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Lecture 8

Lecture 8 - Drug Discovery.pdf

2 Pages
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Department
Pharmacology
Course Code
Pharmacology 4350A/B
Professor
Rommel Tirona

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Description
(Average 5.6 years) NDA Submission Average 12 months Hit Lead pha Identification Optimizati In silico modeling First in Human Dose In prediction of pe bility, QSAR Predict DDI absorption, metabolism CYP Phenotyping Metabolic Stability in vitro in different species Hepatocyte Metabolism Metab identifica Transporter Phenotyping Membrane Permeability Protein Binding Pharmacokinetics in rodents Pharmacokinetics in other species CL, V, F dog, monkey Mechanisms of Clearance Dose linearity in PK Metabolite ID in plasma, urine Tissue distribution studies and bile Whole body autoradiography Pharmacokinetics support of pharmacology models of dosage form development disease PK-PD relationships Biomarker validation CYP3A4 Induction Metr (in vivo) nifedipine PXR EC,o (in vitro) bosentan efavirenz phenobarbital rifabutin troglitaz nelfinavi (Average 5.6 years) NDA Submission Average 12 months Hit Lead pha Identification Optimizati In silico modeling First in Human Dose In prediction of pe bility, QSAR Predict DDI absorption, metabolism CYP Phenotyping Metabolic Stability in vitro in different species Hepatocyte Metabolism Metab identifica Transporter Phenotyping Membrane Permeability Protein Binding Pharmacokinetics in rodents Pharmacokinetics in other species CL, V, F dog, monkey Mechanisms of Clearance Dose linearity in PK Metabolite ID in plasma, urine Tissue distribution studies and bile Whole body autoradiography Pharmacokinetics support of pharmacology models of dosage form development disease PK-PD relationships Biomarker validation CYP3A4 Induction Metr (in vivo) nifedipine PXR EC,o (in vitro) bosentan efavirenz phenobarbital rifabutin troglitaz nelfinavi Lecture8 - DrugDiscovery April-21-12 8:35 PM Typesofnewdrugs - FDAspedupprocessin1990 + Biopharmaceuticalin1980 - Comesindifferentform ○ Smallmolecules+peptides+proteins 1. First-in-classdrug 2. Followerdrug - Mostlythroughtarget-basedscreeningstrategy 3. Combinationdrug 4. Modifieddrugdeliveryformulation(extendedrelease) 5. Newindicationforolddrug 6. Newrouteofadministrationforolddrug Diseases 1. Chronicdisease(CNS+metabolic+cardiovascular) 2. Lethaldisease(cancer+infectious) 3. Commondisease 4. Raredisease Drug discoverystrategies 1. Target-based - Highthroughputscreeningassaysbestservesthisstrategy ○ Automatedsysteminconductingchemical,genetic,pharmacologicaltestsandallow identificationofactivecompounds+AB+genesinvolvedinabiomolecularpathway ○ Universitiesusethistomakemoneyandallowacademiateaching - Easyrapidchemicaloptimizationofdevelopmentaldrug - Sometimesthetargetisnotactuallyrelatedtopathogenesis - Firstrationaldrugdesign:Imatinib MonoclonalAB ○ First-in-class+BCR-AB1tyrosinekinaseinhibitor - Murine="o" ○ TargetAB1tyrosinekinase3Dstructureallowedbindingpocketstructure - Chimeric="xi" ○ Discoverypre-clinicaldevelopmenttookmanyyearsbutclinicaldevelopmenttookonly3 - Humanized="zu" yearstoberegisteredonmarket - Human="u" 2. Phenotype-based - Lowthroughputtesting - Hardto optimizechemical - Ex:Ezetimibe(preventscholesterolabsorptionfromdiet) ○ Drugapprovedwithoutknowingwhatthemechanism/targetwas ○ Laterfoundtotarget NPC1L1(cholesteroltransporter)+metaboliteEzetimibeGlucuronide ismoreeffective - Strategymoresuccessfulforinfectiousdisease+CNSdiseases 3. Biologic - Whentargetisidentifiedandrelatedtopathogenesis - Successfulstrategyforimmunediseases - Ex:MonoclonalAntibodies(firstmAB=OKT3) ○ Muronomab-CD3(OKT3) (immunosuppressant) - Ex:Mono AB forPCSK9(proproteincovertasesubstillin/kexin9) ○ inc
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