Bioavailability and Bioequivalence (Leonila Estole-Casanova, MD) Flashcards
Define: Bioavailability
Extent to which an active pharmaceutical agent is absorbed unchanged and becomes available in general circulation
When are two substances bioequivalent?
- Pharmaceutically equivalent or alternatives
- Similar Cmax, Tmax and AUC after administration of same molar dose under same conditions
- Essentially same effects
What is an important assumption with bioavailability?
Amount of drug reaching plasma is the amount that reaches the target site
What are the two types of bioavailability?
Absolute
Relative
How is absolute bioavailability derived?
Comparison of AUCs of extravascular and IV administration
T/F: If the drug is administered by IV, the F is 1.
True
What is the formula for absolute bioavailability?
F = (AUCPo/DosePo)/(AUCIV/DoseIV)
When is relative bioavailability used?
When there is no data from IV administration
- Expensive IV preparation
- Low solubility of drug
- Contraindications of IV route
What is the formula for relative bioavailability?
Relative Bioavailability = (AUCa)/(AUCb)
where AUCb is the reference standard exposure
What are the factors affecting bioavailability with respect to absorption?
- Variable absorption from GIT
- Drug too hydrophilic (atenolol)
- Grapefruit juice (inhibit reverse transporter)
What drugs are degraded extensively by the first pass effect?
Lidocaine and propanolol
T/F: Rate of absorption is measured by Tmax.
True
What is the range of bioavailability for IM and SC routes?
75 - 100%
What is the range of bioavailability for oral and inhalation routes?
5 - 100%
Do rectal and transdermal routes provide less first pass effect? What are their bioavailability ranges?
Yes.
Rectal - 30 - 100%
Transdermal - 80 - 100%
In bioequivalence, the (1) profiles of two formulations must be equal.
(1) plasma concentration vs. time
What is the fundamental reason for performing bioequivalence testing?
To ensure the quality of generic drug products
What is considered one of the most successful pieces of legislation passed?
Hatch-Waxman Amendments to FFD & C Act of 1984
Increased prescription of generics (from 12% - 44% in 16 years)
How long are the innovator drug patents in effect?
Around 20 years
If you are developing a generic or alternative drug, what do you have to prove?
Safety
Efficacy
Affordability
What are the NDA requirements for branded drugs?
- Chemistry
- Manufacturing
- Controls
- Labeling
- Testing
- Animal Studies
- Clinical Studies
- Bioavailability
What are the NDA requirements for generic drugs?
- Chemistry
- Manufacturing
- Controls
- Labeling
- Testing
- Bioequivalence
What are the requirements for a generic drug?
- Same active ingredients
- Same route of administration
- Same dosage form
- Same strength
- Same condition of use
Define: Pharmaceutical Alternative
Same molar amount and active pharmaceutical moieties
Different dosage form and chemical form
Give examples of pharmaceutical alternatives
Tetracycline phosphate and tetracycline hydrochloride
Metformin immediate and extended release tablets
Define: Pharmaceutical Equivalence
Same molar amount, active pharmaceutical ingredients, dosage form and route
e.g. diazepam 5 mg
Can bioequivalent substances be either pharmaceutical alternatives or equivalents?
Yes
Define: Therapeutic Equivalence
Pharmaceutical equivalents or alternatives administered in same molar dose, route and with same effects
T/F: Therapeutically equivalent drugs must be bioequivalent.
False
T/F: Pharmaceutical equivalence = therapeutic equivalence
False
Pharmaceutical equivalence is acceptable in which dosage forms?
Aqueous solutions
Powders for reconstitution
Gases
What factors contribute to the differences in drug performance in vivo?
- Drug particle size
- Excipients
- Manufacturing equipment or process
- Site of manufacture
Are bioequivalent drugs therapeutically equivalent?
They should be.
What is the battle cry of bioequivalence?
We want to be the same!
What is the standard model of testing in bioequivalence trials?
2-treatment cross-over study
There is a wash-out period.
What parameter refers to the total amount of active drug that reaches the systemic circulation?
AUC 0 - t
Cmax and Tmax assess the (1) of absorption, while AUC assesses the (2) of absorption.
(1) rate
(2) extent
T/F: If Cmax and AUC are the same, CL, Vd, k, and half life won’t be very different.
True
What is the statistical requirement for bioequivalence?
AUC and Cmax must be in between 80 - 125% for a 90% confidence interval.
Good manufacturing practices entails that the producers take proactive steps to ensure that their products are?
Safe, pure and effective
