Population pharmacokinetics of piperacillin in plasma and subcutaneous tissue in patients on continuous renal replacement therapy

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Population pharmacokinetics of piperacillin in plasma and

subcutaneous tissue in patients on continuous renal replacement therapy

MatsBueâ,b,c,*,TomásSou^d,Anna Sophie L.Okkels^b,Pelle Hanbergâ,c,Anders Thorsted^d, Lena E.Friberg^d,TorbenL.Anderssonê,Kristina Öbrink-Hansen^f,SteffenChristensen^b

aDepartmentofOrthopaedicSurgery,HorsensRegionalHospital,Sundvej30,8700Horsens,Denmark

bDepartmentofAnaesthesiaandIntensiveCareMedicine,AarhusUniversityHospital,PalleJuul-JensensBoulevard99,8200AarhusN,Denmark

cOrthopaedicResearchUnit,AarhusUniversityHospital,PalleJuul-JensensBoulevard99,8200AarhusN,Denmark

dDepartmentofPharmaceuticalBiosciences,UppsalaUniversity,Box591,75124Uppsala,Sweden

eDepartmentofClinicalBiochemistry,AarhusUniversityHospital,PalleJuul-JensensBoulevard99,8200AarhusN,Denmark

fDepartmentofInfectiousDiseases,AarhusUniversityHospital,PalleJuul-JensensBoulevard99,8200AarhusN,Denmark

ARTICLE INFO

Articlehistory:

Received7September2019

Receivedinrevisedform11January2020 Accepted13January2020

Keywords:

PK/PD Modelling β-lactams Microdialysis Tissuedistribution

Continuousrenalreplacementtherapy

ABSTRACT

Objectives:Piperacillinisaβ-lactamantimicrobialfrequentlyusedincriticallyillpatientswithacute kidney injurytreatedwithcontinuousrenal replacementtherapy(CRRT).However, dataregarding piperacillintissueconcentrationsinthispatientpopulationarelimited.Aprospectiveobservational studywasconductedoffreepiperacillinconcentrationsduringasingle8-hdosingintervalinplasma(8 samples) and subcutaneoustissue (SCT) (13 samples),in 10patients treatedwith CRRTfollowing piperacillin4ggivenevery8hasintermittentadministrationover3min.

Methods: A population pharmacokinetic model was developed using NONMEM 7.4.3, tosimulate alternative administration modes and dosing regimens. SCT concentrations were obtained using microdialysis.Piperacillinconcentrationswerecomparedtotheclinicalbreakpointminimuminhibitory concentration (MIC) for Pseudomonas aeruginosa (16 mg/l), with evaluation of the following pharmacokinetic/pharmacodynamicstargets:50%fT>1MIC,100%fT>1MIC,and100%fT>4

MIC.

Results:SCTconcentrationsweregenerallylowerthanplasmaconcentrations.Forthetargetof50%free time(fT)>1MICand100%fT>1MIC,piperacillin4gevery8hresultedinprobabilityoftarget attainment(PTA)>90%inbothplasmaandSCT.PTA>90%forthetargetof100%fT>4MICwasonly achievedforcontinuousinfusion.

Conclusions:Piperacillin4gevery8hislikelytoprovidesufﬁcientexposureinbothplasmaandSCTto treatP.aeruginosainfectionsincriticallyillpatientsonCRRT,giventhattargetsof50%fT>1MICor100%

fT>1MICareadequate.However,ifamoreaggressivetargetof100%fT>4 MICisadopted, continuousinfusionisneeded.

ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc- nd/4.0/).

Introduction

Septicshockisacommoncauseofacutekidneyinjury(AKI) incriticallyillpatients(deMendoncaetal.,2000;Bagshawetal., 2007).Piperacillin/tazobactamisaβ-lactam/β-lactamaseinhibi- torcombinationcommonlyusedbothforempiricalandtargeted treatment in theintensive care unit(ICU setting. It exhibits a broadspectrumantibacterialactivityagainstbothgram-positive and gram-negative bacteria, including Pseudomonas aeruginosa (Pinder and Lipman, 2002).The efﬁcacy is related to thetime duringwhichthefreedrugconcentrationismaintainedabovethe

* Corresponding author at: Department of Orthopaedic Surgery, Horsens RegionalHospital,Sundvej30,8700Horsens,Denmark.

E-mailaddresses:matsbue6@rm.dk(M.Bue),tomas.sou@farmaci.uu.se(T.Sou), asokkels@hotmail.com(A.S.L. Okkels),pehanb@rm.dk(P.Hanberg),

anders.thorsted@farmbio.uu.se(A.Thorsted),lena.friberg@farmbio.uu.se (L.E. Friberg),t.l.a@stofanet.dk(T.L. Andersson),

kristina.Obrink.Hansen@auh.rm.dk(K.Öbrink-Hansen), steffen.christensen@auh.rm.dk(S.Christensen).

https://doi.org/10.1016/j.ijid.2020.01.010

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

ContentslistsavailableatScienceDirect

International Journal of Infectious Diseases

j o u r n a l h o m ep a g e : w w w . e l s e v i e r . c o m / l o c a te / i j i d

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minimum inhibitory concentration(fT >MIC). For piperacillin, achievementof50%fT>1MICinplasmahasbeenassociated withclinicalcure(Drusano,2004;Seyleretal.,2011);however, the exact association between piperacillin concentrations and clinicalefﬁcacyremainsuncertain.Sincemostbacteriaresidein theinterstitialspaceof solidtissues, information ontarget site concentrations is needed in order to evaluate the existing treatment targets more closely (Drusano, 2004). Microdialysis hasevolvedasapromisingtooltocontinuouslysamplethefree fraction of antimicrobials from the interstitial ﬂuid of the investigated tissue (de la Pena et al., 2000; Joukhadar and Muller,2005).Incontrasttoexistingmethodsfortheassessment of tissue concentrations, microdialysis has the potential to generatedynamicantimicrobialpharmacokinetic(PK)datafrom targetsites.

Continuousrenalreplacementtherapy(CRRT)isusedin5–10%

ofcriticallyillpatientstreatedin theICU(Uchinoet al.,2005).

During CRRT, plasma–water and solutes with low molecular weight,includingmanytypesofantimicrobials,areremovedfrom the circulation. In particular, water-soluble drugs with low albuminbinding, suchas piperacillin, maybe removed (Seyler etal.,2011;Robertsetal.,2012).Still,dataregardingpiperacillin tissueconcentrationsincriticallyillpatientstreatedwithCRRTare limited(Ulldemolinsetal.,2014;Vargheseetal.,2014).Therefore, wesetouttoassessthePKoffree(unbound)piperacillinduringa single8-hdosingintervalinplasmaandsubcutaneoustissue(SCT) using microdialysis in critically ill patients treated with CRRT followingpiperacillin4 ggivenevery8h(q8h)as intermittent administration(IA) over3min.ByestablishingapopulationPK model,alternativedosingregimensandmodesofadministration weresimulated,andtheirprobabilityoftargetattainment(PTA) wasevaluated.

Methods

This prospective observational study was conducted in the DepartmentofAnaesthesiaandIntensiveCareMedicine,Aarhus UniversityHospital,Denmark,betweenDecember2017andJune 2018. Chemicalanalyses wereperformed in theDepartment of ClinicalBiochemistry,AarhusUniversityHospital.

Patientpopulation,CRRT,andpiperacillin

Patients treated with intravenous piperacillin/tazobactam(4 g/0.5g)q8hgivenasanIAover3minandrequiringCRRTwere eligibleforthestudy.CRRTtreatmentandpiperacillin/tazobactam therapywereinitiatedindependentofthecurrent study,atthe discretionofthetreatingphysician.Aminimumoftwodosesof piperacillin/tazobactamweregivenbeforestudyinclusion,withall priorpiperacillin/tazobactamdosesrecordedforincorporationin thedataset.

Exclusioncriteriawerepregnancy, plateletsbelow510⁹/l, internationalnormalized ratio(INR) above 5,known allergy to benzylpenicillinorpiperacillin,lactate>4mmol/l,andtheneedfor noradrenalin>0.50m^g/kg/minôr ^theêquivalent^doses ôf ^vaso-

pressors.Thefollowingdatawerecollectedandregisteredforeach enrolledpatientonthedayofinclusion:age,sex,weight,typeof anticoagulant required for CRRT, admission diagnosis, urine output,microbiology,plasmacreatinine,plasmabilirubin,plasma albumin, plasma urea, Simpliﬁed Acute Physiology Score III (SAPS3),andCRRTsettings.

ThePrismaflexCRRTsystemwasused(BaxterInternationalInc., Deerfield,IL,USA)andallpatientsweretreatedusingtheM100 filter.AllCRRTsettingswereprescribedatthediscretionofthe treatingphysicianfollowing standardproceduresin thedepartment, including continuous veno-venous haemodiafiltration

(CVVHDF),citrateanticoagulation,and theaimfora prescribed efﬂuentdoseof30ml/kg/h.

Microdialysis

Brieﬂy,microdialysisisacatheter-basedtechniquethatfollows adiffusionofwater-solublemolecules,includingantimicrobials, fromtheinterstitialspaceofaccessibletissuesacrossasemiper- meablemembranelocatedatthetipof thecatheter(Bueetal., 2018a,b;Tottrupetal.,2019).Duetocontinuousperfusionofthe microdialysiscatheter,equilibriumwillneveroccur.Accordingly, thefreeconcentrationofthedialysatewillonlyrepresentafraction of the actual free concentration in the tissue. This fraction is referredtoas‘relativerecovery’andcanbedeterminedbyvarious calibration methods, which is imperative when assessing free tissueconcentrations(BouwandHammarlund-Udenaes,1998;de laPenaetal.,2000;Joukhadarand Muller,2005).Inthisstudy, benzylpenicillinwasusedasaninternalcalibratorforpiperacillin (Robertsetal.,2009).Nopatientreceivedbenzylpenicillinbefore orafterinclusioninthestudy.Therelativerecoveryofpiperacillin wascalculatedfromthelossoftheinternalcalibratoracrossthe microdialysis membrane, using the retrodialysis by calibrator method(BouwandHammarlund-Udenaes,1998;Hanbergetal., 2018).Allcatheterswerecalibratedindividually.Detaileddescrip- tions of microdialysis can be found elsewhere (Muller, 2002;

JoukhadarandMuller,2005;Hanbergetal.,2018).Thisstudyused equipment from M Dialysis AB (Stockholm, Sweden). CMA 63 catheterswereused(membranelength30mmwith20kDacut- off), and CMA 107precisionpumps produced a ﬂow rate of 2

m^l/min.

Samplingprocedures

Richmicrodialysisandbloodsamplingwereperformedduring a single 8-h dosing interval. The microdialysis catheter was insertedintheSCToftheupperarmaminimum30minpriortoa new piperacillin/tazobactam administration. The catheter was ﬁxedtotheskinwithasinglesuturetopreventdisplacement.The microdialysis system was perfused with 0.9% NaCl containing benzylpenicillin at a concentration of 4 m^g/l ^(provided ^by ^the

Pharmacyat Aarhus UniversityHospital). Single blood and SCT trough samples were obtained prior to the administration of piperacillin/tazobactam (time 0), after which dialysates were collectedevery20minfortheﬁrst3handevery60mininthe following5h,providing13dialysatesintotal.Bloodsampleswere drawnfromaperipheralarterialcatheterat10,20,30,60,120,240, and480minpost-dose,resultinginatotalofeightbloodsamples perpatient.

Blood samples were kept for a maximum of 3 h at room temperaturebeforebeingcentrifugedat3000gfor10min.Plasma aliquots were frozen and stored at 80 C until analysis. All dialysateswereimmediatelyfrozenondryiceforamaximumof10 hbeforebeingtransferredandstoredat 80Cuntilanalysis.

Quantiﬁcationofpiperacillinandbenzylpenicillinconcentrations

Unbound piperacillin concentrations in microdialysates and plasma and benzylpenicillin concentrations in microdialysates weresimultaneouslyquantiﬁedwithastandardassayusingultra- highperformanceliquidchromatography(UHPLC)intheroutine hospitallaboratoryfortherapeuticdrugmonitoringinhospitalized patients. The UHPLC system consisted of an eluent pump, autosampler, column compartment, and a UV detector(Agilent 1290 Inﬁnity; Agilent Technologies, Waldbronn, Germany), equippedwitha Poroshell 120,EC-C18 2.1 100mm, 2.7-m^m

column(Agilent).BeforeUHPLCanalysis,plasmawascentrifuged

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ina96-wellultraﬁlterplatewitha30-kDamolecularmasscut-off retaining protein (mainly albumin) with unspeciﬁcally bound antimicrobials, leaving only thefree fractionof piperacillin for analysis. Five microliters of microdialysate orplasma was then mixed with 20 m^l ^phosphate ^buffer ^pH ^3.0 ⁽⁵⁰ ^nM ^NaH2PO4, adjustedwitho-phosphoric acid,85%).Aftermixing,10m^l^was

injectedintotheUHPLCsystem.Calibrationstandardsof1.56,3.13, 6.26, and 25.0 m^g/ml piperacillinand 1.56, 3.13,6.25, and 25.0

m^g/ml^ofbenzylpenicillinin15m^l^0.9%^NaCl^were^prepared^and

analysed.Nosigniﬁcantmatrixeffectonthecalibrationcurveswas observed.Chromatographywasconductedat40C,withagradient of acetonitrile and phosphate buffer (50 nM NaH₂PO₄, 5%

acetonitrile,pH3.0).Theconcentrationofacetonitrilewaselevated from20%to30%overatimespanof4min,andthetotaltimeof analysiswas4minwithapostruntimeof1min.Piperacillinand benzylpenicillinwere detected at 210 nm. The lower limits of quantiﬁcationwerefoundtobe0.5m^g/ml^forpiperacillinand0.3

m^g/ml^forbenzylpenicillin.Inter-runimprecisions(percentcoef- ficientsofvariation(CV%)were15.3%at4.5m^g/mlând^8.2%ât^15.6 m^g/ml^for^quantificationofpiperacillin,and13.3%at2.6m^g/mlând

14.4%at12.0m^g/ml^for^quantiﬁcationofbenzylpenicillin.Dilution experimentsusinghigh-concentrationsamplesshowedlinearity in measurement response within 0.5 m^g/ml ^to ⁵⁰⁰ m^g/ml ^for

piperacillin,andwithin0.5m^g/ml^to⁶⁰m^g/ml^forbenzylpenicillin.

All samples were diluted before bulk analyses as appropriate, basedonpilotexperiments.

MIC

The clinicalbreakpoint MIC for planktonic P.aeruginosa (16 mg/l) deﬁned by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (EUCAST, 2019) was used to evaluate thefollowing pharmacokinetic/pharmacodynamic(PK/

PD)targets:50%fT>1MIC,100%fT>1MIC,and100%fT>4 MIC.P.aeruginosaisaproblematicpathogenfrequentlyseeninthe ICUsetting,andtheclinicalbreakpointMICmayreﬂectaworst case scenario regarding bacterial susceptibility in empirical antimicrobialtherapy(Shorr,2009).

Pharmacokineticmodelling

All available samples were included and analysed using populationPKmodellingin NONMEM7.4.3(ICONDevelopment Solutions,Hanover,MD,USA)(Boeckmannetal.,2013),withthe supportofPerl-Speaks-NONMEM(PsN)andPiraña(Keizeretal., 2013). The ﬁrst-order conditional estimation method with interactionwas usedforparameterestimation. Rversion3.5(R FoundationforStatisticalComputing,Vienna,Austria)wasusedfor datamanagement,andthexpose4packagewasusedtosupport modeldiagnosticsandgraphicalevaluationoftheresults(Keizer etal.,2013).

Thelikelihoodratiotest(LRT)wasusedtoevaluatestatistical significancefortheinclusionofadditionalparametersinnested models,withtheobjectivefunctionvalue(OFV)assumedtobeChi- squaredistributed.AreductioninOFV(DÔFV)ôf^3.84^between^two

nestedmodelswithone parameterdifference wasconsidereda statisticallysignificantdifferenceatthe5%significancelevel,with a p-value of 0.05. Model selection was guided by statistical goodness-of-fit,graphicalevaluationofresidualdiagnosticplots, and simulation-based prediction-corrected visual predictive checks (VPC)(Bergstrandet al.,2011), andplausible parameter estimateswithacceptableprecision(Nguyenetal.,2017).

Initially, a model was developed to describe the plasma samples,forwhichone-,two-,andthree-compartmentdisposition modelswereevaluated.Thereafter,the modelwas extended to includemicrodialysisobservationsusingmethodologydescribed

previously(Tunbladetal.,2004).Theobservationsweretreatedas obtained,i.e.,asdialysateconcentrationattheendofthecollection intervalaftercorrectionforrecovery.Duringmodeldevelopment, thecentral,peripheral,oraseparatecompartmentwasevaluated toreﬂectthecollectionsiteofthemicrodialysisdata.Todescribe thevariabilitybetweenpatients,inter-individualvariability(IIV) terms were included if signiﬁcant, assuming log-normally distributedparameters.

To explain some of the observed random variability, the following patient characteristics were evaluated in a covariate analysis:age,weight,andserumalbumin.Covariateselectionwas guidedbygraphicalevaluationandtheLRT,withprimaryfocuson the clearance parameter. Since piperacillin is predominantly eliminatedrenally(about70%)(Andersenetal.,2018),thereisa physiological relationship between creatinine clearance and piperacillinclearance. However,sincethepatientsinthis study were anuric and on dialysis,it was not possibleto evaluate a covariateeffectofcreatinineclearanceonelimination.Clearance andvolumeparameterswerescaledtobodyweightinlinewith allometry, whereweightwas normalized to70 kgfora typical adultandscaledusingaﬁxedexponentof0.75forclearanceand1 forvolume.Categoricalcovariateswereincludedasashiftinthe typical value from the most common category. The covariate search was performed by stepwise covariate model building supported by PsN, starting with forward addition followed by backward elimination, with a signiﬁcant p-value of 0.05 for forwardadditionand0.01forbackwardelimination(Jonssonand Karlsson,1998).

Simulations

Alternativedosingregimensandmodesofadministrationwere assessedatsteadystate(definedasthethirddayofdosing)with respecttothePTAforthethreePK/PDtargets. Piperacillindaily dosesof16,12,and8gwereassessed,administeredbycontinuous infusion(CI),extendedinfusion(EI),orintermittentadministration (IA).TheEIdosingregimenswere4gq6h(infusionover3h),4g q8h(infusionover4h),and4gq12h(infusionover6h).TheIA dosingregimenswere4gq6h,4gq8h,4gq12h,2gq4h,and2g q6h.Apopulationof100000individualsweresimulatedforeach regimen with the final model, with values for any identified covariate sampled from the observed values in the study population,oracorrespondingpopulationdistribution.

Results

Patientcharacteristicsandpiperacillinconcentrations

Tenpatientswereincludedinthestudy;theircharacteristics are summarized in Table 1. No microdialysis or piperacillin/

tazobactamadverseeventswereobserved.Relativerecoverycould notbedeterminedforoneofthemicrodialysiscatheters.Sincethe dialysatepiperacillinconcentrationsfromthiscatheterresembled those of theother catheters,the mean valueof theremaining relativerecoverieswasappliedforthiscatheter.Relativerecovery (meanstandarddeviation(SD))was0.230.12,andtroughfree piperacillinconcentrationswere76.2933.42m^g/mlⁱⁿ^plasma

and65.0843.27m^g/mlⁱⁿ^SCT.

Pharmacokineticmodelling

Ingeneral,freepiperacillininSCTwaslowerthanthatobserved inplasma,asshowninFigure1.Theparameterestimatesofthe ﬁnal PKmodel,inconjunctionwiththeuncertainties andinter- individualvariabilityoftheparameters,aresummarizedinTable2.

Theplasmasamplesweredescribedbyatwo-compartmentmodel

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Table1

Patientbaselinecharacteristics(n=10).^a Patient Age

(years)

Sex Weight (kg)

AC Admission

diagnosis

Urine output

Microbiology^b Creatinine (mmol/l)

Bilirubin (mmol/l)

Albumin (g/l)

Urea (mmol/l)

SAPS3 Prescribed efﬂuentdose (ml/kg/h)^c

1 81 F 65 Citrate Pneumonia Anuria Klebsiella

pneumoniae¹

131 9 30 6.6 54 45

2 71 M 86 Citrate PIVSD Anuria NF 259 20 33 11.8 65 37

3 78 F 74 Heparin Pulmonary

embolism

Anuria NF 85 22 22 14.3 73 31

4 70 M 98 Citrate Sepsis Anuria Enterococcusfaecalis² 244 21 27 12.8 68 40

5 72 M 60 Citrate Cardiac

arrest

Anuria NF 103 35 19 5.8 70 55

6 65 M 91 Citrate Aorta

dissection

Anuria Staphylococcusaureus² 191 334 26 16.2 65 37

7 62 F 58 Citrate Pneumonia Anuria InﬂuenzaAvirus³ 109 41 15 7.5 - 38

8 80 M 70 Citrate Pneumonia Anuria InﬂuenzaAvirus⁴ 140 15 26 9.2 91 44

9 46 M 84 Citrate Aorta

dissection

Anuria NF 649 9 33 24.1 51 40

10 64 F 84 Citrate Cardiac

arrest

Anuria InﬂuenzaBvirus³ 186 10 35 16.4 91 34

Median 70.5 79 163 20.5 26.5 12.3 68 39

AC,anticoagulant;SAPS3,SimpliﬁedAcutePhysiologyScoreIII;F,female;M,male;PIVSD,postinfarctventricleseptumdefect;NF,notfound.

aAlldatawereregisteredonday1.

b Theoriginofthepathogensisindicatedbysuperscriptnumbers:1,pleuraleffusion;2,trachealsecretion;3,respiratorysecretion;4,throatswab.

cCRRTwasnotinterruptedduringthestudyperiodinanyofthepatients(prescribeddose=delivereddose).

Figure1.Overviewofthefreemicrodialysisconcentrations(closedcircles)andplasmaconcentrations(opencircles)availableforeachofthe10individualsincluded.The predictedfreeconcentration–timecoursesfromthemodelareshownforbothplasma(darksolidlines)andsubcutis(lightsolidlines)compartments.Theobserved microdialysisconcentrations(theaverageconcentrationoverthecollectioninterval)areplottedatthemid-pointofthesamplingintervalforillustration.Bodyweightandage aregivenforeachpatient.

Table2

Finalparameterestimatesandvariancesfromthepopulationpharmacokineticmodellinganalysis,includingparameteruncertaintyandshrinkageininter-individualand residualvariability.

Parameter Parameterdescription Estimate (RSE%)[SHR%]

CL(l/h) Eliminationclearance 3.30 (3.9)

Vc(l) Centralvolumeofdistribution 6.77 (8.3)

Q(l/h) Inter-compartmentalclearance 15.4 (21)

Vp(l) Peripheralvolumeofdistribution 10.0 (9.2)

fpl,sc Scalingfactorbetweenplasmaandsubcutis 0.661 (11)

CV%CL Inter-individualvariabilityinCL 10.9% (25)[6.6]

CV%Q Inter-individualvariabilityinQ 54.8% (29)[9.1]

CV%Vp Inter-individualvariabilityinVp 26.0% (33)[12]

CV%fpl,sc Inter-individualvariabilityinfpl,sc 35.7% (17)[0]

ERR(%) Proportionalresidualerror 16.6% (15)[7.9]

CV%,coefﬁcientofvariationinpercent;RSE,relativestandarderrorinpercent;SHR,shrinkageinpercent(onstandarddeviationscale).