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

Advice for Next Test Normalized means /kg, unless otherwise specified – Normalized dose = mg/kg Don’t totally depend on the handouts – Check website for changes and updates, student questions answered, etc. Bonus Points – Rules on the (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 Project Your Own Data to Analyze4 Excercises

BIOAVAILABILITY Lecture #14

AUC?, C MAX ?, t MAX ?, k a ?, k? Elimination “Rate” Limiting ~Slope Shallow ~Slope Steep

Bioavailability

Drug Interactions My version Book’s Cryptic Version

Relative Bioavailability Dosage Forms Different Extravascular Administration Routes Different Conditions

Relative Bioavailability (A vs. B)

Dosage Forms Tablet Capsule

Extravascular Administration Routes Oral Intramuscular (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 C MAX

On the NDA = New Drug Application IND = 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 Double BlindBlind Triple BlindBlind

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 – 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: C MAX (Directly Plasma) t max – Total Exposure AUC – Partial Exposure Partial AUC MEC = Minimum Effective Concentration MTC = 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 Parameters AUC ev = (mg*hr)/L A ev = 7 mg F? AUC iv = (mg*hr)/L A iv = 4 mg