human GR show that FF dissociates very slowly from the GR with a half-life of 10–11 hours which will further enhance the duration of action of FF.References:Adcock I, Ito K, data on file.Valotis A, Högger P. Respir Res 2007;8:54.30 hFluticasone furoate remains bound to glucocorticoid receptor at its cellular site of action for >24 hoursHigh retention of fluticasone furoate in tissues enhances its duration of actionAdcock I, Ito K, data on file.Valotis A, Högger P. Respir Res 2007;8:54.
11 Fluticasone furoate shows greatest in vitro cell retention 206040Epithelial cell association after 6 hours (% of total recovered)FFFPMFBudesonideFlunisolideTriamcinolone acetonideKey message:FF binds more avidly to respiratory tissue than other currently used glucocorticoids.Key points of information:The aim of this study was to investigate the binding of FF to epithelial tissue compared with other glucocorticoids.The transport of FF across respiratory tissue was investigated using a monolayer of human lung epithelial cells.FF (500 nM) was added to one side of the monolayer; the concentration of FF reached in the monolayer were greater than that for other glucocorticoids, including MF, FP and BUD.Furthermore, the rate of transport from the cell layer was lower with FF than that with the other glucocorticoids.These data support the greater cellular retention of FF and the rationale for once-daily dosing.Additional points of information:Prolonged retention time is a desirable property with topically applied glucocorticoids because it increases the retention time at the site of actionIn turn, this reduces the risk of systemic transport and associated side effects.The high tissue association, extended binding to the GR, and high potency suggest that FF should maintain efficacy over the entire 24-hour dosing period.Reference:Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667.Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667.
12 Fluticasone furoate shows enhanced affinity for the glucocorticoid receptor 500100015002000250030003500Fluticasone furoateFluticasone propionateMometasone furoateCiclesonide active principleRelative Receptor Affinity (RRA)DexamethasoneBudesonideKey message:FF binds to the human GR with a greater affinity than any of the other clinically used glucocorticoids; this permits a greater duration of anti-inflammatory action in the body.Key points of information:Please note this slide is based on in vitro data.The most fundamental and focused biological test for glucocorticoids is to see how effectively they bind to the GR.In preclinical studies, FF displayed a higher affinity for the GR than currently available glucocorticoids: relative receptor affinity (RRA) of FF for the human GR is 2988±135 with reference to dexamethasone RRA = 100±5.1,2FF also dissociates from the GR very slowly which will increase its anti-inflammatory duration of action in the body.Additional points of information:X-ray diffraction studies with the crystals of the GR ligand binding domain have shown that the improved affinity of FF appears to be due to the 17-α furoate ester group of fully occupying a key pocket in the ligand binding site of the GR.Conversely, the propionate ester group of FP only partially occupies this pocket giving a weaker interaction with the GR.Reference:Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667.Valotis A, Högger P. Respir Res 2007;8:54.FF has the highest GR affinity compared with othercurrently available INSValotis A, Högger P. Respir Res 2007;8:54.Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667.Key slide
13 Fluticasone furoate – nudi boljšo zaščito pred poškodbo celic Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;doi: /ajplung
14 Fluticasone furoate: highly selective for GR 1020304050500600700Fluticasone propionateFluticasone furoateHuman steroid hormone receptor selectivityMometasone furoateCiclesonide active principleBudesonide800900Mineralocorticoid receptorProgesterone receptor-bKey message:FF demonstrates greater selectivity for the GR than other glucocorticoids, thereby limiting the potential for unwanted side effects.Key points of information:Please note this slide is based on in vitro data.The GR is structurally related to other receptors from the steroid hormone family. Since the receptors are similar, some glucocorticoids also bind to these other receptors.It is important that a therapeutic glucocorticoid has high potency for the GR and minimal potency for the other steroid hormone receptors (i.e. high selectivity), to avoid unwanted effects.Of the steroids tested, FF has the highest selectivity for the GR and lowest selectivity for other receptors. This is in contrast to MF and budesonide (BUD), which have the same potency for the progesterone receptor as for the GR and also poor selectivity for the GR vs the mineralocorticoid receptor (MR), which indicates that they are equally likely to bind to these receptors as the GR, thereby allowing for reduced efficacy and the potential for other unwanted effects.The arrow in this slide depicts that the greater the value, the greater the selectivity for the GR. If a glucocorticoid has the same potency against a steroid hormone receptor as its potency against GR (i.e. totally non-selective) it will have a selectivity ratio of 1.Additional points of information:The log EC50 values of FF, FP, MF, ciclesonide active principal (CIC-AP) and BUD have been negatively logged to show potency as a molar concentration (i.e. the concentration that produces 50% of the maximal effect on either the progesterone-b receptor, MR, androgen receptor or the alpha and beta subtypes of the oestrogen receptor).The negative log of the molar concentration that produces 50% of the maximal effect on GR-mediated inhibition of the NFkB pathway is also included as an indicator of GR activity.The potency for each steroid hormone receptor is divided by the potency for GR-mediated NFkB inhibition to give each selectivity value.Reference:Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667.1:1Lower selectivity for GR Greater selectivity for GR800:1FF has greater selectivity for the GR than other INSKey slideSalter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667.
15 Wound area (% of control) Glucocorticoid concentration (nM) Fluticasone furoate: protection against mechanically induced inflammatory damage120Fluticasone furoateFluticasone propionateMometasone furoateBudesonide1101009080Key message:FF is a powerful anti-inflammatory INS, as demonstrated by its highly effective protection against elastase-induced and mechanically induced damage of the human lung epithelia.Key points of information:Please note this slide is based on in vitro data.Mechanically induced damage to cells can be reduced by steroids.The presented data indicate that FF has the greatest protective potency against elastase-induced monolayer damage as assessed by cell detachment.Moreover, the more potent the steroid, the greater the protection at the lowest doses. FF protected the cells at very low doses; doses at which other steroids did not prevent damage.This indicates that FF has a powerful anti-inflammatory effect.Additional points of information:The maintenance of epithelial monolayer integrity is monitored by measuring the detachment of the cell layer from the cell membrane after treatment of the monolayer with the protease elastase.In addition, pre-treatment of an epithelial monolayer with glucocorticoid can also mitigate some of the secondary inflammatory damage caused as a consequence of an initial mechanical insult. FF also shows the most potent protective effect of all glucocorticoids when tested in this system.Reference:Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667.70Wound area (% of control)60504030200.0010.010.1110Glucocorticoid concentration (nM)Salter M et al. Am J Physiol Lung Cell Mol Physiol 2007;293:L660–L667.
16 Fluticasone furoate: low bioavailability Bioavailability of currently used INSKey message:The absolute bioavailability of FF is 0.5%, which minimises potential for unwanted systemic effects.Key points of information:The bioavailability of FF is similar to FP and MF and less than that of other INS, for example budesonide.Additional points of information:Older drugs with high bioavailability have been associated with steroid-related adverse events, for example growth suppression.1–3The levels of FF are generally below the limit of quantitation (LLQ) at the clinically relevant dose for adults and adolescents (110 µg/day).4Therefore, to enable estimation of absolute bioavailability, supra-therapeutic doses of 880 µg were administered at 8-hourly intervals for 10 doses (total dosage µg/day).4The slide shows that the resulting absolute bioavailability of FF is 0.5%.4This data indicates that systemic exposure to intranasal FF is very low, which minimises the potential for unwanted systemic effects at the maximum therapeutic dose (110 µg/day).4References:Bryson HM, Faulds D. Drugs 1992;43:760–75.Daley-Yates PT, Baker RC. Br J Clin Pharmacol 2001;51:103–5.Daley-Yates PT et al. Eur J Clin Pharmacol 2004;60:265–8.Allen A et al. Clin Ther 2007;29:1415–20.Bryson HM, Faulds D. Drugs 1992;43:760–75.Daley-Yates PT, Baker RC. Br J Clin Pharmacol 2001;51:103–5.Daley-Yates PT et al. Eur J Clin Pharmacol 2004;60:265–8.Allen A et al. Clin Ther 2007;29:1415–20.Key slide
17 Nazalno okularni živčni refleks 1. FF ima visoko afiniteto do glukokortikoidnega receptorja1-32. To lahko povzroči boljšo inhibicijo nasalno okularnega refleksnega mehanizma3. Sproščanje mediatorjev, ki povzročajo okularne simptome je zmanjšanoKey message:FF consistently demonstrates efficacy against the ocular symptoms of AR.Key points of information:The mechanism of action of FF on the ocular symptoms of AR has yet to be established.A systemic effect is unlikely due to the low bioavailability, rapid first-pass metabolism, and low systemic concentration of FF; in addition, safety analyses show no evidence of ocular adverse events in patients.Evidence suggests a neural mechanism (portrayed visually in the diagram above):Bilateral nasal secretions occur post unilateral allergen exposure.1Increased symptom scores on the side contralateral to allergen challenge have been observed.1–6In a nasal challenge study, authors reported that approximately 20% of AR sufferers experienced ocular symptoms during nasal provocation with grass pollen.7These data suggest that allergic ocular symptoms can occur without direct allergen contact to the conjunctiva.Additional point of information:The enhanced affinity for the GR, greater GR selectivity, longer duration of action compared with other INS are possibly the reasons why FF has consistent efficacy for the ocular symptoms of AR.References:Konno A, Togawa K. Ann Otol Rhinol Laryngol 1979;88:258–66.Wagenmann M et al. Clin Exp Allergy 1996;26:371–8.Malmberg H et al. Acta Otolarygol 1989;107:446–9.Raphael GD et al. J Allergy Clin Immunol 1991;88:33–42.Baroody FM et al. Am J Respir Crit Care Med 1998;157:899–906.Sheahan P et al. Clin Exp Allergy 2005;35:45–51.Lebel B et al. J Allergy Clin Immunol 1988;82:869–77.
18 Delivery system is designed to meet the needs of patients Easy to use devicePatient-friendly sprayNo taste or smellLittle or no drip down the throat (half the spray volume of other intranasal steroidsGentle spray, a consistent amount each timeKey message:The new FFNS nasal drug delivery system was designed with patients in mind to overcome the issues experienced by patients with devices used to administer other currently available INS.Key points of information:Patients remain reluctant to use INS owing to the negative sensory characteristics of the nasal spray formulation, and to issues relating to ease-of-use of the device.1The FFNS delivery system has been designed with the patient in mind and demonstrates a number of advantages:1-3The FFNS is formulated to be delivered as a gentle mist with a favourable sensory characteristics profile, in terms of reduced odour, aftertaste and drip down the throat.Consistent delivery of the recommended 50 µl volume ensures that effectiveness against the symptoms of AR is achieved and sustained.The delivery system is ergonomically designed with a contoured grip and side-actuated device to ease grip and triggering, making it user-friendly to a wide population of patients, including the elderly and young children.The short delivery nozzle ensures comfort and eases administration in children.The see-through window ensures that the patient can visualise the precise amount of medication remaining to prevent wastage and aid with timely refill.The features of the FFNS delivery system may aid in promoting patient acceptance of, and compliance with, prescribed INS.1Additional points of information:The FFNS delivery device has been tested in clinical efficacy and safety studies conducted in adult/adolescent patients.In a 2-week, US-based, randomised, double-blind, placebo-controlled, parallel-group study (FFR104861), 90% of patients were satisfied with the FFNS delivery system and FFNS formulation; while two-thirds found the delivery system to be extremely easy to carry and operate and over 50% reported that the mist spray was gentle with minimal or no aftertaste.4References:Berger W et al. Expert Opin Drug Deliv 2007;4:689–701.Berger W et al. J Allergy Clin Immunol 2007;119(1 Suppl):S231.Godfrey JW et al. J Allergy Clin Immunol 2007;119(1 Suppl):S230.FFR (patients with SAR aged ≥12 years). Kaiser HB et al. J Allergy Clin Immunol 2007;119:1430–7.Comfortable for patientsNozzle is short and ergonomically designedEasy to grip with side actuationViewing windowSee how much is leftKey slide
Your consent to our cookies if you continue to use this website.