Grade Statistics without Bonus with Bonus Average = 86 Median = 87 Average = 88 Median = 89 Undergraduates Average=88 MS Average=92.

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