Unit 3 - Bioequivalence

Question 1

What is bioequivalence?

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
- warn them which brand they should have
- especially if they go to a different pharmacy

Question 3

What factors need to be measured for pharmaceutical equivalence?

Answer 3

Release of drug from dosage form (dissolution) under simulated GI conditions
- pH 1.1, 4.2, 6.8
- 37 C
- volume
Stability in physiological fluids
- 3 hours
- check drug concentration
Permeability
- in silico
- logP
- PAMPA/CaCo-2
- perfusion studies

Question 4

How can bioavailability be assessed?

Answer 4

Plasma concentration
- time curves

Question 5

How can bioequivalence be assessed?

Answer 5

Normally adopt a crossover design
- test drug
- reference drug
- washout = 8.5 x elimination t1/2
Inter-subject variability and intra-subject variability
- sample size not < 12
Healthy volunteers
- > 18 years
- male/female
Single dose
Fasted
- overnight/minimum of 10 hours
Measurement of active and/or metabolites
- AUC
- Cmax
- Tmax
- Cmin/av

Question 6

When is equivalence likely to be a major problem?

Answer 6

Narrow therapeutic window
- warfarin
- digoxin
- carbamazepine
- lithium
Narrow absorption window
- specific absorption site
- active transport in small intestine
Dose dependent pharmacokinetics
- drugs that show dose dependent absorption or distribution
- phenytoin
Low water solubility or poor dissolution
- < 5 mg/ml
- determined by in vitro assays
High potency drugs
- high excipient:drug ratio
- > 1000:1
- potential for excipient interactions
Special coatings
- drugs that require protective coating
- enteric coated

Question 7

Give examples of drugs that should be prescribed by brand

Answer 7

Anti-epileptics
- phenytoin
- carbamazepine
- sodium valproate
Diltiazem MR
- variable release profiles
Nifedipine MR
- variable release profiles
Aminophylline
Theophylline
Lithium
Buprenorphine patches