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Bioavailability and Bioequivalence
289
13. Pharmaceutical Equivalent: It has been frequently observed that such drug products available
in identical dosage forms which consist of the same active ingredient(s), i.e., the same salt or ester,
do designate the same dosage form and hence
∑ may be administered via the same route and
∑ show same strength or concentration.
Chlordiazepoxide hydrochloride capsules: 5 mg;
Tobramycin—2 mL vial: 80 mg;
Dextromethorphan hydrobromide syrup: 10 mg.
Examples
Valid Requirements: These essentially include
(a) Pharmaceutically equivalent dosage forms are specifi cally formulated in such a way so as to:
∑ comprise same quantum of ‘active substance’ in the same drug product and
∑ fulfi ll the same or compendial or recognized applicable standards, e.g., identity, purity, quality
and strength; however, they could be altogether different properties, for instance: shape; scoring
profi le; release mechanisms; packaging modalities; expiration time; labelling pattern and excipi-
ents (viz. preservatives, colour, permissible fl avours).
(b) Pharmaceutical equivalents should comply with the following characteristic features, such as:
∑ uniformity,
∑ disintegration time and/or
∑ dissolution rates.
Modifi ed-release drug products: These essentially need such features as:
∑ adequate overage and
∑ reservoir of ‘active principle’.
Interestingly, there are certain dosage forms, e.g., ‘Prefi lled Syringes’
(Erythropoietin 4,00,000 IU SC-Injectables), wherein the ensuing residual volume may change
and should be able to deliver identical quantum of the ‘active drug ingredients’ over a certain stipu-
lated ‘identical dosing period’.
14. Pharmaceutical Substitution: The pharmaceutical substitution refers to the phenomenon of
dispensing a pharmaceutical alternative for the prescribed dosage form:
Following are a few typical examples:
∑ Tetracycline hydrochloride—given instead of tetracycline phosphate;
∑ Testosterone undecanoate—dispensed in place of testosterone propionate;
∑ Ampicillin suspension—dispensed instead of ampicillin capsules.
Examples
Note
The ‘pharmaceutical substitution’ invariably requires the physician’s prior approval of recommendation.
15. Reference Listed Drug (RLD): FDA defi nes the reference listed drug (RLD) as ‘the drug product
(or dosage form) upon which an applicant relies at the time of seeking approval of an Abbreviated
New Drug Application (ANDA)’.
Essentials of Biopharmaceutics and Pharmacokinetics
290
RLD invariably designates the ‘brand name drug’ which has a fi ll New Drug Application (NDA).
FDA Guidelines: There are two important aspects:
∑ It represents a ‘single reference listed drug’ as the standard to which almost all generic versions
should be proved to be bioequivalent.
∑ FDA intends to circumvent any possible signifi cant variations among the ‘generic drugs’ plus
their contemporary brand name drugs. Evidently, such variations might come into being when
the ‘generic drugs’ are compared with various listed ‘reference drugs’.
16. Therapeutic Equivalents: In general, the dosage forms are known to be therapeutic equivalents
provided they happen to be ‘pharmaceutical equivalents’. Besides, they may be expected to possess
∑ same ‘clinical effi caciousness’ and
∑ same ‘safety profi le’
on being given to the patients strictly as per the specifi ed guidelines provided on the ‘label’ itself.
FDA-Classifi ed Therapeutically Equivalent Dosage Forms: In reality, these ‘drug prod-
ucts’ must comply with the following fi ve important criteria, namely:
(a) They should be approved as safe and effective.
(b) They are pharmaceutical equivalents, whereby they specifi cally fulfi ll the following critical aspects:
∑ Consist of similar quantum of the same ‘active drug component’ in the same drug product
and essentially the same route of administration,
∑ Should comply with compendial or other approved standards related to: strength, purity,
quality and identity.
(c) These are ‘bioequivalent’ in nature, and in that,
∑ They do not present either an already known or a potential ‘bioequivalence’ problem; how-
ever, they do comply with a stipulated acceptable in vitro standard and/or
∑ In case, they really pose a defi nite known or potential problem, they must afford a mutually
suitable bioequivalence standard.
(d) They must be labelled properly.
(e) These ‘drug products’ are normally manufactured in complete adherence to and compliance
with the Current Good Manufacturing Practice (cGMP) regulations and guidelines.
Note
FDA reposes total confi dence and belief that all such ‘dosage forms’ duly recognized and approved
under the category of ‘therapeutically equivalents’ may be substituted freely with the utmost
expectation that the substituted product would certainly give rise to the same ‘clinical effect’ with
required ‘safety profi le’ in comparison to the ‘prescribed product’.
17. Therapeutic Alternatives: The therapeutic alternatives invariably refers to the drug products
(or dosage forms) comprising variant ‘active components’ which are recommended for the same
therapeutic or clinical objectives.
It is worthwhile to add here that the selected ‘active ingredients’ duly incorporated in the thera-
peutic alternatives do normally belong to the same pharmacologic category; and, therefore, are
obviously expected to display the same therapeutic effect on being administered to the patients by
physicians (for all such conditions of usage).
Following are two typical examples:
∑ Cimetidine is administered in place of ‘ranitidine’ and
∑ Ibuprofen is recommended instead of ‘aspirin’.
Example
Bioavailability and Bioequivalence
291
18. Therapeutic Substitution: The therapeutic substitution relates to the careful phenomenon of
dispensing a therapeutic alternative instead of the prescribed drug product (or dosage form).
Following are two typical examples:
(a) Ibuprofen may be dispensed in place of ‘naproxen’ and
(b) Amoxicillin may be given instead of ‘ampicillin’.
Examples
Importantly, one may also come across the therapeutic substitution in the event when one NDA-approved
drug substance is being substituted for the same drug that has been duly approved by a different NDA.
Nicoderm
®
—a nicotine transdermal product may be judiciously substituted by another drug
product, viz. Nicotrol
®
(also a nicotine transdermal system).
Example
2. Bioavailability
2.1. Preamble
In true sense, ‘bioavailability’ designates the precise quantum of the ‘active drug’ duly administered in a phar-
macological dose that eventually penetrates the systemic circulation soon after the oral administration. One
may observe the fundamental underlying fact that different dosage forms (formulations) of the same active
drug may not be equivalent therapeutically for the simple reason that their bioavailability differs grossly.
In other words, the present-day physicians do understand and appreciate the enormous importance of
∑ underlying concept of bioavailability and
∑ wide practical applications.
Mechanism: The ‘bioavailability’, also sometimes known as ‘systemic availability’, of an orally given
drug product (dosage form) depends exclusively on the following two cardinal aspects:
∑ Systemic absorption profi le and
∑ Degree of ‘hepatic metabolism’.
These are exerted upon its ‘fi rst-pass via the liver’—over and above its due action at the level of the receptors.
Important Points These essentially include:
1. Bioavailability is duly estimated by assessing either the plasma concentration or the wine concen-
tration stretched over a stipulated time following the oral administration of drug product.
2. For being therapeutically equivalent, it is necessary that various available dosage forms of the same
active drug must be bioequivalent, suggesting thereby that they should possess almost similar sys-
temic availability.
Observation: The drug products from different manufacturers, and even different batches of
‘drugs’ from the same pharmaceutical enterprise, do exhibit
∑ non-compliance of bioequivalency and
∑ dissimilar systemic availability.
Major differences in bioavailability represent clinical relevance;
Minor differences in bioavailability also seem to be important for such ‘active ingredients’ that show:
∑ steep dose–response curve and/or
∑ narrow margin of safety.
Essentials of Biopharmaceutics and Pharmacokinetics
292
3. Amazingly, a large volume of marketed ‘drug products’ or ‘dosage forms’ invariably possess prominent
‘fl at dose–reponse curves’, in order that exclusively marked and pronounced observed differences in
‘bioequivalence’ shall eventually give rise to the ultimate difference in the therapeutic equivalence.
2.2. Absolute Bioavailability
The absolute bioavailability of an active ingredient (drug) present in a dosage form duly administered
by an extra vascular (EV) route, including the oral route penetrating the systemic circulation is desig-
nated by the fraction of the same dose of the drug being administered via the IV route. Thus, we have
two distinct situations:
IV route—the entire administered ‘active drug dosage’ gets directly introduced right inside the sys-
temic circulation; and, therefore, regarded to be bioavailable even up to 100%;
EV route—the ‘active ingredient’ (drug) needs to be absorbed so as to make its way right into the
‘systemic circulation’.
In this manner, one may calculate the ‘absolute bioavailability’ by the following expression:
abs
iv
y
(AUC)
Absolute bioavailabilit
(AUC)
=
(a)
where,
(AUC)
abs
= Total area under the curve following administration of ‘single dose of the drug’ via a given
absorption site and
(AUC)
iv
= Total area under the curve following administration of ‘single dose of the drug’ via rapid
IV injection.
Obviously, Equation (a) holds good in a situation when the same doses are usually employed for both the
routes, i.e., EV- and IV-routes. Importantly, when these doses are actually different from one another, a
necessary correction for the defi nite dose size (strength) is required to be made as given by the following
modifi ed expression:
abs iv
iv abs
D(AUC) ×
Absolute bioavailability
(AUC) × D
=
(b)
where,
D
iv
= Dose size being administered via IV-route and
D
abs
= Dose size of the single-dose being given via the absorption site.
2.3. Relative Bioavailability
The relative bioavailability designates explicitly a measure of a ‘fraction’ of a given ‘active drug’ which
gets adequately absorbed right into the systemic circulation duly emanated from a specifi c dose level in
comparison to a clinically established and proven standard dose of the same drug substance.
Evidently, it may be determined for the specifi c drugs which cannot be administered and an IV
bolus injection. Therefore, to circumvent such a typical diffi cult situation, both products—‘Test Dose’
and ‘Standard Dose’—comprising equal quantum of the drug need to be given via the same route of
Bioavailability and Bioequivalence
293
administration to the same subject at different occasions; and ultimately, the necessary calculations is car-
ried out based upon the previously discussed ‘plasma-concentration time curves’. Thus, we may have the
following modifi ed expression for the ‘relative bioavailability’:
test
standard
(AUC)
Absolute bioavailability
(AUC)
=
(c)
where,
(AUC)
test
= Total area under the curve following administration of a ‘Single Test Dose’ and
(AUC)
standard
= Total area under the curve following administration of a ‘Single Standard Dose’.
Nevertheless, in a situation when different ‘Test Dose’ and ‘Standard Dose’ are duly administered, it is
absolutely mandatory and necessary that a ‘correction’ has to be made for the size of the dose. Thus, we
may have the following modifi ed version of the ‘relative bioavailability’.
test standard
standard test
D(AUC)
Relative bioavailability
(AUC) D
×
=
×
(d)
where,
D
standard
= Size of the single dose of ‘Standard Dose Form’ and
D
test
= Size of the single dose of ‘Test Dose Form’.
Note
In general, the ‘absolute or relative bioavailability’ can be logically expressed in terms of either a ‘frac-
tion’ or ‘percentage’ of the ‘Test Drug’ relative to the ‘Standard Drug’ dosage forms (or formulations).
2.4. Bioequivalance Assessment and Data Evaluation (or Importance of Bioequivalence)
Vigorous research in pharmaceutical sciences have ascertained that an array of parameters are invariably
used to provide a general evaluation of
∑ the overall rate and
∑ degree of absorption of an active drug substance.
Importantly, a comprehensive analysis of almost all characteristic features is essentially needed before it
could be rendered possible to implicate either a ‘single factor’ or ‘parameter’ showing
∑ prevalence of ‘bioequivalence’ and
∑ absence of ‘bioequivalence’.
2.4.1. Bioequivalence Assessment
The focal point of the ‘bioequivalence assessment’ is given by the plasma concentration–time curve (see
Section 4(3.2): Fig. 4.9), which is duly obtained when sequential blood samples are taken after drug
administration and are subjected to assay of drug by standard method.
Obviously, when a dosage form (or drug product) is administered orally at time ‘zero’, the prevalent
drug concentration at this material time must also be ‘zero’. From this point onwards, the fateful ‘drug
product’ takes the course via the GI tract (i.e., stomach, small intestine, colon) and it should pass through
a ‘sequence of events’ as illustrated clearly in Figure 5.1.
Essentials of Biopharmaceutics and Pharmacokinetics
294
2.4.2. Urinary Drug Amount–Time Profiles
It would be worthwhile to state at this point in time that one may not be solely confi ned to the usual
drug blood-level profi les, but in a similar manner, can also be accomplished through the cumulative
urinary drug amount–time profi les.
Modus Operandi: The following are the various steps involved:
1. Determination of ‘drug concentration’ in discharged urine at specifi ed time intervals.
2. The quantum of ‘drug’ excreted per interval is duly estimated by multiplying the concentration of
drug by the volume of urine collected in that time interval.
3. The quantities of drug collected in each interval are now combined, and fi nally the ‘total amount’
excreted in the urine is arrived at.
4. The resulting value is almost analogous to the area under the curve (AUC).
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Figure 5.1 Diagrammatic representation of sequence of events involved in the dissolution and absorption of a
drug from a solid oral dosage form.
The ‘drug product’ (or dosage form), viz. solid oral dosage form (tablets), granules (in capsules) and small
particles (microcrystalline drug, e.g., microcrystalline aspirin) all undergo dissolution to result in the forma-
tion of ‘drug in solution’ form, which upon systemic drug absorption reaches the circulating blood system.
Explanation
An elaborated ‘cumulative urinary drug amount–time profi le’ for many marketed ‘nitrofurantoin
formulations’ is duly represented in Figure 5.2.
4
Example
4
Adapted from Gennaro AR: Remington: The Science and Practice of Pharmacy, Vol. I, 20th edn., Lippincott Williams &
Wilkins, New York, 2004.
Note
It is almost total and unquestioning that the analytical methodology employed for the analysis of
drug in the samples is not only precise and accurate, but also specifi c and sensitive.
Bioavailability and Bioequivalence
295
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Figure 5.2 Diagrammatic representation of the average cumulative quantum of nitrofurantoin excreted
from three different lots (A, B and C) of two marketed dosage forms after a single oral dose of 100 mg of
nitrofurantoin.
2.4.3. Peak-Height Concentration
The ‘peak-height concentration’ actually refers to the observed height of the peak of the blood level–
time curve that critically represents the highest drug concentration accomplished after the oral adminis-
tration. In usual practice, it is reported invariably as a quantity per volume measurement, such as:
mcg mL
−1
: microgrammes per milliliter or
g 100 mL
−1
: grammes per 100 milliliter.
Importance: The most decisive importance of the ‘peak-height concentration’ is depicted in an elabo-
rate fashion in Figure 5.3, wherein the blood concentration–time curves of two altogether different
dosage forms of a drug substance are duly represented.
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Figure 5.3 Graphic representation of blood concentration–time curves for two different dosage forms of the
same drug substance showing explicit relationship of the profi les to the minimum effective concentration (MEC).
Essentials of Biopharmaceutics and Pharmacokinetics
296
Example of a cardiac glycoside (e.g., Digoxin and Digitoxin):
Let us assume that the two curves do designate the observed blood concentrations after administration
of ‘equal doses’ of two entirely different drug products (or dosage forms) of the same cardiac glycoside
(viz. Digoxin or Digitoxin). Thus, at a dose level of 4 mcg mL
−1
, this particular instance duly represents
the minimum toxic concentration (MTC), and at 2 mcg mL
−1
it designates the MEC, as illustrated in
Figure 5.4. However, it never gives rise to any sort of toxicity levels in vivo.
2.5. Bioavailability Studies in Human: Pharmacokinetic Profiles
Largely, the observed inter-individual variations in the pharmacological response in subjects following
administration of the same active drug product (or dosage form) may be duly attributed to a host of factors.
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Figure 5.4 Graphic representation of the blood concentration time–curves obtained for two different dosage forms
of the same drug (digoxin or digitoxin), clearly showing the relationship of the profi les to the MTC and to the MEC.
The following is the explanation of the various aspects of Figure 5.3:
1. A horizontal line, parallel to X-axis, has been drawn across the ‘average blood concentration’
(on Y-axis) at 4 mcg mL
−1
.
2. Assuming that the ‘drug’ happens to be an ‘analgesic’, and 4 mcg mL
−1
designates the MEC
of the ‘drug’ present in the circulating blood.
3. Here, the blood concentration–time curves in Figure 5.3 do distinctly signify the accom-
plished blood levels after due administration of ‘equal doses’ of the two formulations (or
dosage forms) of the drug, and it is also supported by the fact that ‘analgesia’ will never
come into effect unless and until the MEC was either duly obtained or exceeded. It
obviously becomes explicit and clear that “Formulation-‘A’” would be expected to give
required ‘pain relief ’ to the patient, whereas, “Formulation-‘B’”, even though exhibits
adequate degree of systemic absorption, may prove to be totally ineffective in causing
‘analgesic effect’.
Explanation
Bioavailability and Bioequivalence
297
Nevertheless, of these divergent factors, ‘bioavailability’ could hold the gum for an important role that
in normal course may even be totally unrecognized. In true sense, there are two vital conditionalities,
namely:
∑ time required for the absorption of an ‘active drug’ and
∑ exact amount of the drug being absorbed
that do exert their direct infl uence upon the speed of acquired onset of action, and the observed
intensity of pharmacological effects of drug. Therefore, the aforesaid two critical parameters should by
all means be precisely ‘quantifi ed’ by making use of an exhaustive ‘bioavailability studies’ that would
determine the
∑ rate of drug availability and
∑ degree of drug availability
in the systemic circulation after the ingestion of ‘drug product’.
2.5.1. Comparison with a Reference Drug/Formulation
In usual practice, a comparison either with a ‘reference drug’ or a ‘reference formulation’ is determined
preferably in the solution form or an altogether separate brand of the drug product (or dosage form),
which is known to be well absorbed on being administered via the oral route.
In this regard, the ‘samples’ drawn for carrying out the necessary bioavailability of drugs must be
taken from a location wherein the ‘drugs’ shows its maximum therapeutic effect, because it would be
rather diffi cult to ‘draw sample’ from the site of action. Therefore, the desired ‘sample’ for such a study is
generally taken from the
∑ venous or arterial blood (i.e., circulating blood) and
∑ urine (another biological fl uid).
Importantly, for the locally acting drug products and those that act specifi cally upon GI-lumen, the nec-
essary bioavailability study need to be performed at other levels.
Ritschel (1974)
5
suggested that the bioavailability studies being carried out on healthy subjects should
also be extended to simultaneous testing using in vitro tests, such as:
∑ disintegration,
∑ degradation and
∑ speed of dissolution
to establish critically that a relevant correlation do exist particularly between the in vitro tests and bio-
availability studies in humans.
2.5.2. Bioavailability Studies as per the Helsinki Declaration
6
It is, however, pertinent to state here that the bioavailability studies are required to be performed strictly
as per the Helsinki declaration.
5
Ritschel WA: Bioavailability testing and clinical signifi cance, Pharma. Acta Helv., 49: 77–83, 1974.
6
Azarnoff DL: Clin. Pharmacol. Ther., 13: 796–802, 1972; Moris RC: Ibid, 13: 782–795, 1972.
Essentials of Biopharmaceutics and Pharmacokinetics
298
Modus Operandi: The following are the various sequential recommended steps by the Helsinki declaration:
1. Each bioavailability study has got to be approved duly by an ‘Expert Committee’/‘Ethics Committee’,
whose prime objectives and responsibilities would be to:
(a) verify that the method strictly conforms to the permitted moral standards for experiments
with ‘human volunteers’, and
(b) all experimental studies must be carried out with perfect guidelines duly approved.
2. All ‘human volunteers’
7
must be thoroughly briefed with regard to the aims and objectives of the
on-going bioavailability studies. For this, a properly signed consent need to be taken unreservedly;
and the human volunteers or patients must be duly informed about the necessary protective pro-
cedures to be followed so as to ensure their good health and well-being.
Recommended/Approved Methods: These essentially include:
1. Comparative ‘bioavailability studies’ in humans.
2. Comparative ‘pharmacodynamic studies’ in humans.
3. Comparative ‘clinical investigative trials’.
4. Exhaustive ‘in vitro studies’ for dissolution and disintegration tests.
Evidently, the aforesaid four recommended/approved methods are frequently used to access and deter-
mine whether the ‘pharmaceutically equivalent products’ are found to be also ‘therapeutically equivalent’
to one another so that the ‘physician’ could interchange them appropriately for the patients.
8
2.5.3. Drug Dissolution Rate and Bioavailability
It has been proved beyond any reasonable doubt that the inherent physicochemical characteristic fea-
tures of several drug molecules do exert the greatest infl uence upon their ‘absorption properties’ from
the gastrointestinal tract (GIT). It relates ultimately to the actual dissolution rate of the drug product.
Importantly, the most preferred means of assessing the therapeutic effi cacy of drugs depend solely on
the ‘slow dissolution rate’, which is duly given by the in vivo estimation of their respective bioavailability
profi le. Therefore, it forms the essential pre-requisite mandatory for a ‘new dosage-form’ intended to be
launched into the commercial market successfully.
In reality, therefore, the “best reliable, dependable and repeatable analytical equivalent ‘tool’ that may
promise quantitatively the pharmacologic availability of the ‘active drug’ from its respective dosage form
represents clearly its in vitro dissolution test.”
The most preferred monitoring of the ‘batch-to-batch uniformity’ via the stipulated in vivo tests
(on humans) is not only exorbitantly costly, but also tedious, time consuming and subjecting nor-
mal healthy volunteers to possible hazards of newer drug entities (molecules).
Bearing in mind the above ground realities, it is always desirable to replace reasonably the in vivo
bioavailability tests with relatively cheaper (cost-effective) in vitro methods. Evidently, depending on
the corresponding in vitro disintegration test may not always prove to be 100% trustworthy and reliable.
Note
7
They refer to all healthy human volunteers and patients as well.
8
It should be noted clearly that even the ‘pharmacist’ attached to a ‘Hospital Pharmacy’ is not empowered to change
the ‘drug product’ of a specifi c brand with another, unless he receives the substituted dosage form by the physician.