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A Phase I, 3-Part Placebo-Controlled Randomised Trial to Evaluate the Safety, Tolerability and Pharmacokinetics of Aztreonam-Av

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A Phase I, 3-Part Placebo-Controlled Randomised Trial to Evaluate the Safety, Tolerability and Pharmacokinetics of Aztreonam-Av EV0643 Contactinformation: A phase I, 3-part placebo-controlled randomised trial to evaluate the safety, SeamusO’Brien AstraZenecaResearch&Development Macclesfield,Cheshire,UK tolerability and pharmacokinetics of aztreonam-avibactam in healthy subjects [email protected] Timi Edeki1, Diansong Zhou2, Frans van den Berg3, Helen Broadhurst4, William C. Holmes5, Gary Peters3, Maria Sunzel6, Seamus O’Brien4 1AstraZeneca, Wilmington, DE, USA; 2AstraZeneca, Waltham, MA, USA; 3Hammersmith Medicines Research, London, UK; 4AstraZeneca, Macclesfield, UK; 5AstraZeneca, Gaithersburg, MD, USA; 6Contractor at AstraZeneca, Wilmington, DE, USA Background Table 1.Subjects’baselinecharacteristics Figure 1. Geometricmean(A)aztreonamand(B)avibactamconcentration-timeprofilesinPartAfollowingindividualandcombinedadministrationofaztreonam2000mgandavibactam600mgby1-hIVinfusion Part A Part B Part C • Theemergenceandglobaldisseminationofmetallo-β-lactamase(MBL)-producing (A) (B) Enterobacteriaceae,includingNDM-typeandVIM-type,whichareresistanttocarbapenems, Active Placebo Active Placebo Active Placebo 100 Aztreonam 2000 mg alone (n=7) 100 Avibactam 600 mg alone (n=8) representsanurgentthreattohumanhealthforwhichfewtreatmentoptionscurrentlyexist.1, 2 (n=8) (n=4) (n=40) (n=16) (n=18) (n=6) Aztreonam-avibactam 2000-600 mg (n=7) Aztreonam-avibactam 2000-600 mg (n=7) • Aztreonam,amonobactamβ-lactam,isstabletoAmblerclassBMBLsincludingNDM-typeand Mean(SD)age,years 31(7) 34(7) 30(7) 27(5) 49(19) 51(19) VIM-type.However,bacteriathatexpressMBLsfrequentlyco-expressotherclassesofβ-lactamase Sex,n(%):Female 0 0 0 0 2(11.1) 1(16.7) thatwillhydrolyseaztreonam. 10 10 Male 8(100.0) 4(100.0) 40(100.0) 16(100.0) 16(88.9) 5(83.5) Avibactamisanovelnon-β-lactamβ-lactamaseinhibitorwithinvitroactivityagainstmanyserine • Race: Asian 2(25.0) 0 3(7.5) 2(12.5) 1(5.6) 0 β-lactamasesincludingAmblerclassA(e.g.extended-spectrum-β-lactamaseandKlebsiella Black 1(12.5) 1(25.0) 8(20.0) 2(12.5) 1(5.6) 1(16.7) pneumoniaecarbapenemase[KPC]),classC(e.g.AmpC),andsomeclassDenzymes,butnot 1 1 classBMBLs.3-5 White 5(62.5) 3(75.0) 27(67.5) 11(68.8) 16(88.9) 5(83.3) • Thecombinationofaztreonamplusavibactamhasthepotentialtotreatinfectionscausedby Other 0 0 2(5.0) 1(6.3) 0 0 EnterobacteriaceaeproducingbothMBLsandserineandβ-lactamasesashasbeendemonstrated Mean(SD)BMI,kg/m2 23.4(2.6) 24.3(4.6) 24.0(2.5) 23.8(2.2) 24.5(2.6) 25.0(3.1) byin vitro and in vivoevaluationoftheefficacyofthecombination.6-9 0.1 0.1 BMI,bodymassindex –Thecombinationofceftazidime-avibactamwasapprovedin2015bytheUSFDAforthetreatment Plasma avibactam concentration (µg/mL) ofcomplicatedintra-abdominal(incombinationwithmetronidazole)andcomplicatedurinarytract Plasma aztreonam concentration (µg/mL) 10 infectionsinpatientswithnoorlimitedalternativetreatmentoptions; anapplicationforapproval 0.01 0.01 intheEuropeanUnionhasbeensubmitted. • InadditiontothethreediscontinuationsduetoabnormalliverfunctiontestsinPartB,afurthersix 0 4 8 12 16 20 24 0 4 8 12 16 20 24 subjectsinPartB(Cohort2,n=2;Cohort3,n=4)hadAEsofabnormalliverfunctiontestsor Theceftazidime-avibactamclinicaldevelopmentprogrammehasestablishedthatavibactamhas Nominal time (h) Nominal time (h) • transaminaseincreasedthatdidnotleadtostudydiscontinuation.Cohort2washaltedafterfour limitedpotentialfordrug–druginteractions11andceftazidime-avibactamhasasafetyprofile 12, 13 subjectshadreceivedaztreonam-avibactambecauseoftheabnormalliverfunctiontestAEs. consistentwithadministrationofceftazidimealone. However,avibactamincombinationwith Table 3.Geometricmean(%CV)plasmaandurinaryaztreonamandavibactamPKparametersaftersingledosesofaztreonam,avibactamandaztreonam-avibactam aztreonamhasnotpreviouslybeenadministeredtohumans. –Abnormalliverfunctiontestandtransaminaseelevationsareconsistentwiththeknownsafety Part A Part B Part C ThisPhaseI‘first-in-man’randomisedtrialassessedthesafety,tolerabilityandpharmacokinetics profileofaztreonammonotherapy.14 • Aztreonam-avibactam Aztreonam Avibactam Aztreonam- Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Young cohort Elderly cohort (PK)ofsingleandmultipledosesofaztreonam-avibactaminhealthyadultsubjects. –Theaztreonam-avibactamdosereductionsimplementedinPartBCohorts4and5,andfurther dosage group/cohort 2000 mg 600 mg avibactam 2000-375 mg 2000-600 mg 1500-600 mg 1500-450 mg 1500-410 mg 2000-546.7 mg 2000-546.7 mg modifiedinPartCwiththeadditionofaloadingdose,wereassociatedwithareducedincidence (n=7) (n=7) 2000-600 mg (n=8) (n=4) (n=8) (n=10) (n=10) (n=10) (n=8) (n=7) ofliverenzymeabnormalities(elevationofAST≥2xULNwasobservedforonesubjectinPart C,butwasnotreportedasanAE). Infusionduration,h 1 1 1 1 1 2 3 3 3 3 Aztreonam Allofthehepaticenzymeabnormalitieswereasymptomatic,transientandreversible.Noother Methods • AUC,μg.h/mL 372(15) – 375(13) 345(16) 326(6) 283(18) 270(10) 250(13) – – ThisPhaseI,randomised,double-blind,3-parttrial(NCT01689207)wasconductedatHammersmith laboratoryabnormalitiesorclinicalsymptomsattributabletohepaticdisorderwereobserved • AUC0–6h,μg.h/mL 325(13) – 325(10) 299(15) 286(5) 245(15) 222(9) 205(13) 276(14) 308(12) MedicinesResearch,London,UK. (i.e.therewerenootherliver-relatedAEs). Cmax,μg/mL 143(14) – 137(11) 123(17) 123(6) 82(16) 63(9) 59(13) 76(14) 82(12) • PopulationPKmodels,developedusingaztreonamdatafromtheliteratureandavibactamfromthe ThemostfrequentlyreportedAEsbysystemorganclasswere: ceftazidime-avibactamdatabase,takingintoaccountvariabilityinpatients,wereusedtocalculate • CLr,L/h 3.9(19) – 3.8(18) 4.0(14) 4.1(7) 4.2(14) 4.1(22) 4.4(12) 4.2(17) 3.4(17) † † probabilityoftargetattainment(PTA)againstpharmacodynamictargetsestablishedfrom –PartA:metabolismandnutritiondisordersinonesubject(12.5%)andnervoussystemdisorders Ae (0–24h), mg 1440(7) – 1400(8) 1380(8) 1310(3) 1170(9) 1080(19) 1090(7) 1160(7) 1050(12) 9 inonesubject(12.5%)onactivetreatment;andgeneraldisordersandadministrationsite † † preclinicaldata. fe (0–24h),% 72.1(7) – 70.2(9) 69.2(8) 65.7(2) 77.8(9) 72.2(19) 72.7(7) 58.1(7) 52.4(12) conditionsinonesubject(25.0%)andvasculardisordersinonesubject(25.0%)onplacebo • DoseselectionforPartAwasbasedontargetsestablishedfrompreclinicaldatai.e.predicted Avibactam achievementoffreeconcentrationsofaztreonamandavibactamthataremaintainedforatleast60% –PartB:investigationsin10subjects(17.9%)onactivetreatment(noneonplacebo)and AUC,μg.h/mL – 53(23) 58(18) 32(13) 48(13) 53(13) 36(12) 31(15) – – fT>MICof8mg/Lforaztreonamand50%fT>CT2.5mg/Lforavibactaminatleast90%ofpatients. gastrointestinaldisordersinsevensubjects(12.5%)onactivetreatment(noneonplacebo) AUC0–6h,μg.h/mL – 49(21) 54(16) 29(12) 45(12) 49(13) 32(11) 28(14) 42(17) 52(11) DosageregimensinPartsBandCwereselectedbyasafetyreviewcommitteefollowingreviewof • –PartC:gastrointestinaldisordersinsevensubjects(29.2%)onactivetreatment(noneon Cmax,μg/mL – 26.8(14) 28.5(15) 16.0(10) 25.1(6) 19.3(16) 10.0(11) 8.7(14) 12.1(18) 15.2(14) safety(includingliverfunctiontests),tolerabilityandPKdata,andwerealsoinformedbypopulation CLr,L/h – 9.8(22) 8.7(17) 10.6(19) 10.9(13) 11.1(12) 11.9(25) 12.5(16) 10.8(16) 7.8(28) PK-modelledpharmacodynamictargetattainmentpredictions. placebo)andnervoussystemdisordersinfoursubjects(22.2%)onactivetreatmentandtwo subjects(33.3%)onplacebo. Ae , mg – 513(7) 507(3) 336(8) 519(8) 586(4) 423(17) 388(5) 453(3)† 407(21)† InPartA,subjectsaged18–45yearsreceivedsingle1-hinfusionsofaztreonam2000mg, (0–24h) • † † avibactam600mgandaztreonam-avibactam2000-600mg(n=8)ormatchingplacebo(n=4)by fe (0–24h),% – 85.5(7) 84.5(3) 89.7(8) 86.5(8) 97.6(3) 94.1(17) 94.7(5) 82.8(3) 74.4(21) randomisedcrossover,eachseparatedbya≥3daywashoutperiod. Ae (0–24h),cumulativeamountofdrugcollectedinurineover24h;AUC0–6h,areaundertheconcentration-timecurveduringthefirst6h;CLr,renalclearance;fe(0–24h),fractionofdoseexcretedunchangedinurineover24h † Table 2.OverviewofAEs InPartC,urinewasonlycollecteduptothefirst6hafterdosing;datashownareAe(0–6h)/fe(0–6h) • InPartB,subjectsaged18–45yearsreceived11daysofaztreonam-avibactam(n=40)ormatching placebo(n=16)every6h(q6h)onDays2–10;singledoseswereadministeredonDays1and11: Subjects, n (%) Part A Part B Part C Table 4.Geometricmean(%CV)plasmaaztreonamandavibactamPKparametersaftermultipledosesofaztreonam-avibactam –Cohort1:2000-375mg(n=8)1-hinfusion Active Placebo Active Placebo Active Placebo (n=8) (n=4) (n=40) (n=16) (n=18) (n=6) Part B (Day 11) Part C (Day 10) –Cohort2:2000-600mg(n=4)1-hinfusion Aztreonam-avibactam Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Young cohort Elderly cohort AnyAE 2(25.0) 1(25.0) 23(57.5) 3(18.8) 12(66.7) 3(50.0) –Cohort3:1500-600mg(n=8)2-hinfusion dosage group/cohort 2000-375 mg q6h (n=8) 2000-600 mg q6h (n=4) 1500-600 mg q6h (n=8) 1500-450 mg q6h (n=10) 1500-410 mg q6h (n=10) 1500-410 mg q6h (n=10) 1500-410 mg q6h (n=8) –Cohort4:1500-450mg(n=10)3-hinfusion AnyAEwithoutcomeofdeath 0 0 0 0 0 0 Infusionduration,h 1 1 2 3 3 3 3 –Cohort5:1500-410mg(n=10)3-hinfusion. Aztreonam AnySAE 0 0 0 0 0 1(16.7) • InPartC,subjectsreceived10daysofaztreonam-avibactam(n=18)ormatchingplacebo(n=6) AUCss,μg.h/mL 275(14) – 231(16) 223(8) 203(11) 211(16) 259(12) 2000-546.7mg(30minloadingdoseof500-136.7mgATM-AVIplus2.5hmaintenanceinfusionof AEleadingtodiscontinuation RAUC 0.92(9) – 0.94(5) 1.00(4) 0.99(6) 0.77(5) 0.84(6) 1(12.5) 0 3(7.5) 0 0 1(16.7) 1500-410mgATM-AVI)onDay1,followedby1500-410mg(3-hinfusions)q6hon ofstudytreatment Cmaxss,μg/mL 124(9) – 80.9(13) 62.6(9) 55.7(9) 57(15) 66(13) Days2–9;singledoseswereadministeredonDay10: RCmax 1.01(14) – 0.97(7) 0.99(8) 0.94(10) 0.76(4) 0.81(4) Subjectswithmultipleeventsinasinglecategoryarecountedonceforeachcategory
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