PHA 337 - Bioequivalence and Drug L5

Bioavailability

The rate and extent to which a drug is absorbed from a dosage form and becomes available in systemic circulation

What two things does bioavailability measure?

Rate and extent of drug absorption

What is the bioavailable fraction (F)?

The fraction of administered drug that reaches systemic circulation unchanged

What is the bioavailability of IV drugs?

F = 1.0 or 100%

Why is IV bioavailability 100%?

The drug enters systemic circulation directly

What is the bioavailability range for extravascular administration?

0 to 1

What does F = 0.75 mean?

75% of the drug reaches systemic circulation

What does bioavailability NOT measure?

Drug concentration at the site of action

Which oral dosage form has the fastest bioavailability?

Solution

Which oral dosage form has the slowest bioavailability?

Controlled release tablet

Order oral dosage forms from fastest to slowest bioavailability

Solution > Suspension > Capsule > Tablet > Coated tablet > Controlled release tablet

Why do solutions have the fastest bioavailability?

The drug is already dissolved

Why do controlled release tablets have slow bioavailability?

The drug is released slowly over time

What happens first before absorption of a tablet?

Disintegration

What happens after disintegration?

Deaggregation into fine particles

What must happen before a drug can be absorbed?

Dissolution into solution form

What dosage form skips the disintegration step?

Suspension

What dosage form goes directly to absorption?

Solution

What is pharmaceutical equivalence?

Two products contain the same amount of API, same dosage form, same purity, content uniformity, and disintegration rate

What is bioequivalence?

Two drug products have similar bioavailability when administered the same way

What parameters are compared in bioequivalence?

AUC, Cmax, and Tmax

Why is bioequivalence important?

It is the main requirement for generic drug approval

What is pharmaceutical alternative?

Two products contain the same API but differ in crystal form, salt form, ester form, or release characteristics

Are pharmaceutical alternatives interchangeable?

No

What is therapeutic equivalence?

Two products produce the same therapeutic and toxic effects

What is absolute bioavailability?

Comparison of bioavailability between IV administration and another route

What route must be included in absolute bioavailability studies?

IV administration

What is relative bioavailability?

Comparison of bioavailability between two dosage forms

Examples of relative bioavailability comparison

Solution vs tablet or solution vs capsule

What additional parameters must be compared in relative bioavailability?

Cmax and Tmax

What is AUC?

Area under the plasma concentration versus time curve

What does AUC represent?

Extent of drug absorption

What does Cmax represent?

Maximum plasma concentration

What does Tmax represent?

Time required to reach maximum plasma concentration

Which parameter reflects rate of absorption?

Tmax

Which parameter reflects extent of absorption?

AUC

Formula for absolute bioavailability

F = (AUC oral × Dose IV) / (AUC IV × Dose oral)

Formula for relative bioavailability

Frel = (AUC test × Dose reference) / (AUC reference × Dose test)

If oral and IV doses are equal, how is absolute bioavailability simplified?

F = AUC oral / AUC IV

Why is absolute bioavailability always less than or equal to 1?

Some drug may not be absorbed or may undergo first-pass metabolism

After how many half-lives is bioavailability usually determined?

About 7.5 half-lives

What are formulation factors affecting bioavailability?

Drug formulation-related properties that alter absorption

Examples of formulation factors

Excipients, particle size, crystal polymorph, hydrate or solvate form

What are physiological factors affecting bioavailability?

Body-related factors that alter absorption

Examples of physiological factors

Gastric emptying, intestinal motility, GI pH, intestinal wall changes

How does smaller particle size affect bioavailability?

Increases dissolution and absorption

How does crystal polymorphism affect bioavailability?

Different crystal forms may dissolve differently

How does amorphous form compare to crystalline form?

Amorphous form generally dissolves faster

How does permeability affect bioavailability?

Higher permeability usually increases absorption and bioavailability

How does solubility affect bioavailability?

Higher solubility generally increases dissolution and absorption

What are excipients?

Inactive ingredients added to drug products

Examples of pharmaceutical ingredients

Filler, binder, coating agent, disintegrating agent, lubricant, surfactant, coloring agent

How can enteric coating affect bioavailability?

It delays drug release until reaching the intestine

How does gastric emptying affect bioavailability?

Faster emptying may increase absorption rate

How does intestinal motility affect bioavailability?

Changes contact time for absorption

How does gastrointestinal pH affect bioavailability?

It alters drug ionization and absorption

How does food affect bioavailability?

It can increase or decrease drug absorption

How does grapefruit juice affect bioavailability?

It inhibits intestinal CYP enzymes and can increase drug bioavailability

What is a metabolite?

A byproduct formed after drug metabolism

How do dosage form characteristics affect bioavailability?

They influence disintegration and dissolution rates

Examples of dosage form characteristics

Disintegration rate, dissolution time, storage conditions

How can storage conditions affect bioavailability?

They may alter drug stability and dissolution

What are physico-chemical drug properties affecting bioavailability?

Particle size, crystal form, salt form, hydration, pH, pKa

What is the equation for AUC after IV administration?

AUC = Dose / Clearance

What is the equation for oral AUC?

AUC oral = F × Dose / Clearance

What does clearance represent in the AUC equation?

The body's ability to eliminate drug

What methods are used to assess bioavailability?

Plasma concentration, urinary excretion, pharmacodynamic effect, clinical observation, in vitro studies

Most common method for assessing bioavailability

Plasma drug concentration measurements

Why can urinary excretion data be used?

Amount excreted may reflect amount absorbed

What is an acute pharmacodynamic effect study?

Measuring immediate drug effects to estimate bioavailability

What is an in vitro study?

Laboratory testing outside the body

What factors must be considered when designing a drug product?

Biopharmaceutics, pharmacodynamics, pharmacokinetics, bioavailability, dose, dosing frequency, patient factors, route of administration

What are biopharmaceutic factors?

Factors affecting drug bioavailability and absorption

What pharmacokinetic factors are considered in drug design?

Absorption, distribution, metabolism, and elimination

Why are patient considerations important in drug product design?

Age, disease state, and compliance affect therapy success

Why is route of administration important in drug product design?

Different routes affect absorption and bioavailability

Why is dosing frequency important in drug product design?

It affects patient compliance and drug levels

Why is dose consideration important in drug product design?

The dose must achieve therapeutic effect without toxicity

Which dosage form generally has higher bioavailability: suspension or capsule?

Suspension

Which dosage form generally has higher bioavailability: tablet or coated tablet?

Tablet

Which dosage form is not usually interchangeable with another due to different crystal forms?

Pharmaceutical alternative

Which equivalence type requires similar AUC, Cmax, and Tmax?

Bioequivalence

What does systemic circulation mean?

Drug circulating in the bloodstream throughout the body

What is first-pass metabolism?

Metabolism of a drug before it reaches systemic circulation

How does first-pass metabolism affect bioavailability?

It decreases bioavailability

Why is oral vancomycin bioavailability very low?

It is poorly absorbed from the GI tract

Example of a drug with oral bioavailability near 1

Theophylline

What percentage bioavailability corresponds to F = 0.25?

25%

What is the relationship between dissolution and absorption?

A drug must dissolve before it can be absorbed

What is the major difference between pharmaceutical equivalence and bioequivalence?

Pharmaceutical equivalence focuses on formulation similarity, while bioequivalence focuses on similar absorption

What is the major difference between pharmaceutical alternative and therapeutic equivalence?

Alternatives may differ in form, while therapeutic equivalents produce the same effect

What is API?

Active pharmaceutical ingredient

What does Cmax indicate about a drug?

The peak drug concentration in plasma

What does Tmax help determine?

The speed of drug absorption

Why is dissolution important for oral drugs?

The drug must dissolve before absorption can occur

How do controlled release products affect Tmax?

They usually increase Tmax

What is the purpose of a disintegrating agent?

To help tablets break apart

How can surfactants affect bioavailability?

They can improve wetting and dissolution

How does particle size reduction improve drug absorption?

It increases surface area for dissolution

What happens to bioavailability if permeability decreases?

Bioavailability usually decreases