Inspiratory Flow Profiles of PAH Patients with AOS™ Device Intended to Administer Inhaled Vardenafil.

Inspiratory Flow Profiles of PAH Patients with AOS™ Device Intended to Administer Inhaled Vardenafil Sandeep Sahay1, Royanne Holy2, Shirley Lyons3, Ed Parsley3, Mari Maurer3, and Jeffry Weers3 1 Houston Methodist Hospital, Houston, TX, USA; 2Houston Methodist Research Institute, Houston, TX, USA; 3Respira Therapeutics, Inc., Burlingame, CA, USA Study Design Thiswasanoninterventional,observationalstudyconductedatHouston MethodistLungCenter,HoustonMethodistHospital,Houston,Texas,USA.No activedrugorplacebowasadministeredtosubjects.Thestudywasapprovedby thelocalIRB.Informedconsentwasobtainedfromeachparticipatingsubject. Studydesign.InspiratoryflowprofilesofPAHsubjectswereassessedintwo randomizedcrossoverstudies:SubjectsinGroupA(N=18)weretestedwiththree variantsoftheRS01DPI(PlastiapeS.p.A.,Italy),thatdifferedintheirresistanceto airflow.TheRS01DPIisavailableinlowresistance(R=0.019kPa0.5L-1min)and mediumresistance(R=0.031kPa0.5L-1min)designs.TheAOS™DPI,avariant designedbyRespira,hasahighresistance(R=0.050kPa0.5L-1min).Eachdevice wasloadedwithanemptycapsulethatwaspiercedpriortotheinhalation maneuver.Subjectswereinstructedtoexhaletoemptytheirlungs,theninhale withmaximaleffortuntiltheirlungsarefull.SubjectsinGroupB(N=17)were testedwiththeAOSDPIandthreedifferentsetsofinhalationinstructions,viz: 1.Exhaletoemptylungs,theninhalewithmaximaleffortthroughinhaleruntil yourlungsarefull;2.Exhaletoemptylungs,theninhalecomfortablythrough theinhaleruntilyourlungsarefull;3.Inhalewithmaximaleffortthroughinhaler untilyourlungsarefull(noexhalationstepbeforeinhalation). 0 2 4 6 8 10 12 0.0 0.5 1.0 1.5 2.0 2.5 Max Comfort No Exh Vi (L) PIP (kPa) N=69 Conclusion Despitehavingreducedmusclestrength,PAHpatientscaneffectivelyusea breath-actuatedDPI.Theprobabilityofachievingeffectivedosedeliveryis increasedbyusingDPIswithhigherdeviceresistance,particularlywhenpatients donotfollowprescribedinhalationinstructionsandinhalecomfortably. Figure 2: Plot of the Viversus PIP achieved by PAH patients when using the AOS DPI with different inhalation instructions 97% of PAH patient inspiratory flow profiles with the AOS DPI exceed Vi > 0.5 L and PIP >1 kPa needed for effective drug delivery. Methods Patient inspiratory flow profiles were recorded with a calibrated custom data acquisition device designed by iPharmaLimited (Union City, CA). Profiles were analyzed with a LabView software program (iPharma). Figure 1: Parameters used to define the inspiratory flow profiles *p<0.05; **p<0.01Results Thestudyenrolled35subjectswithaconfirmeddiagnosisofPAH.Consistent withthePAHpatientpopulation,alargepercentageofthesubjects(92%)were female.Meanagewas50years,with63%functionalclass(FC)IIand31%FCIII. Thereducedmusclestrengthleadstodecreasedpeakinspiratorypressures (PIP)whenusingportableDPIs.PIPscanbemaximizedbyusingaDPIwitha higherresistance,andinstructionsthatasksubjectstoinhalewithmaximal effortuntiltheirlungsarefull.ThemeasuredPIPandViobservedwere significantlydependentonthesubject’slungfunction.Whilepatientswith asthma,COPDandCFtypicallyhavereductionsinPIPbyabout20%with decreasinglungfunction,thedecreaseinPIPinpatientswithPAHis>50%. Table 1: Inspiratory flow profile parameters for subjects with PAH when using DPIs ERS INTERNATIONAL CONGRESS 2020 Background TheuseofinhaledtherapiesinPAHhasbeenlimitedbytechnicalandadherence difficulties,whichmaybeovercomewithdrypowderinhaler(DPI)therapies. However,littleisknownabouthowinspiratoryflowprofiles(IFP)areaffectedin PAHpatients,andwhethertheywillbeabletogeneratetheinspiratorypressures andinhaledvolumesneededtoachievetherapeuticdruglevelswithDPIdevices. Itisimportantthatsubjectsexceedtheminimum∆𝑃neededtoprovideeffective dosedeliveryofdrugtothelungs.Relativetohealthysubjects,manysubjects withPAHhavedecreasedmusclestrength1.Decreasedmusclestrengthmayalso negativelyimpacttheirabilitytouseaDPI.Theobjectiveofthisstudywasto assesstheimpactofinhalerresistanceandpatientinstructionontheinspiratory flowprofilesofsubjectswithPAHwhenusingbreath-actuatedDPIs.

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