Lecture 3

Question 1

3 Potential Rate Limiting Steps to Bioavailability

Answer 1

1. Dissolution
2. Disintegration
3. Absorption

Question 2

Bioavailability

Answer 2

Rate & extent to which the active ingredient or therapeutic moiety is absorbed from a product & becomes available at the site of drug action

FDA just asked for the blood concentration of drug

Question 3

Types of Bioavailability (2)

Answer 3

1. Absolute - I.V.

2. Relative - any other dosage form (I.M. is next preferred)

Question 4

Drug Characteristics Affecting Bioavailability (4)

Answer 4

1. Dosage form/drug chemical form
2. Route of administration
3. Stability
4. Metabolism

Question 5

Cmax

Answer 5

Peak concentration of drug in blood serum, connected to bioequivalence.

Question 6

Tmax

Answer 6

Time at which Cmax is reached, connected to bioequivalence.

Question 7

AUC

Answer 7

Area under curve. Extent of drug absorption over a given amount of time. Connected to bioequivalence.

Question 8

Assessments of Bioavailability (4)

Answer 8

1. Speed and quantity
2. Absolute Bioavailability (I.V.)
3. Comparison - blood & urine
4. Relative Bioavailability or Secondary Standard when I.V. isn’t available

Question 9

Relative Bioavailability

Answer 9

• Use plasma or urine to study

- 2 different dosage forms utilized (like oral and I.M.)

Question 10

Metabolism & Bioavailability

Answer 10

Drug is broken down by mucosa, liver, bacteria, or other mechanisms in the body. This affects the bioavailability by changing the amount of drug absorbed.

Amount of Drug Absorbed = Dose * F

**F for parent drug = 1

Question 11

Dosage Forms & Bioavailability

Answer 11

Different dosage forms have different bioavailability factors. This affects the doses given by different forms.

Dose for New Dosage Form = (Amount of Drug Absorbed in Current Form) / (F of New Form)

Question 12

Chemical Form (S) & Bioavailability

Answer 12

Varying salts or ester forms of a drug affect its bioavailability. Causes you to multiply F by fraction of active moiety (S)

Amount of Drug Absorbed = S * F * Dose

Dose of New Form = (Amount Absorbed in Current Form) / (S * F)

Question 13

Calculating S

Answer 13

S = [(Molecular Weight of Parent) / (Molecular Weight of Salt Form)] * Active Moiety

Question 14

IVIVC

Answer 14

In Vitro In Vivo Concentration

Question 15

Level A IVIVC Correlation

Answer 15

BEST ONE TO HAVE

• 1:1 Relationship
• Two or more formulations
• Production modifications allowed

Question 16

Level B IVIVC Correlation

Answer 16

• Mean in vitro v.s. MRT or MDT
• Not a point-to-point correlation
• Not the best correlation, not the worst

Question 17

Level C IVIVC Correlation

Answer 17

WORST CORRELATION TO HAVE

• Single- point relationship
• Tenuous link to one parameter that ties it to IVIV data like PK parameters or dissolution parameters

Question 18

Equivalency Terms

Answer 18

• Purity
• Disintegration
• Constant Uniformity

Question 19

Alternatives Terms

Answer 19

• Therapeutic moiety
• Dosage Form
• Strength
• Controlled Release

Question 20

Therapeutic Equivalence Terms

Answer 20

• Efficacy
• Toxicity
• Same Individuals

Question 21

Bioequivalence Terms

Answer 21

AUC, Cmax, Tmax

Question 22

What are not interchangable?

Answer 22

Pharmaceutically ALTERNATIVE dosage forms

Question 23

Bioequivalence Aims

Answer 23

• Cheaper alternatives
• Therapeutically equivalent (not specifically studied) - same effectiveness desired, not less OR more
• Scientific evidence to its equivalence
• Prescribeability (PD)
• Switchability - efficacy & safety profile

Question 24

Bioequivalence Studies

Answer 24

• Based on relative bioavailability studies
• 2+ chemicals or pharmaceutical equivalent products used
• Innovator (brand) product and chemically equivalent product

Question 25

Statistical Considerations of Bioavailability

Answer 25

• must fall within 90% confidence
• between 80% & 125% of a given value
• Ex: Cmax and AUC are subject to this for bioequivalence while Tmax is observed

Question 26

Bioequivalence Statistical Criteria

Answer 26

-Two one-sided tests procedure
-T cannot be significantly less than R and vice versa
(T/R = 80% & R/T = 80%)
-Significant difference is 20%