grade statistics without bonus with bonus average = 86 median = 87 average = 88 median = 89...
TRANSCRIPT
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Grade Statisticswithout Bonus
with Bonus
Average = 86Median = 87
Average = 88Median = 89
Undergraduates Average=88MS Average=92
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Advice for Next Test
• Normalized means /kg, unless otherwise specified– Normalized dose = mg/kg
• Don’t totally depend on the handouts– Check www.pharmwiki.org website for changes
and updates, student questions answered, etc.• Bonus Points– Rules on the www.pharmwiki.org (0.5 and 1.0
points)
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Advice for Next Test
• Multiply Normalized Values by the weight.– V Normalized = 0.1 L/kg – V = 0.1 L/kg * 70 kg = 7L
• (Experts Only) Keep normalized values consistent.
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MS Project
• NCA Modeling Project due today• Due 9/28/15: More Comprehensive Project– Plotting– Table– NCA– Compartment Modeling (Classic)
• Grading?
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MS ProjectYour Own Data to Analyze 4 Excercises
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BIOAVAILABILITYLecture #14
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AUC?, CMAX?, tMAX?, ka?, k?
Elimination “Rate” Limiting
~Slope Shallow
~Slope Steep
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Bioavailability
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Drug InteractionsMy version
Book’s Cryptic Version
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Relative Bioavailability
• Dosage Forms• Different Extravascular Administration Routes • Different Conditions
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Relative Bioavailability (A vs. B)
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Dosage Forms
TabletCapsule
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Extravascular Administration Routes
OralIntramuscular (I.M.)
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Conditions
Without food With food
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Urine Data
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Bioavailability and Urine
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Relative Bioavailability and Urine
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Assessment of Product Performance
• Formulation– Biopharmaceutics– Excipients
• Bioequivalence (BE)• Bioavailability (BA) and BE Testing
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Biopharmaceutics
• Physical/Chemical Drug Properties• Dosage Form (Tablet, Capsule)– Formulations (Industry)
• Route of Administration• Rate/Extent of Systemic Drug Exposure
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Excipients
• Inactive stuff that you put with the drug• Natural/Synthetic• Bulking up the formulation– “bulking agents”, “fillers”, “diluents”
• Therapeutic Enhancement– drug absorption– solubility
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Bioequivalence
• Essentially similar– Different Dosage Forms/Same PK
• Generic products• 0.8 to 1.25 (Test/Reference Ratio) 90% CI• AUC and CMAX
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On the http://www.pharmwiki.org
NDA = New Drug ApplicationIND = Investigational New Drug Application
Not in Textbook
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BA and BE Testing: Study Types
• Longitudinal Study – Same Subjects over a Period of Time– Cohort (Defined)/Panel (Cross-Section)– Retrospective
• Clinical Trials– Randomized– Crossover– Blind, Double blind and Triple Blind
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Randomized vs. Crossover Clinical Trials
Tablet
Patient 1
Capsule
Patient 2
Placebo
Patient 3
Randomized (Treatments Random)
Tablet
Capsule
Placebo
Capsule
Tablet
Placebo Tablet
Capsule
Placebo
Patient 1 Patient 2 Patient 3
Crossover (Sequence of Treatments Random)
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Randomized vs. Crossover Trials
• Randomized– Pros
• Relatively simple to execute.• Not susceptible to carry-over effects.
– Cons• Wide variation significant error in the analysis.
• Crossover– Pros
• Compare treatments with a patient, so variation between patients is eliminated
– Cons• Susceptible to carry-over effects.
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Blind Clinical Trials
Patient Receiving the Drug
Person Administering the Drug
Person Overseeing the Trial
Blind Blind
Double Blind Blind Blind
Triple Blind Blind Blind Blind
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BA and BE: Considerations by the FDA
• Study Type• Dosing Frequency• What is measured? • PK? • Other• Documentation (Lots)
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Study Type
• Pilot Study– 8-12 Subjects
• Full-Scale– 24-34 Subjects
• >18 years old and healthy • Cohort or Panel– (gender?)
• Fasting conditions (>10 hours overnight)
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Dosing Frequency
• Single Dose– Preferred– Easier to assess PK parameters than multiple dose
(steady state)• Multiple Dose– Differences absorption rate, not the extent of
absorption.– Excessive variability in bioavailability (BA)– [drug]plasma too low with single dose– Extended release dosage form
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Moieties to be Measured
• Preferred: Active Ingredient or moiety• Active Metabolite– [Active ingredient or moiety] too low– Contributes to safety/efficacy
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PK?
• Appropriate Fluid: blood, plasma, serum• PK– Peak Exposure:• CMAX (Directly Plasma)
• tmax
– Total Exposure• AUC
– Partial Exposure• Partial AUC
MEC = Minimum Effective ConcentrationMTC = Minimum Toxic Concentration
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Other
• In vitro to human in vivo correlation (IVIVC)– in vitro dissolution/drug-release characterization
• PD studies– not recommended for orally administered drugs– PK measurements preferred (More
accurate/sensitive/reproducible)– only if PK fails
• Clinical Endpoints (e.g. Cured) (Rare)• In vitro (e.g. dissolution testing)
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Bioavailability Example
ParametersAUCev = 0.422 (mg*hr)/L Aev = 7 mg F?AUCiv = 0.275 (mg*hr)/L Aiv = 4 mg