1 Office of Clinical Pharmacology Review NDA 21368, S‐030 Submission Date 8/21/17 Submission Type Efficacy Supplement (Response to Pediatric Written Request) Brand Name Cialis TM Generic Name Tadalafil Dosage Form & Strength Tablets Route of Administration Oral Proposed Indication None. Due to failed clinical program in boys with Duchenne Muscular Dystrophy (DMD) Applicant Eli Lilly and Company OCP Review Team Atul Bhattaram, Ph.D., Kevin Krudys, Ph.D., Sreedharan Sabarinath, Ph.D. Reference ID: 4198880
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Office of Clinical Pharmacology Review · Brand Name CialisTM Generic Name Tadalafil Dosage Form & Strength Tablets Route of Administration Oral Proposed Indication None. Due to failed
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BackgroundEli Lilly and Company conducted a clinical trial with tadalafil in boys with DuchenneMuscularDystrophy(DMD)tofulfilltheWrittenRequestissuedbytheAgency.ThePediatricWritten Request (PWR) for tadalafil was originally issued on 11/16/2006 and wassubsequentlyamended(Formoredetails,refertothereviewbyDr.Rainer,MedicalOfficer,DivisionofNeurologyProducts,CDER).
Tadalafil is a selective, reversible inhibitor of cGMP‐specific phosphodiesterase type 5(PDE5).ItwashypothesizedthatbyinhibitingPDE5,theenzymeresponsiblefordegradingcGMP (cyclic guanosine monophosphate), tadalafil may enhance the residual NO (nitricoxide) signaling coming from active skeletal muscle by selectively boosting cGMPbioavailabilityandinducingvasodilationasneeded,inresponsetoexercise.
TheApplicantconductedarandomized,double‐blind,placebo‐controlledstudy(StudyH6D‐MC‐LVJJ [LVJJ]) to evaluate the efficacy and safety of tadalafil 0.3mg/kg and 0.6mg/kgadministeredorallyoncedailyinambulatoryboyswithDMDwhoarereceivingtreatmentwithcorticosteroids. A totalof331boyswithDMDwererandomized toreceiveplacebo(N=116), tadalafil0.3mg/kg(N=102),ortadalafil0.6mg/kg(N=113) for48weeks).ThemeanageofboyswithDMDwas9.6years.Mean6‐minutewalkdistance(6MWD)atbaselinewas329meters(54%ofthepredictedvalueforageandheight).Asrequiredforinclusioninthe study, all boys with DMD were taking a corticosteroid at baseline, eitherprednisone/prednisolone(53.8%)ordeflazacort(45.9%).Meandurationofcorticosteroidtherapywas40.6monthsatbaseline,andmost(71.9%)weretakingadailycorticosteroidregimen.
DoseselectionwasbasedonthesingledosesoftadalafilthatwereshowntorestorenormalhemodynamicresponsesinstudiesofadultswithBecker’sMuscularDystrophy(BMD)andboyswithDMD.Inarandomized,placebo‐controlled,crossoverstudyinadultmen(meanage,37years)withBMD,asingledoseof20mgtadalafilalleviatedmicrovascularischemiaandfullyrestoredbloodflowregulation(MartinEA,BarresiR,ByrneBJ,TsimerinovEI,ScottBL,WalkerAE,GurudevanSV,AneneF,ElashoffRM,ThomasGD,VictorRG.Tadalafilalleviatesmuscle ischemia in patients with Becker muscular dystrophy. Sci Transl Med.2012;4(162):162ra155). Based on an adult weight of 75 kg, this equates to a dose ofapproximately0.3mg/kg. Inaddition,singledosesof tadalafil (0.5mg/kgor1.0mg/kg)dose‐dependentlyrestorednormalmusclehemodynamicresponsestoexerciseinboyswithDMD assessed by both functional sympatholysis (that is, the NO‐dependent, exercise‐inducedattenuationofsympatheticvasoconstriction)andexercise‐inducedbrachialarteryhyperemia(NelsonMD,RaderF,TangX,TavyevJ,NelsonSF,MiceliMC,ElashoffRM,SweeneyHL,VictorRG.PDE5 inhibitionalleviates functionalmuscle ischemia inboyswithDuchenne
Tadalafilpharmacokinetics(PK)andrelationshipsbetweentadalafilexposureandefficacyand safetywill be characterized using a population PK (PPK) approach. Patientswill berandomizedtooneoftwodosesoftadalafilorplaceboina1:1:1ratio.
The Applicant conducted population pharmacokinetic analyses using acceptablemethodologythatincludedbasemodeldevelopmentalongwithscreeningofcovariatesfortheir influenceontadalafilpharmacokinetics.TheanalysisreportalongwiththedatahasbeensubmittedtotheAgency.
Reference ID: 4198880
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WrittenRequestItem#2:StudyEndpoints
Pharmacokinetic/PharmacodynamicEndpoints:
Thepharmacokineticendpoints in thepopulationpharmacokinetic analysismust includevolumeofdistributionandclearance.Sparsepharmacokineticsamplesmustbecollectedtoexploretherelationshipsbetweentadalafilexposureandefficacyandsafetyendpoints.
Exposure‐Efficacy Relationship: The relationship between the study’s primary efficacyoutcomeandtadalafilexposurewasevaluatedfromascatterplotofchangefrombaselinein6‐minutewalkdistance(6MWD)atWeek48versustadalafilAUC.TherewasnodiscernablerelationshipbetweenAUCandchangein6MWD.
Noindependentexposure‐responseanalysiswasconductedbytheAgency.Sincethestudyfailed todemonstrateanybenefit from the twostudieddosesof tadalafil, nodiscernablerelationshipbetweenAUCandchangein6MWDisexpected.ThereportingofsafetyresultsbyAUCquartilesoftadalafilisacceptable.
Reference ID: 4198880
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WrittenRequestItem#3:Age‐AppropriateFormulation
Bioavailabilityofanyformulationusedinthestudiesmustbecharacterized,andasneeded,a relative bioavailability study comparing the approved drug to the age appropriateformulationmaybeconductedinadults.
InformationSubmitted/Applicant’sresponse
TheApplicantdidnotdevelopanewpediatricformulationforStudyLVJJ,asperEMEACHMPReflection Paper Formulation of Choice for the Pediatric Population dated 21 September2006,tadalafiltabletsareconsideredofappropriatesizefordosinginthepediatricpatientsage7‐14years.
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