Pharmaceutics Final

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  1. Amendments in the FDA Regulation
    • 1.) Food & Drug Act (1906): Strength & Purity
    • 2.)Food, Drug, & Cosmetic Act (1938):Safe
    • 3.) Durham-Humphrey Amendment (1951): Seperate Rx from Non
    • 4.) Kefauver-Harris Amendment (1962): Efficous & Adverse Rxns Required
    • 5.) Orphan Drug Act (1983): D Affects Fewer People
    • 6.) Drug Price Competition & Patent Term Restoration Act (1984): Generic markets Faster & Extend D Patent to 7 yr
    • 7.) Rx D User Fee Act (PDUFA): D Co. pays FDA for Quicker Review for Approval
    • 8.) Food & Drug Administration Modernization Act (1997): Extend Patent for Pediatric Studies on D
  2. 3 Main Categories of New Drug Developement
    • Discovery
    • Developement
    • Marketing
  3. Understand how a Lead Molecule is Discovered & Optimized
    • Universities, Research Institutions, & Pharmaceutical Companies
    • Isolate Active Ingredient from Traditional Remedies
    • Serendipitous (by chance) Discovery: ex. Flemming's Penicillin from Bacteria on Petri
    • New Molecule w/ Desired Biological Activity
    • Structural Changes/Modeling
    • Opt: Physio-Chemical/ADME Properties
  4. Differentiate between the types of clinical trials
    Phases 1-3 (sometimes 4)
  5. Phase I
    • 20-100 Healthy Humans
    • Single Dose
    • Start Low then Increase
    • Not Blinded
    • ~ 1 yr
    • Goals: Acute Safety & ADME
    • Adverse Effects & Safe Dosage Range
  6. Phase II
    • 100-300 w/ Disease
    • Double-Blinded & Randomized (sometimes Cross Over)
    • ~ 2 yr
    • Goals: Efficacy
  7. Phase III
    • 1,000-3,000 w/ Disease
    • Diverse (age, sex, health, etc.)
    • ~ 3 yr
    • Goal: Efficay & Safety
    • Risk v. Benefit, Dosing, etc.
  8. Understand the importance of post-marketing surveillance
    • D's Entire Life on Market
    • Office of D Safety (ODS) in Center for Drug Evaluation & Research (CDER)
    • Adverse Event/Problem--> Label Change, Box Warning, Recall, Medical & Safety Alerts
  9. Know your role in contributing toward the Med-watch program
    • Report to ODS
    • Voluntary for all Except Pharmaceutical Co.
  10. Discuss the benefit of conducting Phase IV studies after drug approval
    After D in Use; Long Term EffectsInteractions, Alternate Dosing, Response to Specific Sub Populations (age, ethnicity, etc.)Co. may conduct Post Approval Studies (^ Indications, Optimize Dosing Schedules, New Info to Label)Better Marketing (fewer Adverse Effects & better Efficacy/Cost Effectiveness than competitor)
  11. Describe Important Info that can be obtained from Time Course of D Conc in Plasma for IV Adm & for RoA Requiring Absorption
    • IV: Start @ Top then go down
    • Require Absorption: Down Up Down

    • Tpk: Time @ which Cpk is highest )how fast D works); Less Sensitive Measure of Rate of Absorption
    • Curve Shows how Long D works
    • Cpk: Max Conc; Rate of Absorption
    • AUC: Measure of Extent of Absorption
  12. Decribe how Rate of Absorption affects Time Course of D Conc in Plasma
    • Rate of Absorption Depends on how Fast D Dissentigrates
    • Fast: ^ & Early Tpk, ^ Cpk (on graph)
    • Slow: Wider Tpk, Lower Cpk
  13. Describe how Extent of Absorption affects Time Course of D Conc in Plasma
    the longer it takes to Absorb to Reach and Effective Conc the slower D works but stays in system longer
  14. Bioavailability (F)
    • Rate & Extent to which Active Ingredient in Pharmaceutical Equivalents become Available @ Site of D Action
    • Quality of D Reaching System or Extent of Drug Absorption Circulation/Quantity of D Administered
  15. Factors that Limit BioAvailability
    • Disintegration & Dissolution of D from Dosage Form
    • Absorption Characteristics of D
    • Dosage Form
    • RoA
    • Stability of A Ingredient @ Absorption Site
    • Extent of Biotransformation prior to Reaching System Circulation
  16. 1st Pass Effect & Impact on BioAvailability
    • D is Biotransformed by Enzymes Prior to Reachign Systemic Circulation
    • Decreases BioAvailability
    • Sites: Liver & GI
  17. Understand which Drugs are Most affected by 1st Pass
    Ds that are Extensively & Efficiently Metabolized
  18. Absolute BioAvailability
    • RoA/[AUC (IV)]
    • AUC (ex. Oral)/AUC (IV)
  19. Relative BioAvailability
    • RoA/Most BioAvaible RoA
    • AUC (ex. tablet)/AUC (ex. liquid)
  20. When Absolute BioAvailability is used
    Everytime (unless IV RoA BioAvailability is Not Available)
  21. When Relative BioAvailability is Used
    Only if IV RoA BioAvailability is Not Available (then use most BioAvailable)
  22. Important Legislation
    Food & Drug ActFederal Food, D, & Cosmetic Act (FFDCA)Kefauver-Harris Amendments to FFDCAAbbreviated New D Application (ANDA)Maximum Allowable Cost Program (MAC)Orange BookWaxman-Hatch Act (D Price Competition & Patent Term Restoration Act)
  23. Important Legislation which has Impacted Evaluation of BioEquivalence of Drugs
    • Orange Book
    • Waxman-Hatch Act (D Price Competition & Patent Term Restoration Act)
  24. Food & Drug Act
    • 1906
    • Strength & Purity
  25. FFDCA
    • Federal Food, D, & Cosmetic Act
    • 1938
    • New D Application (NDA)
    • New D referred to A Ingredient
    • Safety
  26. Kefauver-Harris Amendments to the FFDCA
    • 1962
    • Efficacy
    • D Efficacy Study Implementation (DESI): review for Ds b/t 1938-1962
    • New D referred to Entire Dosage form
  27. ANDA
    • Abbreviated New D Application
    • 1970
    • originally for Ds b/t 1938-1962
  28. MAC
    • Maximum Allowable Cost program
    • 1975
    • DHHS (US Dept. of Human & Health Services) Established for Reimbursement of Selected Generic Ds in Medicaid Program
  29. Orange Book
    • 1980
    • Approved D Products w/ Therapeutic Equivalence Evaluations
  30. Waxman-Hatch Act
    • D Price Competition & Patent Term Restoration Act
    • 1984
    • Applied ANDA process to Ds Marketed after 1962
  31. Therapeutic Equivalence
    • Approved by FDA as Safe & Effective
    • ~No Ds b/f 1938
    • ~No Ds Marketed b/t 1938-1962 which are Safe ~But Not Approved as Effective
    • Adequately Labeled
    • Manufactured in Compliance w/ FDA GMP (good manufacturing practice) Regulations
    • Must be Pharmaceutically Equivalent & Bioequivalent
  32. Pharmaceutical Equivalence
    • Require Same:
    • ~Amounts
    • ~Active Ingredient
    • ~Dosage Form
    • ~RoA
  33. FDA Scale used ot Rate bioEquivalence
    • (in order)
    • Pharmacokinetic (PK) Studies
    • Pharmacodynamic (PD) Studies
    • Comparative Clinical Trials
    • In vitro Trials
  34. Interpret FDA Rating for BioEquivalence w/ Regard to D Product
    • 1st Letter:
    • ~A: D Product Considered Therapeutically Equivalent to Other Pharmaceutically Equivalent Products
    • ~B: Not Equivalent
    • *BD: Active Ingredients & Dosage Forms w/ Documented BioEquivalence Problems
    • *BP: Potential
    • *BX: Data Reviewed by FDA is Insufficient to Determine Therapeutic Equivalence
    • 2nd Letter:
    • ~AA: No Bioequivalency Problems (No BioEquivalency Testing comparing Innovator & Generic)
    • ~AB: Meets Necessary BioEquivalent Requirements But Actual or Potential BioEquivalency problem Solved thru Appropriate Scientific Testing
    • 3rd #:
    • ~more than 1 Referenced Product of Same Strength Exists (generic proves equivalent to 1 or more products)
  35. How FDA Scale should be used by Pharmacists to Determine Product Selection & Substitution
    • Limits of Dating System:
    • ~Lacks Data (Comparatie BioEquivalence Data, Pre-1938 D, DESI Ds)
    • ~Difference in D Release Dosage Forms
    • ~Serious Disease (Dr. only used Brand Manufacturer--they're only/most accountable)
    • ~Narrow Therapeutic Range (NTI)
    • *D w/ Small DIff. b/t Therapeutic & Toxic Range
    • *n% of Potential Diff. could be HUGE (even if small) When giving Patient Generic Use Same 1 Every Time)
    • Only way to Assure Patient Receives Same P each time is Write for Trade Name w/ No Sub
  36. D Stability
    • Extent to which Dosage Form Retains, w/i Specific Limits & throughout its Storage & Use, the Same Properties & Characteristics that it Possessed @ Time of Manufacture
    • Expressed in terms of Shelf-Life
  37. D Instability
    D Degrades too quickly
  38. D Incompatibility
    • Visually Evident
    • *1 D Not of Suitable Composition be Combined w/ Another Excipient/Dye (D alone is not instable, just can't be mixed w/ other things)
    • *Manifests as Change in Physical State
    • * IV D (ex. w/ Saline-->forms Chrystals, Precipitation, etc.)
    • Ex. Antiobiotics or Dilante 5% Dextrose?
  39. 6 Measures of D Stability
    • 1.) Chemical Degredation (irreversible)
    • 2.)Physical Visual Apperance (Color or Clarity)
    • *Predicts Factors Affecting Chemical & Physical Stability: Temp, Moisture, pH, & Oxidation
    • 3.) Microbiological: sterility or resistence to microbial growth
    • 4.) Therapeutic: D Potency Doesn't Change
    • 5.)Toxicological: no ^ in Toxicity
    • 6.) Aesthetic: Visually Acceptable
  40. Define how you ensure drug stability
    • 3 Factors:
    • 1.)Dry Formulation (D+Excipients)
    • 2.)Environmental Conditions (heat/temp/moisture)
    • 3.)Packaging
  41. Discuss the adverse effects of instability in drug dosage forms
    • Loss of Active
    • *D P or Active Ingredient Drop b/l Label Content
    • ^ Active Conc
    • *Volatile Solvent (ex. Alburterol Alcohol Evaporates, ^ D Conc.)
    • BioAvailability Alteration
    • *Active-->Inactive D, decreases BioAvailability decreasing amount Available to be Absorbed
    • Form Toxic Degredation P
    • *Rare (ex. exposure to light)
    • Lose Content Uniformity
    • *Physical Instabilities
    • Lose Pharmaceutical Elegane & Patient Acceptability
  42. Rate Rxn
    • C (conc of reactants)-->P (products)
    • -dC/dt (Reactants Decrease as)-->+dP/dt (^ P)
    • Reactant Conc influences Rate of Chemical Rxn
  43. t 1/2
    • Half Life
    • Time Required for 1/2 Initial Conc of Reactants-->P
  44. How Rate Rxns & Half Life Relate to D Stability
    • Stabilize D in its Dosage Form
    • Assign Shelf-Life
  45. Characteristics of 1st-Order Rxns
    • Most Common in Pharmacy
    • Loss of D is Directly Proportional to Remaining Conc w/ Respect to Time
    • Amount Removed Each Time Decreases
    • Fraction of D Removed Remains Constant
  46. Characteristics of 0-Order Rxns
    • Loss of D is Independent of Conc of Reactants & Constant w/ Respect to Time
    • Same Amount of D Removed Each Time
  47. Know drug examples that undergo zero order and first order rate reactions
    • 1st Order
    • *Tablets: Paracetanel? (Acetaminophen)
    • *Soln: Omeprazole
    • *Eye Drops: Sulfacetamide
    • 0 Order
    • *Suspension: Aspirin?
  48. Discuss the factors that affect the rate of chemical instability
    • 1.) Temp
    • *RoR
    • 2.)Solvolysis
    • *Active D decomposes in Presense of Solvent (usually H2O)
    • 3.)pH & Hydrolysis
    • *Rate of Hydrolysis vary w/ pH
    • 4.)Oxidation
    • *Autooxidation: Rxn w/ Atmospheric O2 under Ambient Conditions
    • * Ps are more Electronically Conjugated
    • *Solution to Problem: ^ Stability by 1. Replace O2 w/ N2 or inert gas? 2. + Anti-Oxidant
    • 5.)Photolysis
    • *L (sun or room) provides E for Degredation
    • 6.)Racemization
    • *Enantiomers (mirror image) have diff. ADME properties & differ in Pharmacological Actions
    • 7.)Vaporization
    • *Some Ds & Excipients have ^VP @ RT; Volatilization thru Container-->Major D Loss
    • 8.)Adsorption
    • *Drug-plastic Interactions becoming Potential Problems
  49. Understand the importance of expiration date calculation for dosage forms and how they can be explained using the Arrhenius equation and activation energy
    Ea (Activation E): there must be enough E present to overcome repulsive forces b/t molecules & Allow Bonds to Break & New Bonds to Form (--> New P)
Card Set:
Pharmaceutics Final
2011-12-03 21:47:08
FDA Drug Clinical Trials

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