Bioequivalence

Question 1

Bioequivalence definition

Answer 1

No significant difference in the rate and extent to which the active ingredient in pharmaceutical equivalents become available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study

Question 2

Why is bioequivalence important?

Answer 2

Increasingly drugs are prescribed generically
Brand continuity important for some medicines
Advice to patients and other healthcare professionals

Question 3

Bioavailability

Answer 3

The rate and relative amount of administered drug that reaches the systemic circulation intact
IV dosing = absolute bioavailability
Encompasses both rate and extent of absorption

Question 4

Equivalence

Answer 4

Pharmaceutical equivalence- in vitro studies
Bioequivalence- PK studies
Therapeutic equivalence- PD studies

Question 5

Pharmaceutical equivalence

Answer 5

Release of drug from dosage form (dissolution under simulated GI conditions)
Stability in physiological fluids
Permeability- in silico, LogP, PAMPA, perfusion studies

Question 6

Bioequivalence

Answer 6

Assessment of bioavailability e.g. plasma concentration- time curves

Question 7

Bioequivalence studies

Answer 7

BE studies normally adopt a crossover design
Inter and intra-subject variability- large sample size
Healthy volunteers
Single dose
Fasted (overnight/min. of 10 hours)
Measurement of active and or metabolites

Question 8

Therapeutic equivalence

Answer 8

PD and comparative clinical studies reserved for when PK end point not possible
BE demonstrated- assume safe and efficacious
Post marketing surveillance

Question 9

Urinary excretion

Answer 9

Assume that appearance of drug and or metabolite in urine is a function of both rate and extent of absorption
Only true when extensive urinary excretion exists and where rate of excretion is proportional to blood concentration

Question 10

Equivalence is likely to be a major problem if:

Answer 10

Narrow therapeutic window: e.g. warfarin, digoxin, carbamazepine, lithium; tighter acceptance BE limits; four way crossover studies
Narrow absorption window: specific absorption site e.g. active transport in small intestine
Dose dependent PK: drugs that slow dose-dependent absorption or distribution e.g. phenytoin

Question 11

Equivalence is likely to be a major problem if (2):

Answer 11

Low water solubility or poor dissolution: <5mg/ml, determined by in vitro assays
High potency drugs: high excipient: drug ratio, potential for excipient interactions
Special coatings: drugs that require protective coating e.g. EC

Question 12

Drugs that should be prescribed by brand

Answer 12

Anti-epileptics
Diltiazem MR 
Nifedipine MR
Aminophylline/theophylline
Lithium
Buprenorphine patches