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4. pharmacokinetics and pharmacodynamics of gamithromycin

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Text of 4. pharmacokinetics and pharmacodynamics of gamithromycin

  • 1. 1 Presenter: Ronald K Tessman, DVM, PhD, DACVIM, DACVPM

2. Special thanks to: Laura Letendre, PhD and Rose Huang, PhD For presentation development and technical assistance 3. Outline Principlesofdrugdisposition ADMEpropertiesofdrugs Routesofadministration Pharmacokinetics(PK)ofGamithromycin Absorption Distribution Clearance Pharmacodynamics (PD)Gamithromycin in lungs ComparisonofGamithromycin andTulathromycin PKparameters3 4. Drugdisposition 4 5. Pathofadruginvivo: parenteral administration Absorption Distribution Metabolism Excretion SCIV 5 Tissues/Organs SystemicCirculation FreeDrug BoundDrug Liver Drug&Metabolite Drug& Metabolite Intestine Drug& Metabolite Excretionin Urine Excretionin Feces Absorption BiliaryExcretion Distribution Absorption 6. Parenteral routes Epidermis Dermis Subcutaneous Fattissue Muscle 6 7. Fastacting Gamithromycin pharmacokinetics Absorptionandsystemicexposure 7 8. Pharmacokineticsstudy Treatmentgroups 3mg/kgIVdose;n=12 3,6,or9mg/kgSC;n=4/group Cattlecharacteristics 12malecastrateand12femaleanguscattle Lessthan1yearold Weight=182to260kg Analysis Gamithromycin plasmaconcentration Pharmacokinetics PR&D0099101:EvaluationofthepharmacokineticprofileofGamithromycin inplasmafromcattletreated withasingleintravenousdose(3mg/kg)orasinglesubcutaneous doseat3,6,or9mg/kgofGamithromycin. 8 9. Completeabsorptionof Gamithromycin PR&D0099101 9 Fast,complete absorption Predictable Pharmacokinetic profile Time(day) GamithromycinConcentration(ng/mL) 10. 0 20 40 60 80 100 120 140 160 180 200 0 2 4 6 8 10 12 Time (hour) Gamithromycin PlasmaConcentration(ng/mL) Prolongedabsorptionphaseof Gamithromycin PR&D0099101 Absorptionrate=Eliminationrate 10 Fastabsorption 80%ofmax within15mins Maxwithin1Hr Highconcentrations maintainedfor6Hrs plateau30minto6 Hrs 11. Doseproportionality Doseadjustmentsare madewiththe assumptionofdose proportionality PR&D0099101 Targetdose ZACTRANhasa predictableresponse 11 12. Summaryofpharmacokineticresults Absorptionisfast 80%ofmaxwithin15minutes Maximumwithin1hour Absorptioniscomplete Bioavailabilityis100% Predictableandproportionalexposurewithdose from3to9mg/kg 12 13. Longlasting Gamithromycin pharmacokinetics Clearanceanddistribution 13 14. Definitions 14 15. Concentrationgradient drivingdistribution PlasmaProtein Tissue Plasma Extracellular fluid Membrane 15 Gamithromycin plasmaproteinbinding=26% 16. Volumeofdistribution: aproportionalityconstant PlasmaProtein Tissue Plasma Extracellular fluid Membrane Amountofdruginthebody(t)=Vd *plasmaconcentration 16 17. Volumedistribution 17 18. Physicalchemicalproperties ImportanttoPK LogP:preferencefor wateroroil? Solubilityinwater pKa:howmuchdrugis ionizedateachpH? 18 www.molecularstation.com 19. Gamithromycin Physicalchemicalproperties Lipophilic LogP=4.69 HighH2Osolubility 50mg/mL Dibasic pKa =9.78and8.88 19 O O Me O O Me HO OH H Me N Me H H H Me O O R S S R R R S R S R Me OH OMe Me OH Me HO N H3C CH3 Me 1 15 14 13 12 11 109 8 7 6 5 4 3 2 20. IonizationofGamithromycin inplasma PlasmapH7.4;pKa =9.78 20 pH=pKa 2~100%ionized IfpH=pKa 1:1ratio pH=pKa +2~100%neutral Ionized Neutral Neutral1 Ionized240 21. Iontrappingallowslungaccumulation Membrane Membrane Neutral1: Ionized380Neutral1:Ionized240 Neutral1:Ionized95000 Plasma pH7.4 Cytosol pH7.2 Macrophage Acidic e.g.pHof4.8 21 NonIonizedNonIonized NonIonizedNonIonized ForapKa of9.78 22. Pulmonarydistributionstudy Treatmentgroups 6mg/kgSC;n=33 Cattlecharacteristics 18maleand15female,crossbredbeefcalves Aged78months Weight100300kg Gamithromycin analysis Plasma Lungtissuehomogenate Otherbiofluids PR&D0198501:EvaluationoftheDurationoftheConcentrationof Gamithromycin inPlasma,PELF,LungTissueHomogenate,BALCellsinCattleusinganLCMSMethodthroughoutaTherapeuticTimePeriod 22 23. Gamithromycin tissuedistribution 10daysafterdosing Systemiccirculation Tissues/Organs PR&D0198501 23 Above MIC Ratio 487:1 24. Lungandplasmapharmacokinetics PR&D0198501 24 25. Metabolismstudy Treatmentgroups 6mg/kgSC;n=14 Cattlecharacteristics 7steersand7heifers,healthybeefcalves Aged67months Weight190240kg Gamithromycin analysis Plasma Fecesandurine Tissuesandorgans Liver,kidneys,lungs,muscle,abdominalfatandinjectionsite TotalradioactiveresiduesofGamithromycin Metaboliteprofiles PR&D0078101:DistributionandExcretionofTotalResiduesaftertheSubcutaneousDosinginCattlewithGamithromycin andPR&D0078501:MetaboliteProfilesinSelectedCattleTissueSamplesfromPR&D0078101 25 26. EliminationofGamithromycin PR&D0078101,PR&D0078501 26 Drug metabolism islimited Metabolites proven inactiveand safe 27. SummaryofGamithromycin Metabolism/distributionstudies Proteinbindingislow(26%) Extensivetissuedistribution Lung>>plasma Intracellulariontrappinginthelung Quicksystemicclearanceoffreedrug Excretedprimarilyunmetabolizedinthebile Metabolitesarenotactive 27 28. Effectivelyconcentrates inthelung Gamithromycin pharmacodynamics 28 29. 29 30. TimedependenceofGamithromycin activity PostantibioticEffect(PAE)describeswhat happenstothetestorganismafterthe antibioticisremoved Commonformacrolide class Gamithromycin PAEfrom4.1to8.6hours Consistentwithotherreportedmacrolides 30 31. Gamithromycin concentration dependencestudied 31 PR&D0169301:ActivityoftheGamithromycin againstHistophilus somni strains associatedwithbovinerespiratorydisease:Determinationofantibacterialkillkinetics. 32. Bronchoalveolar lavage study Treatmentgroups 6mg/kgSCintheneck;n=33 Cattlecharacteristics Crossbredbeefcalves 78monthsold 100300kg Analysis Gamithromycin concentrationsinthe Plasma PulmonaryEpithelialLiningFluid(PELF) Lungtissuehomogenate Bronchoalveolar lavage (BAL)cells Pharmacokinetics 32 PR&D0198501:EvaluationoftheDurationoftheConcentrationof Gamithromycin inPlasma,PELF,LungTissueHomogenate,BALCellsinCattleusinganLCMSMethodthroughoutaTherapeuticTimePeriod 33. Uptakekineticsinclinicallyrelevant tissuesandfluids PR&D0198501:DispositionofGamithromycin inplasma, pulmonaryepithelialliningfluid,bronchoalveolar cells,andlungtissueincattle PELF (PulmonaryEpithelialLiningFluid) Alveolarmacrophages CapillaryWall InterstitialFluid Alveolar Epithelium Bronchoalveolar biophase 33 34. Bronchoalveolar lavage Use QuantificationofGamithromycin intheBALfluid BALfluid Pulmonaryepithelialliningfluid&cellcontent (predominatelyalveolarmacrophages) Firstlineofdefenseagainstcommensals andinvading pathogens Strongsupportforfastactingandlonglasting 34 35. 1 10 100 1000 10000 100000 0 2 4 6 8 10 12 14 16 Time, days GamithromycinConcentration Lung (ng/g) BAL cells (ng/mL) PELF (ng/mL) MIC of 1 ug/mL Therapeuticlungconcentrations PR&D0198501 Peaklungconcentration(12hrs) 35 Fast bacteriakill Rapid therapeutic efficacy 36. Therapeuticlungconcentrations PR&D0198501 36 BALandlunghomogenatehavehighexposure (AUC). Concentrationsarereachedquickly aboveMICin 30mins. Longlasting:aboveMICfor1015days. 37. TimeaboveMIC PR&D0198501 37 AboveMICin BALcellsfor15 days Figure 1. Time over which concentrations of gamithromycin in lung tissues exceed MIC90 0 5 10 15 20 M. haemolytica P. multocida H. somni Time in days BAL cells Whole lung PELF 1.0H. somni 1.0P. multocida 0.5M. haemolytica MIC90 g/mlEuropean BRD isolates 38. Conclusionsandclinicalrelevance Fastabsorption PreferentialconcentratesinPELF,BALcellsandlungtissue ConcentrationsinexcessoftheMIC90 forthecommon bacterialpathogens: Mannheimia haemolytica Pasteurella multocida Histophilus somni Presentinspecificbiophases within30minutesof administration Persistsfor7days(PELF)togreaterthan15days(BALcells andlungtissue)followingadministrationofasingledose Summary PR&D0198501 38 39. ZACTRAN ComparisontoTulathromycin 39 40. Tulathromycin references Nowakowski, M.A., et al., "Pharmacokinetics and Lung Tissue Concentrations of Tulathromycin a New Triamilide Antibiotic Cattle" Veterinary Therapeutics. 5. 1. 2004. Print. Evans, N. "Tulathromycin: An Overview of a New Triamilide Antimicrobial for Livestock Respiratory Disease" Veterinary Therapeutics. 6. 2. 2005. Print. 40 41. PharmacokineticKcomparison ZACTRANData:PR&D0198501 Tulathromycin Data:VeterinaryTherapeuticsV5,N1,Spring2004,p60. 41 Tulathromycin Lung Gamithromycin Lung Gamithromycin Plasma 42. Pharmacokineticcomparison Absorptionanddistribution 42 Fastacting Gamithromycin lungconcentrations>MICwithin15mins HigherconcentrationsthanTulathromycin inlung 43. Pharmacokineticcomparison Clearance 43 Fastuptakeplasmatotissue Persistentactivityintissue Efficientterminalelimination 44. Pharmacokineticcomparison Distribution 44 Gamithromycin: higherlungconcentrations 45. Conclusion Alladvantagesassociatedwiththemacrolide class Fastandcompleteabsorption Fastandextensivelungdistribution Lungconcentrations>MIC From15minutes(FastActing) To1015days(LongLasting) Effectivelyconcentratesinthelungtissuefaster thanTulathromycin 45 46. Questions 47. 1 10 100 1000 0 1 2 3 4 5 6 7 8 9 10 11 12 13 GamithromycinPlasmaConcentration (ng/mL) Time (day) Pharmacokineticsatthe Recommendeddoseof6mg/kgSC PR&D0099101 47 Fastabsorption