lecture 4: bioequivalence testing of oral medicines I

Question 1

What is a generic drug?

Answer 1

a copy of a brand name drug which ideally must have the same safety, quality and efficacy

Question 2

What is the difference between a brand name drug and a generic name drug?

Answer 2

brand named drugs are supplied by one drug company and are sold under that company’s trademarked name

generic named drugs may be supplied by more than one company and may be sold under different names

Question 3

Why is generic competition desireable?

Answer 3

helps to keep drug costs down, saving consumers $8-$10 billion pa in the US (at retail pharmacies)
encourages product development

Question 4

What is a patent?

Answer 4

a document which protects the investment of the drug company that developed the drug
This gives the drug company the solre right to sell the drug while the patent is in effect

Question 5

What happens if a patent on a brand-name drug is near expiring?

Answer 5

drug companies that are interested to manufacture generics can apply to the respective health authorities to sell a generic version of the drug

Question 6

What are the main regulatory guidelines for medicines concerned?

Answer 6

section 14: bioequivalence and interchangeability
section 15: bioequivalece testing of oral medicines
section 16: equivalence testing of inhaled medicines

Question 7

Why are bioequivalence studies required by medsafe?

Answer 7

So that they can ensure that a new Rx med can be substituted for a product already on the market

bio-inequivalence of some products can cause significant therapeutic differences e.g. failure or diminished clinical safety
e.g. anti-cholesterol products, anti-hypertensives, anti-anxieties, antibiotics

Question 8

What sort of products require bioequivalence studies?

Answer 8

Products indicated for serious conditions requiring an assured therapeutic reponse

products with a narrow therapeutic index

products with a steep dose-response curve

products where PKs are complicated by absorption (70%)

Products with a high ratio of excipients to active ingredients

products with unfavourable physicochemical properties such as low solubility and/or instability in an acid medium etc.

Question 9

What are the requirements of a Rx generic med in NZ?

Answer 9

must be bioequivalent to the NZ RP before it can enter the NZ market This means that it must be in the same dosage and physicochemical form as the reference product

Question 10

Which two dosage forms are clinically equivalent and interchangeable?

Answer 10

tablets and capsules (generally)

Question 11

What is bioequivalence?

Answer 11

this refers to chemical equivalents

The drug products that contain the same compound in the same amount and meet current official standards which when administered to the same person in the same dosage regiment will result in equivalent concentrations of drug in blood and tissues.

Question 12

What is therapeutic equivalence?

Answer 12

This refers to drug products that when administered to the same person in the same dosage regimen, will provide essentially the same therapeutic effect or toxicity.

Bioequivalent products are expected to be therapeutically/pharmaceutically equivalent

Question 13

when are two medicines considered interchangeable?

Answer 13

they are pharmaceutically equivalent
their bioavailabilities after administration in the same dose are similar to such a degree that safety and efficacy are essentially the same

Question 14

What is bioavailability?

Answer 14

a measure of the rate and extent of absorption of the pharmacologically active form or forms of the active ingredient from a medicine in the systemic circulation after administration

This is reflected by the concentration time curve or by its excretion in the urine

Question 15

What is bioavailability concerned with?

Answer 15

how quickly and how much of a drug appears in the blood after a specific dose is administered

Question 16

What can bioavailability determine?

Answer 16

the therapeutic efficacy of the product because it affects the onset, intensity and duration of the therapeutic response of the drug

Question 17

What does the rate of absorption affect?

Answer 17

the onset of pharmacological action.
we require a rapid onset to treat acute conditions
this absorption can be delayed by food resulting in lower levels in the blood
we desire a slow rate to avoid side effects or to produce a sustained release effect

Question 18

What does the extent of absorption represent?

Answer 18

the effective dose of a drug i.e. the fraction of the dose that actually reaches the blood stream

Question 19

What causes low bioavailability?

Answer 19

extensvie FPM
poor water solule, slowly absorbed drugs ( most common with oral dosage forms)
Insufficient time in the GIT
Reactions such as complexation, hydrolysis by gastric acid or digestive enzymes etc.

Question 20

What kind of medicines are considered non interchangeable?

Answer 20

products with a nrrow TI (warfarin, phenytoin, digoxin, thyroxin)

Product delivery systems which are not pharmaceutically equivalent (e.g. transdermal patches/suppositories vs. oral)

No acceptable method to establish bioequivalence e.g. topical products - theserequire clinical trials

Question 21

Which medicines do not require a bioequivalence test?

Answer 21

OTC medicines
solutions without pharmacologically active ingredients (e.g. artificial tears, contact lens solutions)
vaccines (clinical trial data is always required however.)
nasal sprays intended for local action
dialysis solutions etc.

Question 22

What are the requirements for medicines used in bioequivalence studies?

Answer 22

They should be manufactured in accordance with GMP

Question 23

What evidence is require for bioequivalence studies?

Answer 23

These usually consist of comparative bioavailability data

blood plasma or serum concentration-time curves provide the best measure of bioavailability for medicines with a systemic effect

Question 24

What is considered bioequivalent?

Answer 24

if the 90% confidence intervals for the mean Cmax, Tmax and AUC of the two products are within +/-20%

Question 25

What is relative bioavailability?

Answer 25

Refers to availability of a drug product as compared to similar dosage form of the same drug given in the same dose

Question 26

What can relative bioavailability determine?

Answer 26

the effects of formulation differences on drug absorption.

Question 27

How is relative bioavailability obtained?

Answer 27

by comparing their respective AUCs

e.g. AUC (oral test product)/AUC (oral innovator product)

Question 28

What are the common variables in a compartivie bioavailability study?

Answer 28

extent of abosrption

rate of absorption

Question 29

What is the extent of absorption?

Answer 29

the fraction of the dose which enters the systemic circulation.
This is estimated using the AUC of plasma concentration vs. time
OR from the fraction of the dose excreted in urine as the active form and/or its metabolites

Question 30

What does the rate of absorption determine?

Answer 30

the time delay between admin of a medicine and the time the maximum peak concentration in the plasma being assigned (Cmax, Tmax)

Question 31

What things should be considered when designing a comparative bioavailability study?

Answer 31

single dose vs. steady state studies
parameters to measure
choice of subjects
standardisation of experimental conditions
number of subjects
formulation and quality control data requirements
number and timing of samples
fasting and non fasting studies
administration of medicine

Question 32

What is the difference between a single dose study and a steady state study?

Answer 32

single dose studies are generally more appropriate and common

steady state studies are used for toxic drugs, modified release products and enteric coated preparations

Question 33

What parameters are to be measured in a comparative bioavailability study?

Answer 33

Cmax
Tmax
AUC
ke
ka

Question 34

What choice of subjects need to be considered in a comparative bioavailability study?

Answer 34

generally, healthy adult human volunteers of average weight between 18-60 years of age

Question 35

What standardisation of experimental conditions need to be considered in a comparative bioavailability study?

Answer 35

subjects shoudl be fasted
the quantity, type and timing of food and fluids taken should be standardised.
Their posture, physical activity and sampling times should also be standardised

Question 36

What is the minimum number of subjects in a comparative bioavailability study?

Answer 36

12

Question 37

What is the typical number and timing of samples taken?

Answer 37

12-18 blood samples per dose is sufficient to enable estimates of Cmax, Tmax, AU and ke

Question 38

What is the difference between fasting and non fasting studies?

Answer 38

fasting is required for a single dose study while non fasting is generally used in modified release product or products recommended to be given with food.

if you are conducting a steady state study which occurs over a period of time you cannot ask the volunteer to fast for that entire length of time.

Question 39

What should be considered with medicine administratione?

Answer 39

patients to have the same equivalent doses of test medicine and reference product.

in single dose trials, a sufficient interval should be allowed between the admin of each formulation to ensure the previous dose of med and any metabolites being measured have completely eliminated

Question 40

What are the analytical methods used?

Answer 40

HPLC which is adequately specific and sensitive
GC
assay validation. This should be conducted in the lab which generated the study data, using the same analytical procedures