BIOEQUIVALENCE
PREPARED BY
MD.IMRAN NUR MANIK
LECTURER
DEPARTMENT OF PHARMACY
NORTHERN UNIVERSITY BANGLADESH
DRUG PRODUCT SELECTION
Nowadays the pharmacists are playing an important role in drug product selection. Prescription in which the product selection is permitted,
(saying that, “product selection is permitted”) pharmacist can select an equivalent drug product as he dispenses.
The hospitals or countries where there is a formulary system, the pharmacists are allowed to select an equivalent drug product from those
listed in the formulary.
Proper of a multi-source drug products is a major role and responsibility of the pharmacist. All heath practitioners should be aware that
biopharmaceutical principles can provide a sound basis for rational drug product selection.
Why important?
Drug product selection is very important because-
- The drug products from different manufacturers which contain the same amount of active ingredient may perform differently in patients.
- Differences in formulation can cause significant differences in the bioavailability of the drug. Most of the problems are associated with more compact dosage from e.g. capsules and tablets.
- Manufacturing process and materials used in the formulation of a drug product may very considerably from one drug manufacturer to other.
Therefore, it is not surprising that the various drug products of the same drug entity may exhibit different bioavailability characteristics.
Basis for drug product selection:
a. Types of cross-over study
b. Number of sample used.
c. Number of subject used.
d. Factors such as age range, weight range and sex of the subject.
e. Types of analytical procedure used.
f. The strength and type of dosage form used
B. Bioavailability data:
Blood level drug concentration and urinary drug excretion data can be used to compare the bioavailability of a specific drug form and
under various conditions. Blood level curves and urinary drug excretion profile can be used to evaluate the bioavailability of specific
drug from different drug products (various dosage forms).The data which provides the bioequivalence of drug products will be selected.
Because bioequivalent drug products maybe used as alternatives.
Data should be evaluated carefully to decide whether a drug product whether will be accepted or not.
Fig. Blood level curve for meprobomate drug products.
The data in the figure indicate that the manufacturer’s drug product is equivalent to the standard reference product against which it has
been tested. The blood level of the two products is essentially super impossible. An adequate number of subjects are used in this study.
When the drug concentration time curves for two drug products are superimposable then, there is no problem to deduce that two drug
products are equivalent. Exact super-impossibility is a rare occurrence. If blood level curves for the drug products that two products of
the same active ingredient are significantly different, then it arises the question of “how much difference is allowed before one of the
products can be judged as bioequivalent to the reference standard product?”
The FDA has currently proposed a 75/75 requirement for the bioequivalence studies of certain drug products. It implies that the
relative bioavailability of test product when compare to the bioavailability of a reference products must be greater than or
equal to 75% for 75% of the subjects. When at least 75% of the subjects are administered the drug, the test drug has a bioavailability
of greater than 75% relative of the AUC and/or peak height of a reference standard.
For some drugs with a wide margin of safety e.g. penicillin, a 25% difference in the bioavailability might not significantly affect the
clinical outcome after 1-2 weeks of therapy. On the other hand, for drugs with a narrower margin of therapeutic effectiveness and
safety, e.g. digoxin a 25% decrease in bioavailability could cause significant adverse therapeutic effects.
The act of drug product selection is a legal responsibility. Professional responsibility is achieved if the practitioner selects drug
products on the basis of proper evaluation of bioequivalence data. However, care must be taken to ensure that the product has
been approved by the FDA. To properly select a drug through evaluation of bioavailability, the data is a must.
C. Other manufacturing consideration:
For many products, good bioavailability data maybe made available by many pharmaceutical manufacturers.
Therefore, other manufacturing consideration should be taken into account when selecting a manufacturer of drug products.
Some important criteria for manufacturing products are given bellows-
(1) Upon request of the pharmacist, the supplier should furnish analytical control, sterility testing and bioavailability data,
description of testing procedures for new materials and finished products or any other information which may be indicative of the
quality of a given finished drug product. This information should be supplied at no charge.
(2) The company should permit visits (during normal business hours) by the pharmacist to inspect its manufacturing and control procedures.
(3) All drug products shipped to the hospital should conform to the requirements of the most recent USP-NF criteria.
(4) The name and address of the manufacturer of the final dosage from should be present on the product labeling.
(5) Expiration dates should be clearly indicated on the package.
(After weighing all the evidence and selecting drug product, be sure to follow through on the pharmacist’s professional responsibility)
Thus, it is clear that health care practitioner must rely on their own judgment about the bioavailability of drug products they dispense.
02, Methods of determining bioavailability by clinical observation:
This method is used to establish the efficacy and safety of drugs and drug products and many such studies must be carried out by manufacturers before new product is finally approved for marketing. These studies involve a large number of patients and are very expensive. The subjects are diseased and the drug products are given to them and then asked about clinical response just before dosing, at 30 minutes and one hour after dosing and at hourly intervals, therefore a total 6 hours after dosing.
e.g. Clinical trial of analgesic zomepirac (Etodolac 400 mg) are shown in the following figure. This study used 148 points, randomly divided into five groups and each group was given one of the following drugs :- zomepirac 50 mg (Etodolac 400 mg); zomepirac 100 mg (Etodolac 200 mg) 100mg. APC with codein 60mg and placebo.
Figure I. Etodolac versus codeine/acetaminophen in the relief of pain from oral surgery (Mehlisch). *Significantly (p ~<0.05) superior to placebo. +Significantly (p ~<0.05) superior to codeine/acetaminophen. (Reproduced courtesy of the author and the editor of Rheumatology International [21])
The patients were questioned about their pain just before dosing, at 30 minutes and 1 hour after administration and at hourly intervals, therefore total of the 6 hours after dosing. At each observation patients were asked to rate their pain intensity from none to severe on a four-point scale.
The followings are the cases where bioequivalence test requirements are not relevant;
(i) Certain drug products –e.g. topically applied ointments, creams, and lotions used for local effects.
(ii) Drug products such as antacids and laxatives containing ingredient not intended for absorption.
(iii) Intravenous solution that has the same drug concentration and solvent system, as the FDA approved product.
(iv) Liquid drug products that contain the active ingredients in a solubilized form (oral solution, elixirs, syrups etc) in the same concentration as the drug product that has been the approved by the FDA via NDA ( New Drug Administration )
Types of bioavailability:-
(i) Absolute bioavailability: - When the systemic availability of a drug administered orally is determined in comparison to its intravenous administration, is called as absolute availability.
The absolute bioavailability of a drug in a drug product may be measured by comparing the respective AUC, after oral or iv administration. This measurement may be performed as long as VD & K are dependent of the route of administration.
A B A using plasma data can be determined as follows
AUC = Area under the Curve
D = Dose of administered drug
ABA using urinary drug excretion data determined by the following equation:-
The absolute bioavailability is also equal to F, the fraction of the dose that is bioavailable.
[98,99,02]Importance of bioavailability
The importance of bioavailability are given below:
1. Bioavailability is used to ensure the strength, quality, identity and purity of a drug product.
2. It evaluates the absorption, distribution, metabolism and elimination characteristics of a drug.
3. It helps to minimize the toxic effect of a potent drug .
4. It helps to select the suitable route of drug administration.
5. Dose and frequency of dose can be determined .If the bioavailability of a drug is more then the dose is less.
6. It helps to confirm the bioequivalence of drug product.
[01]Differentiate between bioavailability and bioavailable drug.
Bioavailability: The relative amount of an administered dose of a drug that reaches the systemic circulation intact and the rate at which it occurs is called bioavailability of that drug.
Thus bioavailability is concerned with the amount and rate at which the intact form of a particular drug appears in the systemic circulation following its administration.
Bioavailable dose: The fraction of an administered dose that reaches the systemic circulation intact is called bioavailable dose.
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