Precision and Personalized Medicine and anti-TB treatment: Is TDM feasible for programmatic use?

University of Groningen

Precision and Personalized Medicine and anti-TB treatment

Alffenaar, Jan-Willem C; Akkerman, Onno W; Kim, Hannah Yejin; Tiberi, Simon; Battista

Migliori, Giovanni

Published in:

International Journal of Infectious Diseases

DOI:

10.1016/j.ijid.2020.01.041

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Alffenaar, J-W. C., Akkerman, O. W., Kim, H. Y., Tiberi, S., & Battista Migliori, G. (2020). Precision and

Personalized Medicine and anti-TB treatment: Is TDM feasible for programmatic use? International Journal

of Infectious Diseases, 92, S5-S9. https://doi.org/10.1016/j.ijid.2020.01.041

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Precision

and

personalized

medicine

and

anti-TB

treatment:

Is

TDM

feasible

for

programmatic

use?

Jan-Willem

C.

Alffenaar

a,b,c,

*

,

Onno

W.

Akkerman

d,e

,

Hannah

Yejin

Kim

a,b

,

Simon

Tiberi

f,g

,

Giovanni

Battista

Migliori

f,h

a_{SydneyPharmacySchool,FacultyofMedicineandHealth,TheUniversityofSydney,Camperdown,NSW2006,Australia} b

WestmeadHospital,Westmead,NSW2145,Australia c

MarieBashirInstituteforInfectiousDiseasesandBiosecurity,TheUniversityofSydney,Camperdown,NSW2006,Australia d

UniversityofGroningen,UniversityMedicalCenterGroningen,DepartmentofPulmonaryDiseasesandTuberculosis,Groningen,TheNetherlands e

UniversityofGroningen,UniversityMedicalCenterGroningen,TBCenterBeatrixoord,Haren,TheNetherlands f

BlizardInstitute,BartsandTheLondonSchoolofMedicineandDentistry,QueenMaryUniversityofLondon,London,UnitedKingdom g_{DepartmentofInfection,RoyalLondonandNewhamHospitals,BartsHealthNHSTrust,London,UnitedKingdom}

h_{ServiziodiEpidemiologiaClinicadelleMalattieRespiratorie,IstitutiCliniciScientificiMaugeriIRCCS,Tradate,Italy}

ARTICLE INFO Articlehistory:

Received23December2019

Receivedinrevisedform20January2020 Accepted21January2020 Keywords: AR-JP PINK1 Parkin Parkinson’sdisease Mitophagy Ubiquitin Proteasome Autophagy ABSTRACT

Therapeutic Drug Monitoring(TDM)is increasinglyrecommendedtoensurethecorrect drugdose therebyminimizingadverseeventsandmaximizingregimenefficacy.TofacilitateimplementationinTB programs,aframeworkforTDMisurgentlyneeded.TDMisonlyusefulfordoseoptimizationifapatient isonanappropriateregimenguidedbydrugsusceptibilitytesting.TDMusingatargetedapproach selectingpatientswithriskfactorsforsuboptimaldrugexposure(e.g.diabetes)ornotrespondingto treatmentfordrugswithaclearconcentration-responserelationshipmayprovidethebestvaluefor money.Semiquantitativepoint-of-caretestsfordetectionofloworhighdrugconcentrationshouldbe implementedatcommunitylevelwhilequantitativeassayscanbeperformedatregionalorcentrallevel. ExpandingPK/PDresearchfollowedbyclinicaltrialsincludingbothclinicaloutcomeaswellas cost-effectivenesswillincreasethelevelofevidencesupportingTDM.

©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Traditionally,tuberculosis(TB)controlprogrammesfocustheir resourcesonrapid diagnosis and effectivetreatment to ensure individual benefit to the patient and break the chain of transmission (if the patient is infectious) (Migliori et al. 2019; Nahid et al. 2019). In spite of a comprehensive effort of the internationalcommunity,thetreatment successratesof multi-drug-resistant(MDR)-TBaregloballyintheorderof55%,(loweron extensively drug-resistant(XDR)-TB cases)although recent evi-dence suggests that the use of new drugs (e.g. bedaquiline) (Borisovetal.2017)canincreaseitto80%andbeyondevenoutside clinicaltrials(Ahmadet al.2018).Recently, moreattentionhas been paid to monitoring and management of adverse events,

particularly with new and repurposed drugs (Akkerman et al. 2019;Borisovetal.2019).

Recentlytheconceptof‘precisionmedicine’(Alffenaaretal. 2019) has beena subjectof discussion: more and more new guidelines (Nahid et al. 2017, 2019) are recommending individualised treatment based on drug-susceptibility testing (DST) resultsandDSTideallycoupled withactionable knowl-edgeofantibioticpharmacokinetics(PK)and pharmacodynam-ics (PD). The Pharmacology Committee of the Global TuberculosisNetwork(GTN)(Alffenaaretal.2019)hasworked intensivelytopromote TherapeuticDrugMonitoring(TDM),a techniquewhichisrenderingitincreasinglyeasytodoseanti-TB drugsintheblood,toensurethecorrectdrugdose(notmore, notless),minimizingadverseeventsandmaximizingregimen efficacy.

The aim of the manuscript is to discuss the programmatic feasibilityof TDM(Ghimireetal.2016)takingintoaccountthe specificfeaturesandinterplayofpathogen,patientanddrugand drugassaycharacteristicsusedtoperformTDM.

* Correspondingauthorat:SydneyPharmacySchool,FacultyofMedicineand Health,TheUniversityofSydney,Camperdown,NSW2006,Australia.

E-mailaddress:johannes.alffenaar@sydney.edu.au(J.-W.C. Alffenaar).

https://doi.org/10.1016/j.ijid.2020.01.041

1201-9712/©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

Pathogen(relationshipbetweenPK/PDandpathogenMIC) DSTisessentialforensuringthatapatientisonanappropriate regimenandpreventingdrugresistancedevelopment.Phenotypic DST is however costly (requiring lab capacity), technically demanding(non-viable samples,contamination and interpreta-tioncanleadtodelays)andtimeconsuming(1–2weeksorlonger). In order to help guide physicians more rapidly, genotypic and wholegenomesequencingmethodsarebeingemployedandmay beabletodetectmutationswherethereisnocorrelationtoMICs. TheWHOendorses bothphenotypic and genotypicDST (World Health Organization 2019), the GeneXpert Ultra is a rapid moleculartest(resultinunder80min),totriagepatientsbetween RR-TBandDS-TB.AmolecularlineprobeassayGenoTypeMTBDRsl V2candetectresistancetofirst(isoniazid,rifampicin,ethambutol and pyrazinamide) and second line drugs (fluoroquinolones, ethionamide/prothionamide and aminoglycosides) in order to help triage patients onto the shorter WHO regimen, however changes in regimen (linezolid, bedaquiline and clofazimine replacingaminoglycosidesandethionamide)meansthatwewill need newer tests that can triage MDR/XDR TB patients more effectively.

PhenotypicsusceptibilityallowsforMICdetermination,which canbecombinedwithAUCTDMtodeterminetheappropriatedose of an individual drug. Virtual MICs based on association of phenotypic susceptibility with single or multiple mutations is developinganditispossibletobasetreatmentonthefollowing genotypicDSTresults(Kamblietal.2015b;Miottoetal.2017);for rifampicinsomemutationssuggestthathigherdosesofrifampicin >20 mg/kg may be considered, moreover rifabutin may retain activityandrifampicin35mg/kgmaybeeffective.Normaldose IsoniazidcanbegiveninthepresenceofinhAmutations(atnormal doses),requiringhigherdosesinthepresenceofkatG),withboth inhAandkatG,isoniazidshouldnotbeused(Cambauetal.2015; RiederandVanDeun2017).Fluoroquinolonesalsoappeartohave resistancemutationsthatmaycharacteriselowresistanceMIC<1 andhighresistancemutations(Kamblietal.2015a;Chienetal. 2016).Moxifloxacincanthereforebeexpectedtohaveactivityata higherdoseof800mgadayinthepresenceoflow-levelresistance. We have now identified several mutations correlated with resistance.WewillcontinuetoneedthephenotypicMICtestingin certain cases when lacking molecular or sequencing results or when discrepancies or unknown mutations are encountered (Faksri et al. 2019). Furthermore the CRyPTIC consortium are usingnextgenerationsequencingtoevaluategenetic resistance predictionbycataloguingresistantstrains;thismayleadtorapid universaldrugsusceptibilitytesting(DST).

Host(hostcharacteristicsaffectingpharmacokinetics) TDMisrecommendedforpatientswithseveregastrointestinal abnormalities,diabetesmellitus(DM),HIV,renalimpairmentoron dialysisandpatientswithinadequatetreatmentresponse(Nahid etal.2017,2019).DMoftencausesgastroparesis,whichmayresult inmalabsorptionordelayedabsorption.AlthoughimpactofDMon drugexposure hasbeena subjectofdebate,tworecentstudies showedreducedexposuretofirstlinedrugsandmoxifloxacinin patientswithTBandDM(Dekkersetal.2019;Mtabhoetal.2019). Thisreducedexposurewasduetoincreaseddrugclearanceand partlyduetomalabsorption.

A recentlypublishedsystematic review of the effect of HIV infection on PK in TB patients showed no consistent results (Daskapanetal.2019).Forrifampicinmoststudiesshowed low totalexposureinallTBpatients,unrelatedtoHIVinfection.Several studiesshowedsignificantlowerAUCvaluesforRIFinHIVinfected TBpatients.Howeveronestudyalsoshowedasignificanthigher

AUC in HIV positive TB patientscompared toHIV negativeTB patients. For isoniazid none of the studies showed significant differences in AUC between HIV positive and HIV negative TB patients. For pyrazinamide some studies showed significantly lowerAUCinHIVpositiveTBpatients,whileotherstudiesshowed nodifference.

OtherpossibleindicationstoperformTDMarepatientswhoare malnourishedorwhoarepregnant.MalnutritionduetoTBitself leads to a decreased fat-free mass and is often related to malabsorptionaswell.Thefirstmightleadtoachangeinvolume ofdistributionandthelattermightcauselowexposure.Studieson thistopicarestilllacking(TerBeeketal.2019).Pregnancyleadsto anincreasedvolumeofbodyfluid,whichcausesanincreaseofthe volumeofdistributionofdrugsandthatcanleadtoadecreased peakdrugconcentration.Furthermorepregnancymayenhancethe eliminationofdrugs(VanKampenhoutetal.2017).

Drug

Dose-exposure-responserelationshipsofTBdrugsareaffected by mycobacterial and host-related variability. These include lineage-specific factors, growth phase, phenotypic and genetic susceptibility, location and extent of TB, cavity formation, host immune function, renal and hepatic function (Alffenaar et al. 2019).

AmericanThoracicSociety(ATS)guidelinesrecommendTDMin caseoftreatmentwithsecond-linedrugs,specificallyforlinezolid and cycloserine/terizidone (in renal impairment) (Nahid et al. 2019).UpdatedWHOguidelinesalsosupportTDMforsecondline drugs including linezolid, fluoroquinolones and injectables (i.e. aminoglycosides)(WorldHealthOrganization2019).

Toxicity due to drugs such as ethambutol (ocular toxicity), isoniazid(peripheralneuropathy),pyrazinamide(hepatotoxicity), linezolid(haematologicaltoxicityandperipheralneuropathy)and fluoroquinolone(QTprolongation)aredrug concentration-depen-dent.ATSguidelinesexplicitlystateavoidingcycloserine concen-trations>35mg/LtopreventCNStoxicity(Nahidetal.2019).

Sub-optimal drug exposure can lead to acquired resistance, delayedculture conversionor relapse(Pasipanodyaetal. 2013). Efficacyisoftencorrelatedwith drugexposure,specificallywith pharmacodynamicallylinkedmarkerssuchasAUC0-24/MIC(most commonly),Cmax/MICorT/MIC(Alffenaaretal.2019).SuchPK/PD targetsarelargelyderivedfromtheHollowFiberSystemModelofTB andMonteCarlosimulations.Optimalefficacyoflinezolidappearsto bedrivenbyAUC0-24/MIC>100(Bolhuisetal.2018).AUC0-24/MIC ratioisalsothebestpredictorofefficacyforfluoroquinolones(Van denElsenetal.2018;vandenElsenetal.2019).

Limited sampling strategies have become available for a numberofTBdrugssuchasisoniazid,rifampicin,pyrazinamide, ethambutol, linezolid, moxifloxacin and levofloxacin, and will allowaccurateestimationoftotaldrugexposureswithalimited numberofsamples(Kampetal.2017;VandenElsenetal.2018; vandenElsenetal.2019).Forexample,moxifloxacinAUCcouldbe accurately estimated with 2 samples, i.e. a trough sample combinedwitha sampleat4or6 hafterdrugintake(vanden Elsenetal.2019).

Assay

TDM requires an analytical method suitable for fast and accuratequantificationofanti-TBdrugconcentrations. Tradition-ally high-performance liquid chromatography (HPLC) with UV detection has been used to quantify drug concentrations. The extensivesamplepreparation,longruntimesincombinationwith coldchain shipmentstocentrallaboratorieshavebeena major hurdleforbroadscaleimplementationofTDM.Theintroductionof

highlysensitiveliquidchromatographycoupledwithtandemmass spectrometry(LC–MS/MS)enableddetectionofdrugsinverysmall samples(<50

m

L)andallowedthedevelopmentofassayssuitable formeasurementofdrugconcentrationsindriedbloodspots(Vu etal.2011;Veringaetal.2016).Driedbloodspotssamplesshowan increased stability compared to plasma or serum and could thereforebeshippedatroomtemperatureandevenbymail.Dueto highpurchasecostsandneedforskilledtechnicians,suchmethods canonlybeoperatedatacentrallevel.Thelackofawarenessinthe communityincombinationwithlongturnaroundtimehindered broad scale implementation (Alffenaar et al. 2019). Therefore, there isan urgentneed for asemi-quantitative test tosupport physicianstomakeinformeddecisionsondrugdosing(Alffenaar etal.2019).Suchatestshouldbeabletodistinguishbetweenlow,

normal and high drug exposure. Other matrixes than blood (serum/plasma)likesalivaorurinecouldbeusedastheycanbe easilycollected(non-invasive)andreflectthedrugconcentration inthebody.SimpleUVspectrophotometerscouldbeemployedto measuredrugconcentrationsinthesematrixes.Theadvantageof sucheasytooperateequipmentislowpurchasecosts,allowinguse inthecommunity.

Programmatictreatment—TDM

A targeted approach to implement TDM in a programmatic settingislikelymoreeffectiveandaffordablethanTDMforevery patient.Atargetedapproach reliesonselection ofpatientsthat maybenefitfromTDM.Host,pathogenanddrugrelatedfactorscan

Table1

Therapeuticdrugmonitoringinaprogrammaticsetting.

Xindicatedthemostsuitableassayforeachclinicalsituation.Thegreyshadedareasindicatethelocation(e.g.community,regionalor central)wheretheassayshouldbemadeavailableforoptimaluse.TDM=therapeuticdrugmonitoring.

beusedindevelopingadecisiontreeforTDM(Nahidetal.2017; Alffenaar et al. 2019). Host factors associated with low drug exposure, less susceptible pathogens, and drugs with a high variabilityindrugexposureshouldbeincludedtodecideonthe useof TDM. Based onfrequency of use, level of expertise and facilitiesrequired tooperate an assayand costs,we propose 3 levelsofTDM(Ghimireetal.2016;Alffenaaretal.2019). 1)Communitylevel;easytoaccessscreeningUVassays(saliva/

urine)forkeyfirst(INH,RIF,PZA)andsecondlinedrugs(FQ, LZD)todeterminelow,normalandhighdrugexposure. 2)Regional level;quantitative assays, either HPLC-UV or entry

levelLCMSMS forkey first and secondlinedrugs shouldbe available to performindividualized dosing in those patients withknownlow drugexposure andpatientswithhighdrug exposureincombinationwithsignsofadverseeffects. 3)Centrallevel;quantitativeassaysusingadvancedLCMSMScan

beused for measuring drug concentrationin dried samples (blood,saliva)shippedbymailfromthecommunity.

Withthe3levelsofTDMwerecommendtomakeuseofthe availableexpertise.Resultsobtainedfromscreeningassaysinthe community should be easily translated in uniform clinical decisions,whileresultsfromquantitativeassaysat theregional levelshouldbeaccompaniedbyindividualizeddose recommen-dations.Screeningassayscouldbeofvalueaswellforpatientson preventativetreatmentasitcanhelptodetectmalabsorptionin patientswith,e.g.,Crohn’sdiseaseortohelpassessadherence.For very difficult to treat cases requiring TDM for less frequently assayeddrugsitcouldberecommendedthatthesecaseswillbe discussedinanationalConsiliumwithappropriateexpertise.At thecentrallevel,qualityassuranceforTDMattheprogrammatic levelshouldalsobeaccommodated,includingproficiencytesting programsandtrainingofstaff.Acentralizedmodel(Degelingetal. 2020)forTDM,withareferencecenterwithadequateexpertise, willlikelybebetterequipped(e.g.funding)forimplementationof innovativetechniquesinTDM(Table1).

Knowledgegaps—whattodonext

Adequatedrugselectionandprecisiondosingcanbeconsidered thebestpracticetoincreaseresponsetotherapy,reduceriskof acquireddrugresistanceand preventadversedrugreactions.To supportprecision dosingforallTBdrugs invitroPK/PDstudies using a hollow fibersystem model of tuberculosis have tobe performedandsubsequentresultshavetobevalidatedinclinical trialsforthosedrugswhereevidenceislacking.Thenextstepisto perform a randomized controlled trial to compare TDM with standardofcaretoshowthebenefitsofprecisiondosing.Although a double-blind design may not be feasible due to technical complexityappropriatecontrolmechanismscanbeincludedinthe trialdesigntominimizebiasandconfoundingfactors.Patientsfor whomTDMisalreadybeingrecommendedincurrentguidelines (Nahid etal. 2019;WorldHealth Organization 2019)shouldbe prioritized.Theprimaryend-pointofaTDMtrialshouldnotfocus on a single clinical end-point such as prevention of acquired resistancebutonthecost-effectivenessoftheoptimizedclinical management of TB patients. If costs related to the clinical managementofTBcanbereduced,aprogrammatic implementa-tion is likely to be more feasible. To facilitate broad scale programmatic implementation, robust and affordable point-of-care tests have to be developed. Once evidence and tests are available, guidance documents (including information on evi-dence, cost-effectiveness, technical aspects of TDM) on local implementationshouldbeissuedlikeinthepastfornewtestsor

drugs. Effectiveness of theuseof TDM shouldsubsequently be evaluatedinareal-lifesetting.

Conclusion

ConsiderableprogresshasbeeninprecisionmedicineforTB throughdrugselectionbasedonmoleculardiagnostictestsand drug exposureevaluation inpatients atrisk for low or high drugexposure.Expanding invitroPK/PD researchfollowedby clinical trials will complete the evidence supporting TDM. Development of point-of-care tests and TDM in a multistep approachwillprovidetheframeworkfortestingcost-effectiveness ofprogrammaticTDM.Followingfavourabletrialresults,guidance onprogrammaticimplementationshouldbeissued.

Declarationsofinterest None.

Funding

Thisresearchdidnotreceiveanyspecificgrantfromfunding agenciesinthepublic,commercial,ornot-for-profitsectors Ethics

Noethicalclearancewasrequiredforthisstudy Acknowledgements

This article belongs to the scientific activities of the WHO CollaboratingCentreforTuberculosisandLungDiseases,Tradate, ITA-80, 2017-2020- GBM/RC/LDA. This article is part of a supplement entitled Commemorating World Tuberculosis Day March 24th, 2020: “IT’S TIME TO FIND, TREAT ALL and END TUBERCULOSIS!” published with support from an unrestricted educationalgrantfromQIAGENSciencesInc.

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