Pharmacokinetics Fibrosis Patients - cshp-ab.cacshp-ab.ca/_CMS/Files/Calgary CF Pharmacokinetic talk.pdf 

  • View
    214

  • Download
    0

Embed Size (px)

Text of Pharmacokinetics Fibrosis Patients - cshp-ab.cacshp-ab.ca/_CMS/Files/Calgary CF Pharmacokinetic...

  • PharmacokineticsinCysticFibrosisPatients

    AnnualGeneralMeetingoftheAlbertaBranchoftheCanadianSocietyofHospitalPharmacists(CSHPAB).

    Jackson Wong, MB.BS, FRCPCH, FRCP(Edin)JacksonWong,MB.BS,FRCPCH,FRCP(Edin)PediatricRespirologist,UniversityofAlberta

    jywong2@ualberta.ca

  • Terms of UseTermsofUse

    Th t i l i thi df fil i id d tThematerialsinthispdf fileisprovidedtoyou

    solelyforpersonaluse.Itisnotfordistributiony p

    ortobeusedforanyotherpurposewithoutthe

    permissionoftheauthor.

  • DisclaimerDisclaimer

    Thepresentationisbasedonmypersonalexperienceandp y p popinion

    ThispresentationdoesnotrepresenttheopinionofthefollowingorganizationsorcommitteesthatIserve:

    HealthCanada ExpertAdvisoryCommitteeinCells,TissuesandOrgans CanadianSocietyofTransplantationStandardCommittee,Communication

    Committee

    i l di i l ll b i S InternationalPediatricLungTransplantCollaborative,Secretary InternationalSocietyofHeartandLungTransplantation,RegistryWorkgroup

  • Goals and ObjectivesGoalsandObjectives

    Discuss CF therapeutic goalsDiscussCFtherapeuticgoals

    DiscusstheimpactofPK,drugdeliveryanddosinginpatientswith

    CFCF

    Examples

    I t i l id (t b i ) Intravenousaminoglycosides(tobramycin)

    Oralmacrolides (azithromycin)

    Inhaled antibiotics (a treonam and tobramycin) Inhaledantibiotics(aztreonam andtobramycin)

    PharmacokineticsofIVtobramycin inCFpre andpostlungtransplant

  • LetsTakeACloserLook

    Astroham.com

  • GeneralConcepts

    CFPharmokinetics

    Astroham.comqbn.com

  • CF PharmacokineticsCFPharmacokinetics

    POTENTIALFACTORS Absorption

    gastricacidhypersecretion, bileacidmalabsorption bioavailabilityoflipidsolubledrugs proximal small intestinal mucosal injuryproximalsmallintestinalmucosalinjury

    Distribution Hypoalbuminaemia reducedproteinbinding

    H l b li i Hypergammaglobulinaemia Increasedvolumeofdistribution reducedadiposetissue,moreleanmass

    Elimination Increasedrenalclearance Increasedmetabolicclearance

    Increasedhepaticbloodflow Phase I & II hepatic biotransformation PhaseI&IIhepaticbiotransformation

    D.J.Touw,PharmWorldSci1998,ERay,ClinPharmacokinet1998.JPrandota,AmJTher2011.

  • CF PharmacokineticsCFPharmacokineticsPOTENTIALFACTORS

    Others

    DiseasestateandlowFEV1Multidrug resistance 1 (MDR1) gene polymorphism P glycoprotein (P gp) Multidrugresistance1(MDR1)genepolymorphism Pglycoprotein(Pgp)

    transmembraneATPdependentpump

    Dosedependentpharmacokinetics Pgpcapacity

    Enterohepaticrecirculationofdrugs

    Neonatalpharmacokinetics tissueaccumulation

    Viralinfectionsand/orchronicinflammationsanddepressionofmetabolism

    (CYP450)

    D.J.Touw,PharmWorldSci1998,ERay,ClinPharmacokinet1998.JPrandota,AmJTher2011.

  • Aminoglycosides

    IVDosingg

    Cell.com

  • TobramycinTobramycin

    R id b t i id l t ti d d t Rapidbactericidal,concentrationdependent

    Inhibitbacterialproteinsynthesis,especiallyaerobicgramnegativebacteria

    Drivenbythemembraneelectricalpotential(interiornegative),itdiffuses

    through aqueous channels formed by porin proteins in the outer membrane ofthroughaqueouschannelsformedbyporin proteinsintheoutermembraneof

    gramnegativebacteriaandentertheperiplasmic space

    ThisratelimitingprocesscanbeblockedorinhibitedbyareductioninpHor

    anaerobicconditions,asinanabscess

    H.W.TaberMicrobiolRev1987,VBraunJInfectDis2001,DSchlessingerCMR1988

  • Elective IV Tobramycin q8 vs q24 hrsElectiveIVTobramycin q8vs q24hrs

    RxA:q8hrs,RxB:q24hrsIVtobramycin30childrenage11.2yrs(1.718.1)Changesinperipheralbloodleukocytes,P.aeruginosa,bodyweightandinFEV1after14daysofantibiotictreatmentandat3weeks after the end of the treatmentweeksaftertheendofthetreatmentcycle.

    J.Riethmueller.Infection2009

  • Elective IV Tobramycin q8 vs q24 hrsElectiveIVTobramycinq8vs q24hrsNephrotoxicity oftobramycinwasassessedbymeasuringfirstmorningi t ti f N t l burineconcentrationsofNacetylb

    Dglucosamini dase(bNAG)anda1microglobulinandbydeterminationofproteinuriausingp gSDSPAGEHearing assessedbystandardaudiometryNo stat significant difference in any

    Urinary excretion of Nacetylb

    Nostatsignificantdifferenceinanyofthese

    UrinaryexcretionofN acetyl bglucosaminidase(bNAG)during(day1and14)andaftercourseA(day35).logarithmicscale;boxl t h i di 25% 75%plotshowingmedian,25%75%,

    minimum,maximum.

    J.Riethmueller.Infection2009

  • IVAminoglycosidePharmacokinetics1compartmentvs.2compartmentmodel

    Aprospective,crossovertrial CFadultpatients,pseudomonas+ve Acutepulmonaryexacerbation 3.3mg/kgevery8horasingle10

    mg/kg on day1mg/kgonday1 Crossoveronday2

    Parameter Mean S.D. Range

    Males/females 4/2 Age (years) 29.0 4.6 2334Height (inches) 65.5 1.3 6468TBW (kg) 55.3 13.8 4575

    Bloodsamples(5mL)wereobtainedfromanindwellingvenouscatheterpriortoadministration,attheendofinfusion,then at 10 20 30 45 60 90 120 240

    TBW, total body weight; BSA, body surface area; BMI, body mass index;

    ( g)BSA (m2) 1.6 0.2 1.471.87BMI (kg/m2) 19.7 3.2 16.525.9CLCR (mL/min/1.73 m2) 127.0 5.8 120.6132.9

    thenat10,20,30,45,60,90,120,240and450minpostdose.

    Anadditionalsampleat720minwasCLCR, creatinine clearance.

    A.Aminimanizani1,JAC0250553

    obtainedfollowingtheadministrationofthe10mg/kgdose.

  • IVtobramycin q8hrsdosing

    A.Aminimanizani1,JAC0250553

  • IVtobramycin q24hrsdosing

    A.Aminimanizani1,JAC0250553

  • IV Aminoglycoside PharmacokineticsParameter q8h [median (interquartile range)] q24h [median (interquartile range)] P value

    t (h) 0.54 (0.401.05) 0.40 (0.261.02) 0.39t (h) 3 07 (2 67 5 83) 2 72 (2 22 3 70) 0 18

    IVAminoglycosidePharmacokinetics

    t (h) 3.07 (2.675.83) 2.72 (2.223.70) 0.18Vc (L/kg) 0.20 (0.140.25) 0.16 (0.110.24) 0.39Vss (L/kg) 0.38 (0.260.46) 0.31 (0.220.33) 0.06CLt (mL/min/kg) 2.02 (1.372.46) 1.68 (1.302.04) 0.39CLd (mL/min/kg) 1.17 (0.492.44) 1.61 (0.532.14) 0.59AUC (mgh/L) 97 34 (77 58122 5) 107 7 (95 74123 1) 0 85AUC24 (mg h/L) 97.34 (77.58122.5) 107.7 (95.74123.1) 0.85Cmax (mg/L) 14.0 (11.519.3) 35.9 (33.245.8) Cmin (mg/L) 0.9 (0.81.2) C12 1.4 (0.81.5)

    t, distribution half-life; t, elimination half-life; Vc, volume of central compartment; Vss, steady-state volume; CLt, total clearance;CLd, distribution clearance; AUC24, area under the curve in 24 h; Cmax, maximum serum concentration; Cmin, minimum serum concentration;C12, concentration 12 h after start of infusion.

    ThedistributionphaseT of32and24min(q8handq24hregimens)relativelylong Distribution phase 94% competed after 4 T hence time for peak level @ 2 hrs Distributionphase94%competedafter4T hencetimeforpeaklevel@2hrs. TheeliminationT of3.1and2.7h(q8handq24hregimens)relativelyshortandreflectthe

    excellentrenalfunction.

    NostatisticallysignificantdifferencesinanyofthePKparametervaluesbetweendoses

    A.Aminimanizani1,JAC0250553

    y g y p

    Asignificantve correlationwasnotedbetweenBSAandT withtheq24hregimen(r=0.89,P=0.03);nosimilarcorrelationwasseenwiththeq8hregimen.

  • IVAminoglycosidePharmacokinetics

    Table 2. Model discrimination when using a one- or two-compartment model to describe the individual i

    1compartmentvs.2compartmentmodel

    serum time curves

    q8h q24h

    t t t t t t t t t tone-compartment two-compartment one-compartment two-compartment

    Patient r2 AIC r2 AIC r2 AIC r2 AIC

    1 0.94 44.70 0.98 20.36 0.97 69.75 1.00 47.102 0.93 49.89 0.99 18.73 0.88 194.92 0.97 179.453 0.86 60.60 0.99 15.39 0.96 42.32 1.00 31.124 0.79 136.93 0.94 36.03 0.90 85.98 0.99 59.485 0.67 235.33 0.97 15.71 0.90 100.74 0.98 40.566 0 93 73 68 0 99 14 67 0 98 45 17 1 00 35 31

    AIC, Akaike information criteria.

    6 0.93 73.68 0.99 14.67 0.98 45.17 1.00 35.31

    The pharmacokinetics of tobramycin administered either once daily or every 8 h

    A.Aminimanizani1,JAC0250553

    Thepharmacokineticsoftobramycinadministeredeitheroncedailyorevery8hwerebestdescribedbyatwo compartmentmodel,asshownbythelowerAIC(aninformationcriterion)andhigherr2values

  • TOPIC Study Pharmacokinetic AnalysisTOPICStudyPharmacokineticAnalysis

    ASmyth.Lancet2005

  • Volumeofdistributionk b d h dperkgbodyweightandage

    Nonlinearregression,R2 =0.3,N=136,p

  • Renaleliminationrateperml/min/1.73m2 creatinineclearanceandage.

  • TOPIC Study Pharmacokinetic AnalysisTOPICStudyPharmacokineticAnalysis TheVdwassignificantlygreaterwitho.d.Rxcomparedtot.i.d.inchildren.No

    straightforward explanation for the difference in volume of distribution.straightforwardexplanationforthedifferenceinvolumeofdistribution.

    Theeliminationrateoftobramycin,foro.d.,wasprolongedcomparedwitht.i.d.dosinginbothchildrenandadults

    AsignificanttrendforasmallerVd/kgoftobramycinwithincreasingage

    With a good total body clearance of tobramycin serum C largely depends on Vd Withagoodtotalbodyclearanceoftobramycin,serumCpeak largelydependsonVd

    MeanVd/kgbodyweightis0.363l/kg(Ped),0.294(adult),p

  • TOPIC Study Pharmacokinetic AnalysisTOPICStudyPharmacokineticAnalysis

    AsignificantlylowermeanvaluesforKelr(pedandadult)inpatientpopulationsrandomisedtoo.d.comparedwitht.i.d.administration.

    Ameanrateofelimination30%lessinthepopulationreceivingq24hrsIVtobra.

    AlowerKelr(pedandadult)o.d.groupsmaybetheresultofacircadianrhythmindrugclearancecausedbyeither

    i i d activityandrestor dietaryproteinintakeor bothcombined

    i h h d i i i f h i d i h d il i h l withtheadministrationoftheactivedoseintheoncedailygroupintheearlyevening.

  • Rationale of the single daily do