Can diabetes mellitus modify the plasma concentrations of rifampicin in patients under treatment for tuberculosis?

brazjinfectdis2020;24(4):352–355

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

Brief

communication

Can

diabetes

mellitus

modify

the

plasma

concentrations

of

rifampicin

in

patients

under

treatment

for

tuberculosis?

Adriana

Aparecida

Durães

Fonseca,

Ana

Carla

Godinho

Pinto,

Thiago

Portal

da

Paixão,

Carlos

Augusto

Abreu

Albério,

José

Luiz

Fernandes

Vieira

UniversidadeFederaldoPará,FaculdadedeFarmácia,Belém,PA,Brazil

a

r

t

i

c

l

e

i

n

f

o

Received14January2020 Accepted28May2020 Availableonline11June2020

Keywords:

Tuberculosis Diabetesmellitus Rifampicin

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Rifampicinisakeycomponentoftreatmentfortuberculosisanditsefficacyisdetermined bythebloodlevelsattainedaftertherapeuticdoses.However,thereisahighvariability ofrifampicinbloodlevelsthatisrelatedtoboththepatientandtheformulationused.To date,theeffectofdiabetesmellitusontheplasmalevelsofrifampicinwaslowexploited, whichcouldberelevanteitherbythesignificantincreaseofthecomorbidityworldwideas bytheprobableinfluenceofdiabetesontherifampicinexposure.Thestudyaimsto eval-uatewhetherdiabetesmellituscontributetothevariationofthemaximumconcentration ofrifampicininpatientswithtuberculosistreatedwithadailydoseof10mg/kg.Rifampicin andglycatedhemoglobinweremeasuredbyhigh-performanceliquidchromatography,and bloodglucosebyspectrophotometry.Atotalof62malepatientswereincludedinthestudy, and26presenteddiabetesmellitus.Rifampicinplasmalevelsin2-hplasmasamples col-lectedatday61 rangedfrom3␮g/mL to14.2␮g/mL. Drugslevelsweresimilarbetween diabeticandnon-diabeticpatientsandwerenotcorrelatedwithbloodglucoseandglycated hemoglobin.Moreover,ahighpercentageofpatientsinbothgroupspresentedlowlevelsof rifampicin.

©2020SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Tuberculosis(TB)isanimportantpublichealthissueinBrazil, whereapproximately76,000casesarediagnosedeachyear.1

Rifampicin has a potent sterilizing capacity and is used in bothphases of treatment for TB.2 _{Thetherapeutic}

effi-cacyofrifampicinisdependentontherelationshipbetween drug susceptibility of Mycobacterium tuberculosis and the

∗ _{Correspondingauthor.}

E-mailaddress:jvieira@ufpa.br(J.L.Vieira).

achievement ofadequate blood concentration ofthe drug. However,there isahighinter-individualvariation inblood rifampicin levelsafterstandarddosages,whichcanleadto suboptimalconcentration,unsuccessfultreatment,and emer-genceofresistance.3,4

In recent years, several studies evaluated the effect of type2diabetesmellitus(DM)onrifampicin bloodlevels.5–7

Theresults wereinconclusive, however,with somestudies demonstrating significant changes in the pharmacokinetic

https://doi.org/10.1016/j.bjid.2020.05.007

1413-8670/©2020SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

brazj infect dis.2020;24(4):352–355

353

Table1–Baselinecharacteristicsofpatients.

Characteristic TB(n=36) TBDM(n=26) p-value

Age,years 44(29–56) 38.5(30–49) 0.1855b

Weight,kg 54(50–59) 64(57–70) 0.0046b

Fastingbloodglucose,mg/dL 92(87–96) 186(121–251) <0.0001b

FastingHbA1C,% 5.4(5.2–5.6) 9.6(7–12) <0.001b

HbA1C≥6.5,numberofpatients 0 26 – Bloodglucose≥126mg/dL,numberofpatients 0 25 – Conversionofsputumsmearup60days 89(n=32) 85(n=22) 0.7617a

Doseofrifampicin(mg/kg) 10.14(9.73–11.08) 9.82(8.9–10.19) 0.8123b

Plasmarifampicinlevelbelow8␮g/mL,% 75 80 0.6880a

Resultsareexpressedasmedianandrange.

a _{Chi-squaretest.} b _{Mann–WhitneyUtest.}

parametersofthedrugwhileothersrevealedamoderateor nullinfluenceoftype2DMonrifampicindisposition.InBrazil, nostudies have investigatedtheblood levels ofrifampicin inpatientswithdiabetesandtuberculosis.Thecurrentstudy aimedtoevaluatewhethertype2DMcontributestothe vari-ationof2-hplasmaconcentrationofrifampicininBrazilian patientsundertreatmentfortuberculosis.

The study was carried out between January 2017 and July2018 inthe Health Unit ofGuama district, Belem,PA, Brazil.Theinclusioncriteria wereadultmale patients(>18 years)withclinical,laboratory,andradiologicaldiagnosisof pulmonarytuberculosis.Exclusion criteriawereuseof anti-tuberculosisdrugsinthelast30days;HIV,hepatitisA,B,C,or Einfection;drugaddictionincludingregularconsumptionof ethanolandtobacco;hepaticorrenaldiseases;orhistoryof allergytotheanti-tuberculosisdrugs.Patientswereallocated intotwogroups:non-diabetictuberculosispatients(TBgroup) andtype2DMtuberculosispatients(TBDM).Type2DMwas definedasbloodglucoselevelsabove126mg/dLandglycated hemoglobin(HbA1c)above6.5%.8

Each patient received a total daily dose of rifampicin (600mg), isoniazid (300mg), pyrazinamide (1600mg), and ethambutol(1100mg)fortwomonths(intensivephase),and rifampicin(600mg) plusisoniazid(300mg)forfour months (continuationphase).Thedrugsweredispensedasa fixed-dosecombinationinbothtreatmentphases.Thecontinuation phaseinpatientswithDMwasextendedforadditionalthree months.2Theclinicalstaffofthetuberculosisprogramfrom thebasichealthunitprescribedanddispensedthedrugsfor free.Thefirstmonthlydosewassupervisedbytheresearch team.

Venous blood samples (4mL) for analysisof rifampicin, bloodglucose,andHbA1cweretakenonday61at2hafterdrug intakeandafter12hfasting.Thesampleswerecentrifuged at3500g×10minat4◦Cforplasmaseparation.Afractionof plasmawasrapidlyprocessedtodetermineglucoseblood lev-elsandHbA1c.Theotherfractionwasrefrigeratedat−20◦_C

forrifampicinanalysis.

Glucose blood levels were determined in an Archi-tect 8000 spectrophotometer (Abbott Diagnostics). HbA1c was measured by ion-exchange high-performance liquid chromatography.8

Rifampicin was measured by reversed-phase high-performanceliquidchromatographyusingaFlexar® system

(Perkin Elmer) after liquid–liquid extraction from plasma, following the procedure proposed by Prasanthiet al., 2015 withmodifications.9

Qualitativedataarepresentedasfrequenciesofoccurrence andtheconcentrationsofrifampicininplasmaasmedians andranges.Thecategoricalvariableswerecomparedbetween thestudygroupsbythechi-squaretest.TheMann–WhitneyU

testwasusedtocomparecontinuousvariables.Correlation of rifampicin plasmalevels with blood glucose and HbA1c were evaluatedusingSpearmancoefficient. Datawere ana-lyzedusingSPSSsoftware,Release21 (IBMInc,Chicago,IL, EUA).Thesignificancelevelacceptedwas5%.

Theresearch protocol was revisedand approvedby the EthicalCommitteeoftheNucleodeMedicinaTropicalda Uni-versidadeFederaldoPará(Brazil),underthenumber2,711,799. Allpatientsprovidedinformedconsentatadmissiontothe study.

Atotalof62patientscompletedthestudy,26(42%)with tuberculosisandfulfilledthecriteriafortype2diabetes melli-tus.Onlyfourpatientsreportedtheuseofhypoglycemicdrugs. AllpatientsoftheTBgroupshowedglucosebloodlevelsand HbA1c within the normalrange and did not reportuse of hypoglycemicdrugs.Althoughthemeanweightwashigher amongTBDMpatientscomparedtoTBpatients,bothgroups receivedsimilarmeandosesofrifampicin(mg/kg).Allpatients showednegativesputumsmearculturewithin180days,and thepercentageofsputumcultureconversionwithin60days waslowerintheTBDMgroup.Baselinecharacteristicsofthe studypatientsarelistedinTable1.

The median 2-h plasma concentrations of rifampicin were 6.16 (3.0–14.2)␮g/mLand 6.0(4–8.9)␮g/mLinTBand TBDMpatients,respectively.Theconcentrationsofrifampicin were similar inbothgroups ofthestudy (U=404;p=0.365) (Fig. 1). The percentage of patients with rifampicin con-centrations≤8.0␮g/mLwas 75% and80% inTBand TBDM groups, respectively. Plasma concentrations of rifampicin were not significantly associated with blood glucose lev-els in TB (rs=−0.155; p=0.366) and in TBDM (rs=−0.280;

p=0.353)groups.Asimilarresultwasfoundforthe associ-ationofplasmaconcentrationsofrifampicinwithHbA1cin TB(rs=−0.040;p=0.857)andinTBDM(rs=−0.231;p=0.666)

groups.

Themedian2-hplasmaconcentrationsofrifampicinwere chosen to compare drug exposure between the groups of

354

Fig.1–Plasmalevelsofrifampicininsamplescollected2h afterdrugintakeonday61ofpatientswithtuberculosis (TB)andwithtuberculosisandtype2diabetesmellitus (TBDM).Thehorizontallinescorrespondtomedianand range.

study.Overall,thestudiesthatevaluatedtheconcentrations ofrifampicinwereperformedinsamplescollectedat2hafter drugintake.4,10,11_{Themeandailydosesofrifampicingivento}

thepatientsweresimilarinbothgroupsandinconsonance withtherecommendationoftheWorldHealthOrganization (10mg/kg).2

A high proportion of patients of both groups showed median2-h plasmaconcentrationsofrifampicinbelowthe therapeutictargetforrifampicin(8␮g/mL).However,thelow levelofthedrugwasnotassociatedwithtreatmentoutcome, asallpatientsshowedsputumcultureconversionafter180 days. Other studies have also showna high percentage of patientswithadequate therapeuticresponseafter180days andmedian2-hplasmaconcentrationsofrifampicinbelow 8␮g/mL.ThehigherpercentageofTBDMpatientswith cul-turesputumconversion onday61 isnotbeconsidered an adequatepredictoroftreatmentoutcome.7,12,13Additionally, thereisaprobableinfluenceoftheimmunomodulatoryeffect ofmetformin,whichincreasessputumcultureconversionat 60days.14

These studies highlighted the importance of attaining target therapeutic concentrations of rifampicin since the drugbloodlevelsareapredictoroftreatmentoutcome.7,12,13

Van Ingenet al.(2011) demonstrated thatthe 600mgdaily dose of rifampicin leads to blood levels above the MIC (0.2␮g/mL)againstM.tuberculosis,butisatthelowerendofthe dose–responsecurve.Theseauthorsrecommendedtheuseof higherdosesofrifampicintooptimizetreatment.15

DiabetesmellituspromotesanegativeimpactonTB treat-mentoutcomes,aspatientscanshowahighermycobacterial burden,alongercourseforsputumconversion,andagreater risk of treatment failure.7,10,11 _{In this study, most diabetic}

patientsexhibited high levels ofblood glucoseand HbA1c, revealingpoorglycemiccontrol.

Themetaboliceffects ofDM on thedisposition of anti-tuberculosisdrugsincludeimpairmentofdrugmetabolism, alteration induodenal effluxpumpP-glycoprotein, and pH inthe sitesofabsorption.16,17 _{In this study,the median}

2-hplasmaconcentrationsofrifampicinweresimilarinboth

groups, suggesting that DM has no significant effect on rifampicinexposure;thisissupportedbythelackofsignificant correlationsofrifampicinplasmalevelswithboththeblood glucoseandtheHbA1c.Thesedataareinlinewithastudyin Indianpatientswithtuberculosis,whichsuggestsanincrease inthedoseortoextendthelengthoftreatmentindiabetic patientsinordertoreachsimilarexposurelevelsobservedin non-diabeticpatients.7

Thetimeforbloodsamplingcanbeconsideredalimitation ofthisstudy,as2-hsamplescouldnotbethetimeof maxi-mumdrugconcentrationduetotheriskofdelayedabsorption or malabsorptionofrifampicin.However,2-hsampleshave beenusedtoassessdrugexposureinseveralstudies.Another limitationofthestudywasthecollectionofonlyoneblood sampleofeachpatientinsteadofserialbloodsamplesto esti-matethe 24-harea-under-the-curve,whichcouldprovidea betterestimationoftheexposuretothedrug.4,10,11

Inconclusion,thedataofthepresentstudysuggestthat there isnosignificant effectofdiabetes mellituson the 2-h concentrationof rifampicin.Morevoer,ahigh proportion of patients in both groups presented low blood levels of rifampicin.These datacontribute tothecomprehensionof keypointsrelatedtotheuseofrifampicininthetreatment fortuberculosisinBrazilianpatients.

Funding

Thereisnofundingsourcetodeclare.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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