Virtual Drug Development in SouthernCalifornia, A Pre-Clinical Focusin vitro tests to support IND submissionsDavid Johnson...
Development of a SuccessfulNew DrugSource: PMA
Drug Development Path/LifecycleDiscoveryLeadSelectionOptimization I II IIIClinical DevelopmentPreclinicalDevelopmentDevelo...
Ideal Drug Candidate Wish Listfrom a DMPK Perspective• Good aqueous solubility for i.v. formulation and oral absorption• H...
ADME Issues & in vitro Studiesto Address ThemSmall Molecule ADME IssuesAbsorption Clearance/Metabolism DistributionPoor me...
Primary Components of anIND ApplicationThe IND application must contain information in three broad areas:•Animal Pharmacol...
DMPK Studies Typically Includedin IND Submissions• Plasma Protein Binding– Used to assess free fraction• Drug-Drug Interac...
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Presentation by MicroConstants at BIOCOM CRO event May 2013: Virtual Drug Development in Southern California: A Pre-Clinical Focus

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May 2013
8-10am
Location: BIOCOM
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Joining the presenters for a follow-on panel discussion will be: Jennifer Spinella, Vice President, Regulatory Affairs & Quality Assurance at Rare Disease Therapeutics Greg Ruppert, Sr. Study Director and Director of Sales for MPI Research Richard Lin, CEO of Explora Biolabs.

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Presentation by MicroConstants at BIOCOM CRO event May 2013: Virtual Drug Development in Southern California: A Pre-Clinical Focus

  1. 1. Virtual Drug Development in SouthernCalifornia, A Pre-Clinical Focusin vitro tests to support IND submissionsDavid Johnson, Ph.D.Director, DMPKMicroConstants, Inc.(858) 652-4600www.microconstants.comMay 9, 2013
  2. 2. Development of a SuccessfulNew DrugSource: PMA
  3. 3. Drug Development Path/LifecycleDiscoveryLeadSelectionOptimization I II IIIClinical DevelopmentPreclinicalDevelopmentDevelopmentcandidateIND FIH NDA Marketeddrug
  4. 4. Ideal Drug Candidate Wish Listfrom a DMPK Perspective• Good aqueous solubility for i.v. formulation and oral absorption• High bioavailability and acceptable PK characteristics for intended route/dosingregimen• Small first-pass effect• “Balanced” clearance:– Renal excretion of intact drug– Biliary elimination of intact drug– Metabolism to limited number of products• Moderate plasma protein binding (<90%)• Minimal P-450 inhibitory potential (especially mechanism-based)• Metabolism should be catalyzed by multiple CYP enzymes, e.g., CYP3A4, 2C9,1A2• Metabolism should not depend largely on polymorphically-expressed P-450,e.g., CYP2D6, 2C9, 2C19• Key human metabolites also present in tox speciesSource: Carlson, Tim (Amgen). In vitro ADME Assays & Techniques,CACO/BAADME Workshop, March 28, 2013.
  5. 5. ADME Issues & in vitro Studiesto Address ThemSmall Molecule ADME IssuesAbsorption Clearance/Metabolism DistributionPoor membrane permeabilityExtensive P-glycoprotein effluxPoor physicochemical propertiesExtensive gut metabolismExtensive hepatic metabolismInstability in biological fluidsEnzyme induction or inhibitionRapid transporter-mediatedexcretionExtensive protein bindingInadequate CNS penetration• Caco-2 cell permeability• MDCK cell permeability• Caco-2 P-gp screen• Inhibition of P-gp activity• Solubility, log P, log D, pKa• Caco-2 stability• Microsome stability• Microsome stability• S9 stability• Hepatocyte/Tissue slices• Preliminary metabolite ID• Plasma stability• Promoter/reporter gene/cell-basedexperiments• P450 mRNA, protein or activitymeasurements (treated hepatocytes)• Enzyme-specific inhibition studies• Renal/biliary transporter activity• Ultrafiltration/Ultracentrifugation• Equilibrium dialysis• In situ perfusion studies• Brain/CSF collectionSource: Jang, Harris, and Lau,2001, Medicinal ResearchReviews 21:382
  6. 6. Primary Components of anIND ApplicationThe IND application must contain information in three broad areas:•Animal Pharmacology and Toxicology Studies - Preclinical data to permit anassessment as to whether the product is reasonably safe for initial testing in humans.Also included are any previous experience with the drug in humans (often foreign use).•Manufacturing Information - Information pertaining to the composition, manufacturer,stability, and controls used for manufacturing the drug substance and the drug product.This information is assessed to ensure that the company can adequately produce andsupply consistent batches of the drug.•Clinical Protocols and Investigator Information - Detailed protocols for proposedclinical studies to assess whether the initial-phase trials will expose subjects tounnecessary risks. Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimentalcompound--to assess whether they are qualified to fulfill their clinical trial duties. Finally,commitments to obtain informed consent from the research subjects, to obtain review ofthe study by an institutional review board (IRB), and to adhere to the investigational newdrug regulations.Source: http://www.fda.gov/cder/Regulatory/applications/ind_page_1.htm
  7. 7. DMPK Studies Typically Includedin IND Submissions• Plasma Protein Binding– Used to assess free fraction• Drug-Drug Interaction (DDI) Studies– CYP inhibition / induction– Reaction phenotyping– Transporter inhibition / substrate• Metabolite Profiling

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