Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

w w w . e l s e v ie r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Efficacy,

safety,

tolerability

and

population

pharmacokinetics

of

tedizolid,

a

novel

antibiotic,

in

Latino

patients

with

acute

bacterial

skin

and

skin

structure

infections

Alejandro

Ortiz-Covarrubias

a,∗

,

Edward

Fang

b

,

Philippe

G.

Prokocimer

b

,

Shawn

D.

Flanagan

b

_,

_Xu

_Zhu

c

_,

_Jose

_Francisco

_{Cabré-Márquez}

d

_,

_Toshiaki

_Tanaka

e

_,

Julie

Passarell

f

_,

_Jill

_{Fiedler-Kelly}

f

_,

_Esteban

_C.

_Nannini

g

a_{HospitalCivildeGuadalajara,Guadalajara,Jalisco,Mexico} b_{MerckandCo,Inc.,Kenilworth,NJ,USA}

c_{BayerHealthCare,Beijing,China} d_{BayerHealthCare,MexicoCity,Mexico} e_{BayerYakuhin,Osaka,Japan}

f_{CognigenCorporation,asubsidiaryofSimulationsPlus,Inc.,Buffalo,NY,USA}

g_{FacultadCienciasMédicas,UniversidadNacionaldeRosario,SanatorioBritánico,Rosario,Argentina}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received1December2015 Accepted28December2015 Availableonline7February2016

Keywords: ABSSSI Latinoethnicity Oxazolidinone Tedizolid

a

b

s

t

r

a

c

t

AcutebacterialskinandskinstructureinfectionsarecausedmainlybyGram-positive bacte-riawhichareoftentreatedwithintravenousvancomycin,daptomycin,orlinezolid,with potentialstepdowntoorallinezolidforoutpatients.Tedizolidphosphate200mgoncedaily treatmentforsixdaysdemonstratednon-inferiorefficacy,withafavourablesafetyprofile, comparedwithlinezolid600mgtwicedailytreatmentfor10daysinthePhase3 ESTABLISH-1and-2trials.Theobjectiveofthecurrentpost-hocanalysisoftheintegrateddatasetof ESTABLISH-1and-2wastoevaluatetheefficacyandsafetyoftedizolid(N=182)vslinezolid (N=171)inpatientsofLatinooriginenrolledintothesetrials.Thebaselinedemographic characteristicsofLatinopatientsweresimilarbetweenthetwotreatmentgroups.Tedizolid demonstratedcomparable efficacytolinezolidat48–72h intheintent-to-treat popula-tion(tedizolid:80.2%vslinezolid:81.9%).Sustainedclinicalsuccessrateswerecomparable betweentedizolid-andlinezolid-treatedLatinopatientsatend-of-therapy(tedizolid:86.8% vslinezolid:88.9%).TedizolidphosphatetreatmentwaswelltoleratedbyLatinopatients inthesafetypopulationwithlowerabnormalplateletcountsatend-of-therapy(tedizolid: 3.4%vslinezolid:11.3%,p=0.0120)andlowerincidenceofgastrointestinaladverseevents (tedizolid:16.5%vslinezolid:23.5%).Populationpharmacokineticanalysissuggestedthat

∗ _{Correspondingauthorat:HospitalCivildeGuadalajara,CalleHospital#278S.H.,Guadalajara,44100Jalisco,Mexico.}

E-mailaddress:orca0059@prodigy.net.mx(A.Ortiz-Covarrubias). http://dx.doi.org/10.1016/j.bjid.2015.12.007

1413-8670/©2016 Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

estimatedtedizolidexposuremeasuresinLatinopatientsvsnon-Latinopatientswere sim-ilar.Thesefindingsdemonstratethattedizolidphosphate200mg,oncedailytreatmentfor sixdayswasefficaciousandwelltoleratedbypatientsofLatinoorigin,withoutwarranting doseadjustment.

©2016ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Gram-positive bacteria, including methicillin-resistant

Staphylococcusaureus(MRSA),arecommonlyassociatedwith skinand skinstructureinfections (SSSIs),bacteraemia and nosocomial pneumonia.1–3 _{Infections due to MRSA may}

be associated with morbidity and mortality, particularly in the elderly.3 _{MRSA-related infections are an increasing}

problem in Latin America,4–6 _{both in the healthcare}

envi-ronmentandinthecommunity.TheepidemiologyofMRSA is constantly changing; both hospital-acquired (HA) and community-acquired(CA)MRSAcirculatingclonesandtheir antibiotic resistance profiles vary considerably throughout regionsandcountries.7_{In2003,thefirstoutbreakofinfections}

involvingCA-MRSA strainsinLatin Americawas described inUruguayandwascausedbytheSouthwestPacific(SWP) clone/sequencetype(ST)-30/SCCmecIVc.8_{Furthermore,other}

clonesofCA-MRSAhavebeenisolatedinBrazil,9_Argentina,10

Colombia, Ecuador, Venezuela,11 _Mexico,12 _{and Chile.}13 _A

considerableamountofCA-MRSAhasalsobeenfoundamong nosocomialisolates,atleastinColombiaandUruguay.14,15

Vancomycin, teicoplanin, daptomycin, tigecycline, line-zolid,clindamycin,andceftarolinearecommerciallyavailable asparenteralintravenousagentsforMRSAinfectionsinmany countriesinLatinAmerica.16_{Despitethebroadrangeof}

anti-MRSAantibiotics,initialempiricaltherapyisinappropriatein alarge number ofpatientsleading to treatmentfailures,17

increasedhealthcarecosts,18_{andpotentiallyincreasing}

resis-tancelevels.19

Tedizolidphosphateisanoveloxazolidinoneantibiotic20

withatleast4-times higherpotencythan linezolidagainst Gram-positive bacteria including MRSA, vancomycin-resistantenterococci(VRE),linezolid-resistantcfr+S.aureus,

and Streptococcus pyogenes.21,22 _{Tedizolid phosphate is}

con-verted in vivo by non-specific phosphatases to its active moiety tedizolid (TZD).23 _{Two pivotal randomised,}

double-blind, double-dummy, multicentre, controlled, Phase 3 clinicaltrials (ESTABLISH-1and ESTABLISH-2)conductedin patientswithacutebacterialskinand skinstructure infec-tions(ABSSSI;i.e. cellulitis/erysipelas,woundinfection and major cutaneous abscess)24,25 _{demonstrated that tedizolid}

phosphate, 200mg, once daily(QD) treatment for sixdays wasnon-inferiortolinezolid(LZD),600mg,twicedaily(BID) treatmentfor10days.26–28_{Inaddition,TZDhadanimproved}

tolerabilityandsafetyprofilecomparedwithLZD,particularly in terms of gastrointestinal (GI) adverse events (AEs) and haematologicalparameters.26–28

Interethnicpharmacokinetic(PK)differencesexistfor cer-tainantibacterialagentspotentially influencingtheefficacy

andsafetyoftheantibioticdruginpatients.29_Forexample,

ciprofloxacin metabolism inBrazilian subjects differsfrom thatinotherethnicpopulations,whiletigecyclineclearancein younghealthyAfro-Americansubjectsishigherthanin Cau-casiansubjects.29 _{Furthermore,bothintrinsic(e.g. genetics,}

bodysizeandfatdistribution)andextrinsicethnicfactorsmay influencetheeffectsofaninvestigationaldrugviaalteredPK andpharmacodynamics.30–32

The objectives ofthe current post-hoc analysis were to evaluatetheefficacyandsafetyofTZDvsLZDforthe treat-mentofABSSSIinpatientsofLatinooriginenrolledintothe Phase3ESTABLISHstudies.Furthermore,theTZDPKprofileof thesepatientswasevaluatedbasedonpopulationPKanalysis.

Methods

Studydesignandtreatments

Both ESTABLISH-1 (NCT01170221) and ESTABLISH-2

(NCT01421511) wererandomised,multicentre,double-blind, double-dummy,active-controlledPhase3studiescomparing tedizolidphosphate200mgQD(6-daycoursefollowedby 4-dayplacebotreatment)vsLZD600mgBID(10-daytreatment) forthetreatmentofpatientswithABSSSIs.Patientsenrolled into ESTABLISH-1 received exclusively oral (PO) therapy,26

while patients in ESTABLISH-2 received intravenous (IV) therapywithanoptionalswitchtoPOtherapywhencertain criteria were met.27 _{Theintegrated datasetofESTABLISH-1}

andESTABLISH-2trialswasanalysedandreportedbyShorr etal.28

Ethicalapproval

Noethicalapprovalofthis post-hocanalysis wasrequired. TheESTABLISH-1andESTABLISH-2studieswereconductedin accordancewiththe2008DeclarationofHelsinkiandall rele-vantinternational,EuropeanUnion,national,andlocalrules andlegislation.Institutionalreviewboardorethics commit-teeapprovalwasobtainedateachparticipatingcentreandall participantsprovidedwritteninformedconsent.Adataand safetymonitoringboardreviewedsafetydataduringthe con-ductofthestudy.26,27

Enrolmentcriteria

Patients(aged ≥18yearsold inESTABLISH-1and≥12 years oldinESTABLISH-2)wereenrolledinbothtrialsiftheyhadan ABSSSI(cellulitis/erysipelas,woundinfection,ormajor cuta-neousabscess)withaminimumlesionsurfaceareaof75cm2_;

woundinfections andabscesses alsorequiredthelesion to extend≥5cmfromthemarginofthewoundorabscess.In addition, patients had atleastone localand onesystemic signofinfection,andasuspected/documentedGram-positive pathogenatthesiteofinfection.26,27_{Theinstitutionalreview}

boardorequivalentateachstudycentreapprovedthetrials andallpatientsprovidedwritteninformedconsent.26,27

Exclu-sioncriteriawerepreviouslydescribedbyProkocimeretal.26

andMoranetal.27

Demographic data, disease characteristics,

co-medications, comorbidities, race and ethnic origin (Latino ornon-Latino),primarycauseofABSSSI,digitalphotograph of the lesion, lesion size, vital signs, and microbiological specimeninformationwererecordedoncasereportforms.

Populationdefinitions

The intent-to-treat population (ITT analysis set) included allrandomisedpatients(includingtheLatinosubpopulation) who were eligible based on the inclusion criteria outlined above.26,27 _{Theclinicallyevaluable population(CE)included}

allpatientsintheITTanalysissetwho(1)compliedwiththe studyprotocolwithnomajorviolations,and(2)completedthe clinicalresponseoutcomeassessmentattheend-of-therapy (EOT)visit, and (3)had noconcomitant systemic antibiotic therapyortopicalantibioticfrom thefirstinfusionofstudy drugthroughtothe EOTvisitthatwaspotentiallyeffective againstthebaselinepathogen,exceptadjunctiveaztreonam and/or metronidazole in patients with wound infections. Two CE populationswere analysed:the CE-EOTpopulation includedITTpatientswhohadavalidassessmentatthe 48-to72-hvisitandattheEOTvisit,andtheCE-post-treatment evaluation(PTE)populationincludedITTpatientswhohada validassessmentatthePTEvisit.Thesafetyanalysis popula-tionwascomprisedofallrandomisedpatientswhoreceived atleastonedoseofthestudydrugandhadapost-treatment assessment.26,27

Efficacyparameters

The primary efficacy endpoint was early clinical response rate atthe 48- to 72-h visit. The primary endpoint in the integrated analysis was represented by≥20% reduction in lesionsize comparedwithbaseline.28 _{Secondaryendpoints}

included: programmatic and investigator-assessed clinical successratesatEOT(Day11),investigator-assessedsustained clinicalsuccessratesatthePTEvisitintheintent-to-treat(ITT) population,andalsointheCEpopulation.28

Safetyparameters

Safety was assessed by collecting information on adverse events based on System Organ Class and definitions were givenascodedinMedicalDictionary forRegulatory Activi-ties(MedDRA)v13.1.Treatment-emergentAEs(TEAEs)were definedasthosethatoccurredorworsenedafterthefirstdose ofstudydrug.Inaddition,safetyassessmentsincluded clini-calchemistryandhaematologylaboratoryresults,vitalsigns andelectrocardiograms,andphysicalexaminations.

Laboratorymeasurements

Bloodsampleswerecollectedatrandomisation,onDay1,Day 3,Day7,EOT(Day11),andPTEvisitsforassessmentsof vari-oushaematological,toxicologyparameters(e.g.haemoglobin, platelets, neutrophils, bilirubin, creatinine,alanine amino-transferase (ALT), aspartate aminotransferase [AST]), and clinicalchemistryanalysis.

Populationpharmacokineticanalysis

IntheESTABLISHtrials,patients’baselineparameters(height, bodyweight,bodymassindex[BMI],idealbodyweight[IBW], age,sex,calculatedcreatinineclearancebasedon Cockcroft-Gaultformula,andtotalbilirubinlevel)were collected,and raceandethnicity(Latinovsnon-Latino)werealsorecorded oncasereportforms.

The final PK model of TZD (a 2-compartment model withsigmoidalabsorption,absolutebioavailability,andlinear elimination), wasusedtoestimateTZDexposuremeasures for each patient based on measured concentrations and statistically significant predictors (IBW and total bilirubin), including the area under the concentration–time curve at 0–24h(AUC0–24h),minimumdrugconcentration(Cmin), and maximumdrugconcentration(Cmax)onDay1andat steady-state.33_{Thispost-hocpopulationPKanalysisofTZDexposure}

atsteadystateinLatinopatientsincludedsummariesofthe meanvalue,standarddeviation,median,andrange.Boxplots ofTZDAUC0–24h,CmaxandCminatsteadystatearealso pre-sented.

Statisticalanalysis

Thispost-hocanalysisfocusedonasubpopulationofpatients of Latino origin. Data (i.e. efficacy, safety) are expressed as mean±standard deviation (SD). Population PK data are expressedasmean,SDand range,anddataaregraphically shown as boxplots including median, 25th, 50th, and 75th percentiles,andwhiskersas5thand95thpercentiles. Statis-ticalsignificancewasdefinedbyp<0.05.Post-hocstatistical analysiswasdescriptiveinnature.

Results

DemographicsofLatinopatients

IntheintegratedanalysisoftheESTABLISHtrialsatotalof 1333patientswererandomisedandreceivedstudydrug,353of whomwereLatinos(26.5%)intheITTpopulation(TZDN=182; LZDN=171).OftheLatinopatients,85.6%wereenrolledfrom theUS/Canadaregion,13.3%fromthe‘Other’region,which includedLatinAmerica(Argentina,Brazil,andPeru),Australia, NewZealand,andSouthAfrica,andonly1.1%fromEurope.

Thebaselinedemographicparametersand disease char-acteristicsoftheenrolledLatinopatientsinESTABLISH-1and ESTABLISH-2weresimilarbetweenthetwotreatmentgroups (Table 1). Theproportion ofmale patientsin the TZDarm (73.1%)wasslightlyhigherthanintheLZDarm(60.2%),most patientsbeing<65yearsold.Therewasnodifferenceinthe

Table1–Baselinedemographicparametersanddisease characteristicsforLatinopatients.

IntegratedITTanalysisset Tedizolid (N=182)

Linezolid (N=171) Malepatients,n(%) 133(73.1) 103(60.2) Meanage(range),years 40.8(18–86) 42.6(19–84) Agegroup,n(%) <65years 173(95.1) 161(94.2) ≥65to≤75years 7(3.8) 7(4.1) >75years 2(1.1) 3(1.8) Mean±SDBMI,kg/m2 _{29.7±6.9 29.6±6.1} Comorbidities,n(%) Obesity 67(36.8) 74(43.3) Diabetesmellitus 22(12.1) 12(7.0) Hepaticimpairment 1(0.5) 0(0.0) Renalimpairment 2(1.1) 5(2.9) HIVpositive 1(0.5) 0(0.0)

HepatitisCviruspositive 70(38.5) 82(48.0) Current/recentIVdruguse,n

(%)

82(45.1) 91(53.2)

ABSSSItype,n(%)

Cellulitis/erysipelas 66(36.3) 67(39.2)

Woundinfection 61(33.5) 57(33.3)

Majorcutaneousabscess 55(30.2) 47(27.5) AnatomicallocationofABSSSI,n(%)

Chest/Abdomen 14(7.7) 10(5.8) Groin/Buttock/Back 32(17.6) 30(17.5) Head/Neck 5(2.7) 4(2.3) Lowerextremity (Foot/Leg/Knee) 77(42.3) 72(42.1) Upperextremity (Hand/Arm) 54(29.7) 55(32.2) Diseasecharacteristics Lesionsurfacearea, mean(range),cm2

288.9(22.5–1847.0) 295.7(27.0–2397.0) PriorABSSSIlesion,n(%) 50(27.5) 43(25.1) Concurrentsecondary cSSSI/ABSSSIlesion,n(%) 36(19.8) 25(14.6) Temperature≥38◦_C (fever),n(%) 21(11.5) 16(9.4) SIRS,n(%) 27(14.8) 20(11.7) Lymphadenopathy,n(%) 161(88.5) 145(84.8) WBC≥10,000or <4000cells/mm3_n(%) 78(42.9) 64(37.4) Immatureneutrophils >10%,n(%) 7(3.8) 6(3.5) MRSA,n(%) 49(26.9) 39(22.8) Bacteraemia,n(%) 2(1.1) 4(2.3) Regionofenrolment,n(%) US/Canada 156(85.7) 146(85.4) Europe 4(2.2) 0(0.0) Othera _{22(12.1) 25(14.6)}

a _{Other:LatinAmerica(Argentina,Brazil,andPeru),Australia,New}

Zealand,andSouthAfrica.

ABSSSI,acutebacterialskinandskinstructureinfection;BMI, bodymass index;cSSSI, complicatedskinandskinstructure infection;HIV,humanimmunodeficiencyvirus;ITT, intent-to-treat,IV,intravenous;MRSA,methicillin-resistantStaphylococcus aureus; SD, standard deviation; SIRS, systemic inflammatory responsesyndrome;US,UnitedStates;WBC,whitebloodcell.

80.2 86.8 85.2 81.9 88.9 86.0 0 20 40 60 80 100 Tedizolid n=182 Linezolid n=171

% patients with treatment response

−1.7 (−9.9; 6.6) −2.1 (−9.0; 4.9) −0.8 (−7.8; 7.2)

Early clinical response (≥20% lesion area reduction)

End of therapy programmatic clinical response

Investigator assessed response

Fig.1–ProportionofLatinopatientswithclinicalresponse at48–72handclinicalsuccessatendoftherapyand post-treatmentevaluationvisits(ITTanalysisset).ITT: intent-to-treat.

Table2–Clinicalefficacyoftedizolidvslinezolidin Latinoandnon-Latinopatients.

Tedizolid,% (n/N) Linezolid,% (n/N) Treatment difference(95%CI)

Earlyclinicalresponserate(responders)atthe48-to72-hvisit

ITTpopulation

Latino 80.2(146/182) 81.9(140/171) −1.65(−9.88;6.65) Non-Latino 82.2(396/482) 78.5(391/498) 3.64(−1.37;8.55)

ClinicalsuccessrateatEOT

ITTpopulation Latino 86.8(158/182) 88.9(152/171) −2.08(−9.04;4.91) Non-Latino 87.1(420/482) 87.6(436/498) −0.41(−4.64;3.77) CEpopulation Latino 92.5(148/160) 92.6(150/162) −0.09(−6.2;5.93) Non-Latino 91.3(399/437) 94.5(412/436) −3.19(−6.71;0.25)

InvestigatorassessmentofclinicalsuccessrateatPTE

ITTpopulation Latino 85.2(155/182) 86.0(147/171) −0.80(−7.77;7.23) Non-Latino 87.3(421/482) 87.1(434/498) 0.20(−4.05;4.37) CEpopulation Latino 91.9(148/161) 92.7(140/151) −0.79(−7.22;5.27) Non-Latino 94.1(384/408) 96.8(396/409) −2.7(−5.78;0.14) CE, clinically evaluable; CI, confidence interval; EOT, end-of-therapy;ITT,intent-to-treat;PTE,post-treatmentevaluation.

BMI of patients treated with TZD (29.7±6.9kg/m2_{) or LZD} (29.6±6.1kg/m2_{),respectively;onaverage,40%ofallLatino} patientswereobeseand9.6%haddiabetesmellitus(Table1). Theproportionofpatientsenrolledwithcellulitis,wound infection or majorabscess, and themean lesion sizewere similar between treatment groups (TZD: 288.9cm2 _{vs LZD:} 295.7cm2_{)(Table1).MRSAwasthecausative Gram-positive} pathogenin26.9%ofTZD-treatedand22.8%ofLZD-treated patients,respectively.

Table3–Incidenceofadverseeventsinthesafety populationofLatinopatients.a

Tedizolid (N=182) n(%) Linezolid (N=170) n(%) A

Overalladverseevents Anytreatment-emergentAE (TEAE)

86(47.3) 81(47.6)

Drug-relatedTEAE 45(24.7) 56(32.9)

TEAEleadingto

discontinuationofstudydrug

1(0.5) 2(1.2)

SeriousTEAE 3(1.6) 0(0.0)

Drug-relatedseriousTEAE 0(0.0) 0(0.0)

AnyseriousTEAEleadingto death

1(0.5) 0(0.0)

B

Systemorganclasspreferredterm (≥2%TEAE) Gastrointestinaldisorders 30(16.5) 40(23.5)

Nausea 16(8.8) 19(11.2)

Diarrhoea 7(3.8) 13(7.6)

Vomiting 7(3.8) 8(4.7)

Constipation 4(2.2) 4(2.4)

AE,adverseevent;TEAE,treatment-emergentadverseevents.

a _{Dataarereportedbypatients.}

EfficacyoftedizolidandlinezolidinLatinopatients

TheefficacyofTZDwascomparedwithLZDintheITT popu-lation.InpatientswithLatinoethnicityintheintegrateddata oftheESTABLISH studies,comparableefficacy resultswere demonstratedbetweensixdaysofTZDand 10daysofLZD (Fig.1).Similarlytotheoverallpopulation,inLatinopatients tedizolidphosphatetreatmentdemonstratedcomparable effi-cacywithLZDtreatmentatthe48-to72-hvisitintheITT population(TZD:80.2%vsLZD:81.9%;pointdifference:−1.65; 95%confidenceinterval(CI):−9.88;6.65)(Table2,Fig.1).

AtEOT,similar clinical successrates were foundinthe ITT(86.8%inTZDvs88.9%inLZD;pointdifference:−2.08; 95%CI:−9.04;4.91)andCE (92.5%inTZDvs92.6% inLZD; pointdifference:−0.1;95%CI:−6.2;5.93)populations(Table2). Furthermore,investigator-assessedclinicalsuccessrateswere comparableinpatientstreatedwithTZDvsLZDatthePTEvisit intheITTandCEpopulations(Table2).

SafetyandtolerabilityoftedizolidandlinezolidinLatino

patients

AmongLatinopatientsinthesafetyanalysispopulation,182 TZD-treatedpatientsand 170LZD-treated patientsreceived at least one dose of the study drug and were eligible for safetyanalysis.IntheLatinopopulation,overall treatment-emergentadverseevents(TEAE)rateswerecomparableinboth TZD-(47.3%)andLZD-(47.6%)treatedpatients(Table3A).The investigator-assessedrateofdrug-relatedAEswaslowerinthe TZDtreatmentarm(45/182patients, 24.7%)comparedwith theLZDtreatmentarm(56/170patients,32.9%),respectively. Theseresultsaresimilartotheoverallintegratedsafety popu-lation(TZD:148/662patients[22.4%]vsLZD:185/662patients [27.9%],respectively).

Table4–Abnormalplateletcounts(109_{/L)bytimepoint}

inLatinopatients.

Abnormalplatelet counts(109_/L)by

timepointsinthe SafetyAnalysisset

Tedizolid (N=182) Linezolid (N=170) p-Value StudyDay7–9,a_{N1 150 141} BelowLLN,n(%) 9(6.0) 7(5.0) NS Below75%ofLLN, n(%) 3(2.0) 0(0) NS StudyDay11–13,b_{N1 147 142} BelowLLN,n(%) 5(3.4) 16(11.3) 0.012 Below75%ofLLN, n(%) 0(0) 4(2.8) 0.057

Lastdoseofactive drugvisit,c_N1 157 144 BelowLLN,n(%) 10(6.4) 16(11.1) NS Below75%ofLLN, n(%) 4(2.5) 4(2.8) NS

LLN, lower limit ofnormal; NS, not significant;N1, numberof patientsinsafetyanalysispopulationwithnon-missingdataat baselineandthesummarisedvisit.

a _{Day7(upto+2days)visitbyprotocol.} b _{Day11(upto+2days)visitbyprotocol.}

c _{Visitclosesttothelastdoseoftheactivestudydrug(patients}

couldhavediscontinuedstudydrugtreatmentbeforeDay10).

Similar tothe overall population, in Latinopatients the most commonly reported AEs were GI related; however, the incidence of GI-related AEs was lower in TZD-treated patientscomparedwithLZD-treatedpatients(16.5%vs23.5%, respectively).AmongGIadverseevents,lowerincidencesof nausea, diarrhoea, vomiting were reported in TZD-treated Latino patientscompared withLZD-treated Latinopatients (Table3B).

RatesofTEAEsleadingtodiscontinuationofstudy drug were lowandsimilarwithTZD(0.5%)andLZD (1.2%) treat-mentsinLatinopatients(Table3A).Inthisanalysis,ratesof seriousTEAEswerealsosimilarbetweenthetwotreatment groups(TZD:3outof182patients[1.6%]andLZD:0outof170 patients[0%],respectively)(Table3A).Noseriousdrug-related TEAEsoccurred witheitherTZDorLZD,andonlyoneTEAE leadingtodeathwasobserved(intheTZDgroup)whichwas unrelatedtostudydrug(Table3A).

Laboratory

results

Platelets

Among Latino patients, the proportion of patients with reduced plateletcountswassimilarbetweenthe two treat-ment armsatDay 7–9.Abnormalplatelet count(i.e.below lower limitofnormal[LLN])wasobservedatapproximately three-fold higher incidence in patients treated with LZD (11.3%) than TZD(3.4%) atDay 11–13(Table4); similarly,a higher incidenceofabnormalplatelet countwasseenwith LZD(11.1%)thanTZD(6.4%)afterthelastdoseoftheactive studydrug,respectively.

The proportion of patients with substantiallyabnormal plateletcountwasverylowinbothtreatmentarmsatalltime

Table5–Summarystatisticsoftedizolidexposure measuresfromLatinoandnon-Latinopatients.

Exposure measuresof tedizolid Latino N=179a Non-Latino N=468 Overall N=647 AUC(0–24),ss (ng·h/mL) Mean (SD) 21,919.46 (5708.09) 22,715.61 (6407.01) 22,495.35 (6227.37) Range 6570.1; 39,344.0 8885.9; 49,861.0 6570.1; 49,861.0 Cmax,ss(ng/mL) Mean (SD) 1859.94 (509.76) 1984.91 (541.81) 1950.33 (535.67) Range 544.9; 3244.3 520.8; 4518.7 520.8; 4518.7 Cmin,ss(ng/mL) Mean (SD) 357.93 (210.30) 359.70 (215.19) 359.21 (213.69) Range 7.8;1170.4 15.3;1438.9 7.8;1438.9 AUC(0–24),ss, areaundertheconcentrationcurve at steadystate;

Cmax,ss,maximumconcentrationatsteadystate;Cmin,ss,minimum

concentrationatsteadystate;SD,standarddeviation.

a _{Numberofpatientswithevaluablepharmacokineticmeasures.}

pointsindicatingthelackofclinicallysignificant thrombocy-topenia(Table4).

Otherlaboratoryresults

No clinically meaningful changes were observed in haemoglobin, absolute neutrophil or leucocyte counts in eithertheTZDorLZDtreatmentarmsinLatinopatients(data notshown).

PopulationPKresults

InthepopulationPKanalysis,noclinicallymeaningful covari-ateeffectsonTZDPKwerefound,althoughthefinalmodeldid includethestatisticallysignificantcovariatesIBWandtotal bilirubin. Basedon the model, summary measuresof TZD exposureparametersweregeneratedforLatinopatientsand comparedwiththoseofnon-Latinopatients.

InthepopulationusedforthePK modelling,therewere noclinicallymeaningfuldifferencesbetweenLatino(N=182) and non-Latino (N=482) ITT populations with regard to baselinedemographicorlaboratoryparameters.Amongthe Latino patients, there were more males (73.1% vs 61.4%, respectively)and patients aged≤65 years (95.1% vs 86.9%, respectively) compared with non-Latino patients. Latino patients had a slightly higher, but not statistically sig-nificantly, BMI (29.7±6.9kg/m2_{) than non-Latino patients} (27.7±6.6kg/m2_).

PK parameters expressing TZD exposure in Latino patients (N=179) were compared with those of non-Latino patients (N=468). There were no apparent dif-ferences at steady state between Latino and non-Latino patients(Table5)inTZDAUC0–24h(21,919.5±5708.1ng×h/mL vs 22,715.6±6407.0ng×h/mL, respectively; Fig. 2A), Cmax (1859.9±509.8ng/mL vs 1984.9±541.8ng/mL, respectively; Fig.2B)andCmin(357.9±210.3ng/mLvs359.7±215.2ng/mL, respectively;Fig.2C). 50 000

A

B

C

45 000 40 000 35 000 30 000 25 000 20 000 15 000 10 000 5000 0 5000 4500 4000 3500 3000 2500 2000 1500 1000 500 0 0 200 400 600 800 1000 1200 1400 1600 Non-latino Latino Non-latino Latino Non-latino 468 179 468 179 179 468 A UCss (0-24) (ng × h/mL) Cmax,ss (ng/mL) Cmin,ss (ng/mL) Latino

Fig.2–BoxplotsoftedizolidAUC0–24,Cmax,Cminat steady-stateinLatinoandnon-Latinopatients.Boxesare 25th,50th,and75thpercentileswithmedianashorizontal line;whiskersare5thand95thpercentiles.Asterisksshow datapointsoutsideofthisrange.Thenumberofsubjectsis providedaboveeachbox.(A)AUC_(0–24),ssareaunderthe concentrationcurveatsteadystate.(B)C_{max,ss,maximum}

concentrationatsteadystate.(C)C_{min,ss,minimum}

concentrationatsteadystate.

Discussion

Thispost-hocanalysisoftheintegrateddatasetof ESTABLISH-1andESTABLISH-2wasperformedtocomparetheefficacyof tedizolidphosphate200mgoncedailyIV/PO6-daytreatment withthatofLZD600mgtwicedailyIV/PO10-daytreatment inLatinopatients withABSSSIs.Furthermore,thisanalysis aimedtoassessthesafety profileofTZDinLatinopatients and to compare estimates of TZD exposure inLatino and non-Latinopatients.Basedontheprimaryendpointcriteria, the resultsof the analysis showed comparable early clini-cal responserateswithTZD andLZD treatments inLatino

patientsatthe48-to72-hvisit.Similarproportionsofpatients in the two treatment arms had sustained clinical success attheEOTand PTEvisits.TZDwaswell toleratedinLatino patientswithalowerincidenceofGIAEscomparedwithLZD, similartothatseenwithTZDinbothnon-Latinopatientsand the overall population. Theincidenceofthrombocytopenia wasalsolowerforTZDthanforLZDatDay11–13,thoughthe incidencesweresimilarinthetwogroupsatDay7–9andafter thelastdoseoftheactivedrug.

Theseresultsareinaccordancewiththoseintheoverall integrated ITT population ofESTABLISH-1 and

ESTABLISH-2.26–28,34 _{In the overall ITT population at the 48- to 72-h}

visit, approximately 80% ofTZD-and LZD-treated patients demonstratedatleasta20%reductioninlesionsize.A sig-nificantadvantagewasalsoseenwithTZDtreatment with regardtoGIAEs28_{andhaematologicalchangesintheoverall}

population.26–28,34_{Althoughsimilartrendswereobservedin}

theLatinosubpopulation,significancewasnotdemonstrated whichwasprobablyduetothelowernumberofpatientsin eacharm.Nevertheless,thelowerincidenceofGIAEsandthe lowerriskofthrombocytopeniaarefavourablesafetyaspects ofTZDtreatmentwhichmightalsoapplytoLatinopatients. TheimprovedhaematologicaleffectsofTZDvsLZDmaybe theresultofasmallerimpactonmitochondriaduetolower overalldrugexposureandtroughconcentration.35

Itis known that LZD treatment for more than 28 days is associated with neurotoxicity.36,37 _{A 6-month daily LZD}

exposureinrats,at80mg/kg/daydosewhichreproducesthe humandailyexposureof600mgBID, resultedinperipheral (sciatic)neuropathywithinthreemonthsandopticnerve neu-ropathywithinsixmonths.37 _{Onthecontrary,ratsexposed}

todaily administrationofTZD fornine months,at adose providing8-foldhigherexposurethantheapproved therapeu-ticdose, showednosignsofneurotoxicityduringthistime period.38_{Thelowerriskoftoxicitywasalsodemonstratedin}

theESTABLISHstudiesbythesignificantlylowerincidenceof GIAEsduringthefirstsixdaysoftherapywhenbothdrugs were administered, and not only over the entire observa-tion period.26–28 _{Nounexpectedsafety signalwas observed}

intheLatinosubpopulationorthefullstudysafety popula-tion.TZDwaswelltoleratedinbothpopulationswithsimilar incidences ofTEAEs and reduced rate of drug-related AEs comparedwiththoseLatinopatientswhoweretreatedwith LZD.

LZDisanapprovedoralanti-MRSAdruginLatinAmerican countrieswiththeadvantagesof100%oralbioavailabilityand nointerethnicdifferencesinPKproperties.29_{PreviousPhase}

1studieshavedemonstratedhighoralbioavailabilityof tedi-zolid(>90%).23_{ThepopulationPKanalysesrevealedthatthere}

wasnodifferencebetweenLatinoandnon-Latinopatientsin theestimatesofTZDexposuremeasures.Thedemographic parametersandthepopulationPKmodelindicatedthatthere werenoclinicallysignificantcovariates,includingrace33_;this

suggests that the 200mg dose of tedizolid phosphate was appropriateforLatinopatientsforthetreatmentofABSSSI andnodoseadjustmentisnecessaryforpatientsofthis eth-nicity. Previously, no statistical influence ofsex, age, race, ethnicity,bodyweight,BMI,ALT,AST,orcreatinineclearance wasfoundonTZDpopulationPKparameters.33_IBWandtotal

bilirubinwerefoundtobestatisticallysignificantcovariates

forobservedvariabilityofPKparameters;however,neitherof theseeffectsweredeterminedtobeclinicallyrelevant.33

As endorsed by current antimicrobial stewardship rec-ommendations,shortercoursesoftreatmentareadvocated in order to minimise the risk of antimicrobial resistance development,optimisethesafetyprofileandimprovepatient compliance with treatment. TZD demonstrates at least 4-times greater potency than LZD against a wide range of Gram-positivepathogens,includingMRSAandVRE.21,22_The

greater potencywas the result ofmodification ofthe core structureinthreedifferentways.20_{Thesemodificationsand}

the greaterpotencyledtothehypothesisthatTZDmaybe efficaciousatalowerdoseandinshortertreatmentduration comparedwithLZD.Thishypothesiswasdemonstratedina Phase2studywherethelowestdosetested(200mgQD)proved asefficaciousashigherdosesinpatientswithABSSSI,39_and

laterconfirmedinthetwopivotalPhase3studies.Basedon theseresults,tedizolidphosphateisnowapprovedatadose of200mgasaoncedailyIVand/ororaltherapyforthe man-agementofpatientswithABSSSIsintheUS,40_{Europe,Canada,}

Singapore,Kuwait,andChile,withashorttreatmentduration ofsixdays.40

High bacteriological eradication rate and consequently high clinical cure rate were demonstrated in patients at the PTE visit inthe overall population. Susceptibility test-ing toTZDand LZD showedthat allMRSAstrains isolated in thetrials were susceptibleto TZDaccording tothe cur-rent FDAandEU breakpoints[Susceptible:≤0.5␮g/mL].26–28

BacteriologicalresultswerenotobtainedforLatinopatients; however,itisexpectedthatTZDwouldbeefficaciousagainst Gram-positivepathogenscausinginfectioninLatinopatients enrolledintothestudies.Arecentsurveillancestudyofnearly 7000Gram-positiveisolates(includingapproximately4500S. aureusisolates)conductedgloballydemonstratedahighrateof susceptibilitytoTZDandLZDwithonly16isolates(including sevenS.aureus,fiveS.epidermidis,andfourenterococci)being resistanttoLZD.22_{However,someoftheseisolatesremained}

susceptibletoTZDiftheycarriedaplasmidencodingforCfr methylaseonly.22

One of the limitations ofthis analysis was that it was a post-hoc subgroup analysis with lower patient numbers per treatment group; therefore, the analysis was not pow-eredtodemonstratestatisticaldifferencebetweenLatinoand non-Latino populations in efficacy and safety parameters. Consequently,furtherstudiesarerequiredtostrengthenthe clinicalvalueoftheefficacyandsafetyfindingsandresultsof thecurrentanalysis.AnongoingglobalPhase3clinicalstudy whichcompares theefficacyand safetyofTZDand LZDin patientswithnosocomialpneumoniawillprovideadditional informationregardingthesafetyofTZDinLatinopatients.

Ethnic factors havebeen shown to influencethe safety and efficacy of several compounds; in fact, the FDA and EMA have encouraged the presence of patients from dis-tinct ethnicity and/orrace inclinical trials ofdrugs under development.30,31 _{It is hypothesised that inter-ethnic}

dif-ferences in the PK of antibiotics depend on the first-pass metabolismandtransportmechanismsbecausesomeagents demonstrate relatively low bioavailability.29 _These

inter-ethnic differences appear to be common, although their clinical relevancemust beinvestigated.29 _{Thefactthat the}

pharmacokinetic/pharmacodynamicpropertiesofTZDwere notaffectedbyethnicity(orrace)mightexplainthesimilar findings inefficacy and safety ofTZD betweenLatino and non-LatinopatientsenrolledintheESTABLISHtrials.

Conclusion

Inconclusion,theresultsofthecurrentanalysissuggestthat TZDwas efficaciousandwell toleratedinthemanagement ofLatinopatientswithABSSSIs.ThepopulationPKanalysis ofpatientsenrolled intoESTABLISH-1andETABLISH-2 sug-gestthatnodoseadjustmentisneededforLatinopatientsfor thetreatmentofABSSSI.Furthermore,thesefindingsindicate thatTZDmaybeanappropriatechoiceoftreatmentforLatino patientswithABSSSIswhoareeitherhospitalisedor outpa-tientsduetothe highpotencyandhigh oralbioavailability oftheagent;thisisalsosupportedbythefavourablesafety profileofTZDdemonstrated inthecurrentstudy.However, prescriptionofTZD(orlinezolid)forLatinopatientsshould beconsideredaccordingtotheapprovedSummaryofProduct Characteristicsandlocalguidelines.

Funding

FundingfortheESTABLISH-1andESTABLISH-2clinicaltrials wasprovidedbyMerck&Co.,Inc.,Kenilworth,NJ,USA.The post-hocanalysisoftheLatinosubgroupwasjointlyfunded byMerck&Co.,Inc.,Kenilworth,NJ,USAandBayerHealthCare, Germany.

Conflicts

of

interest

SFandPParecurrentemployeesofMerck&Co.,Inc., Kenil-worth,NJ,USA.EFisaformeremployeeofMerck&Co.,Inc., Kenilworth,NJ,USA.XZisanemployeeofBayerHealthcare, Beijing,China.JFC-MisanemployeeofBayerHealthCare, Mex-ico.TTisanemployeeofBayerYakuhin,Osaka,Japan.JPand JF-KareemployeesofCognigenCorporation,asubsidiaryof SimulationsPlus,Inc.,Buffalo,NY,USA. AOparticipated as aclinicalinvestigatorforBayerHealthCare,receivedspeaker honorariafrom Bayerand hasbeenclinicalinvestigatorfor Astellas Pharma, MSD, and Sangui labs. ECNhas received grantsupportfromCubistandNovartis,honorariaasspeaker fromAstraZeneca,PfizerandMerckandasconsultantfrom Cerexa,andhasrecentlyparticipatedasinvestigatorintrials ofAstraZeneca,TriusandCempra.

Acknowledgements

BoththeESTABLISH-1and -2clinical trialswere sponsored byMerck&Co.,Inc.,Kenilworth,NJ,USA.Theanalysisofthe LatinosubgroupwasjointlysupportedbyMerck&Co.,Inc., Kenilworth,NJ,USAandBayerHealthCare,Germany.Editorial supportwasprovidedbyHighfieldCommunications,Oxford, UnitedKingdom,sponsoredbyBayerHealthCare,Germany.

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