PBK 2 Exam 1- Bioavailability

Bioavailability

the rate and extent to which the active ingredient is absorbed and becomes available at the site of action

Bioequivalence (BE)

when pharmaceutical equivalents or pharmaceutical alternatives show no significant difference in rate and extent of absorption at the same molar dose

pharmaceutical equivalents

products with the same active ingredient, strength, dosage form, and route, meeting same UPS standar

what are pharmaceutical alternatives?

same therapeutic moiety but differ in salt/ester, dosage form, or strength; NOT interchangeable 

what are therapeutic equivalents?

products that are pharmaceutically equivalent and bioequivalent, producing same clinical effect and safety

what is the difference between BA and BE?

QBA= how much drug reaches circulation (rate and extent)

BE=compares two products BA to determine equivalence

Difference between pharmaceutical equivalents and alternatives?

Equivalents→ same active ingredient, dosage form, route, strength

Alternatives → same active ingredient but different in salt/ester/dosage form/strength 

why is bioavailability clinically important?

lower A → lower plasma concentration (Cmax) → reduced therapeutic effect and possible need for dose adjustment

factors that cause incomplete absorption

• route of administration

• physiological factors 

• pharmaceutical factors 

Pharmaceutical factors that cause incomplete absorption

• Excipients 

• Particle size

• Polymorphism

• Crystalline vs amorphous 

• Hydrate vs anhydrous form 

Physiological factors affecting BA

• Gastric emptying

• Intestinal motility

• GI pH

• Food/fluid intake 

• Drug transporter 

• First-pass metabolism 

What is first pass effect?

loss of drug during steps of absorption due to metabolism by the liver before reaching systemic circulation

What is absolute bioavailability (Fabs)?

fraction of dose reaching systemic circulation compared to IV

what is relative bioavailability (Frel)?

comparison of two non-IV products

does not give absolute BA

useful for generics 

What does the FDA require for in vivo BA studies?

BA must be measured using plasma concentration-time profiles under a controlled study protocol 

How do PK parameters affect the curve (Cp vs T)?

• ↑ absorption rate → ↑  Cmax,↓ Tmax

• ↓ absorption → ↓Cmax, ↑  Tmax

• AUC changes only with changes in extent of absorption (F)

how does AUC relate to BA?

AUC reflects the extent of drug reaching systemic circulation; directly proportional to bioavailable dose

Which metrics measure rate of absorption?

Cmax and Tmax

Methods to calculate/determine AUC?

• blood level equations

• Trapezoidal rule (using plasma concentrations over time)

Can urinary excretion be used to estimate BA?

Yes. BA is proportional to the amount of unchanged drug excreted in urine

What are the limits of BA (AUC) calculation methods

• blood equations require accurate PK modeling

• trapezoidal rule requires complete sampling

• Urinary methods are not valid if drug is heavily metabolized

When is AUC directly proportional to dose?

when bioavailability is independent of dose 

What is the general BA/BE testing procedure?

• 12-24 healthy adults

• overnight fasting

• Administer the drug with water

• collect urine/blood 

• analyze concentration

• plot data

What is 2×2 crossover design?

subjects receive both products (test &reference), separated by a washout period of ≥ 5.5-8.5 half lives, to minimize variation 

What is the FDA’s BE statistical requirement for BE ("80/125 rule")?

The 90% confidence interval for AUC and Cmax must fall within 80-125% of the reference 

What happens if AUC, Cmax, or Tmax differ significantly?

The products are not bioequivalent. Statistical analysis required if results are close

What does "AA" FDA code mean?

products with no known bioequivalence problems; conventional dosage forms

What does BX mean?

insufficient data to determine BE; not considered therapeutically equivalent

What does "BC" mean?

Controlled release forms with known bioequivalence issues 

What does "BE" mean?

Enteric coated tablets with unresolved BE issues