Grade Statistics without Bonus with Bonus Average = 86 Median = 87 Average = 88 Median = 89 Undergraduates Average=88 MS Average=92
Jan 18, 2016
Grade Statisticswithout Bonus
with Bonus
Average = 86Median = 87
Average = 88Median = 89
Undergraduates Average=88MS Average=92
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)
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.
MS Project
• NCA Modeling Project due today• Due 9/28/15: More Comprehensive Project– Plotting– Table– NCA– Compartment Modeling (Classic)
• Grading?
MS ProjectYour Own Data to Analyze 4 Excercises
BIOAVAILABILITYLecture #14
AUC?, CMAX?, tMAX?, ka?, k?
Elimination “Rate” Limiting
~Slope Shallow
~Slope Steep
Bioavailability
Drug InteractionsMy version
Book’s Cryptic Version
Relative Bioavailability
• Dosage Forms• Different Extravascular Administration Routes • Different Conditions
Relative Bioavailability (A vs. B)
Dosage Forms
TabletCapsule
Extravascular Administration Routes
OralIntramuscular (I.M.)
Conditions
Without food With food
Urine Data
Bioavailability and Urine
Relative Bioavailability and Urine
Assessment of Product Performance
• Formulation– Biopharmaceutics– Excipients
• Bioequivalence (BE)• Bioavailability (BA) and BE Testing
Biopharmaceutics
• Physical/Chemical Drug Properties• Dosage Form (Tablet, Capsule)– Formulations (Industry)
• Route of Administration• Rate/Extent of Systemic Drug Exposure
Excipients
• Inactive stuff that you put with the drug• Natural/Synthetic• Bulking up the formulation– “bulking agents”, “fillers”, “diluents”
• Therapeutic Enhancement– drug absorption– solubility
Bioequivalence
• Essentially similar– Different Dosage Forms/Same PK
• Generic products• 0.8 to 1.25 (Test/Reference Ratio) 90% CI• AUC and CMAX
On the http://www.pharmwiki.org
NDA = New Drug ApplicationIND = Investigational New Drug Application
Not in Textbook
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
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)
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.
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
BA and BE: Considerations by the FDA
• Study Type• Dosing Frequency• What is measured? • PK? • Other• Documentation (Lots)
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)
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
Moieties to be Measured
• Preferred: Active Ingredient or moiety• Active Metabolite– [Active ingredient or moiety] too low– Contributes to safety/efficacy
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
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)
Bioavailability Example
ParametersAUCev = 0.422 (mg*hr)/L Aev = 7 mg F?AUCiv = 0.275 (mg*hr)/L Aiv = 4 mg