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Clinical Pharmacokinetics
279
Three situations may arise with regard to the various interactions affecting metabolism, such as:
∑ metabolic enhancement,
∑ genetic polymorphism and drug interactions and
∑ metabolic inhibition,
which will be treated briefl y in the following sections.
Metabolic Enhancement It has been amply proven that when a particular drug (D
1
) [an ‘inducer’]
enhances the overall metabolism of another drug (D
2
) [a ‘substrate’], it inherits a tendency to reduce the
levels of that drug (D
2
), i.e., the substrate in vivo, and in turn increases the levels of the ensuing metabo-
lites adequately.
CYP2D6 and CYP3A4 designate the major drug metabolizing isoenzyme systems; whereas, cer-
tain drugs are duly metabolizing by other cytochrome systems, for instance,
CYP1A2, CYP2C9, CYP2C19 and CYP2E1.
Isoenzyme-based Mechanisms: Importantly, for several metabolic inter-reactions the logical
isoenzyme-based mechanisms have not yet been fully established.
Examples
A number of deaths have been reported from the critical ‘inhibition of the azallinoprine metabo-
lism’ caused by allopurinol; however, the underlying probable mechanism still remains a mystery.
Example
Various anti-epileptic medicaments, e.g., Phenobarbitone, Carbamazepine and Phenytoin, do serve
as potent ‘inducers’ of the cytochrome [CYP3A4] and, therefore, shall interact with COCs (com-
bined oral contraceptives) to minimize the existing levels of both ‘active oestrogen’ and ‘progestogens’
(i.e., progestational agents).
Example
Another glaring example may be seen when the action or toxicity of a drug substance is critically
produced by the help of an active metabolite. In such a situation, if one enhances the rate of metabolism
of the parent drug, it could signifi cantly enhance the yield of the resulting metabolite.
The above instance may be further expatiated by the typical example of paracetamol (acetaminophen)
being duly metabolized via CYP2E1 (a cytochrome isoenzyme) to a corresponding ‘hepatotoxic metabo-
lite’, that gets eventually conjugated with glutathione
28
into an ‘active form’. Now, with the careful metabolic
induction of paracetamol via CPY2E1-inducer, viz. isoniazid or ethanol, one may achieve high levels of
the toxic metabolite which may ultimately surpass the quantum of glutathione duly stored in liver. Thus,
it would be responsible for affording a hepatic damage from the everlasting prolonged metabolite levels
in vivo.
28
Glutathione: It shows a metabolic role in anti-neoplastic chemotherapy [Arriek BA and Nathan CF: Cancer
Res., 44: 4224–4232, 1984].
Essentials of Biopharmaceutics and Pharmacokinetics
280
Genetic Polymorphism and Drug Interactions It has been reported widely that within altogether
different populations and ethnic groupings, there exists several individuals who may distinctly possess a
glaring ‘defi ciency’ in an isoenzyme and, therefore, shall not be able to handle effi ciently the metaboliza-
tion of drugs by the aforesaid system (also termed as the ‘poor metabolizers’).
An individual when administered with Flecainide
29
(a class IC anti-arrhythmic drug)and serves
as a poor metabolite via CYP2D6) shall critically experience reasonable therapeutic failure by
means of a drug substance seeking conversion to a metabolite for exhibiting its desired activity,
e.g., codeine (an opiate analgesic).
Examples
29
That is, a CYP2D6 substrate.
India has an array of ‘ethnic groups’ who clearly display altogether different proportions of both
extensive and sluggish metabolizers, for instance
Indian population explicitly shows variant extent of poor metabolizer levels, viz.
2%–5%—Poor metabolizers of CYP2DC substrates and
11%—North Indians as poor metabolizers of CYP2C19 substrates.
Metabolic Inhibition In a most critical situation, when a subject is duly treated with a ‘parent drug
substance’ that happens to be an ‘active agent’, the respective metabolic inhibition of the ‘drug’ shall
enhance the plasma levels of that drug possessing:
∑ requisite potential for toxicity and
∑ increased risk of adverse drug reactions.
Salient Features: These essentially comprise:
1. Prodrug (viz. Azathiopurine, Phenylbutazone, Sulindae) must be metabolized for showing its
activity and subsequently, the inhibited metabolism may
∑ retard the onset of action and
∑ prevent the activity of the drug.
2. The ‘metabolic inhibition’ may be preferentially employed to lower the dose level as well as the
cost-effective measure for the highly expensive medicaments.
Dilitazepam (a Class IV ‘anti-arrhythmic drug’) specifi cally causes inhibition of the isoenzyme
CYP3A4; and, therefore may be administrated along with ‘cyclosporin’ (a CYP3A4 substrate) in
order to lower signifi cantly the
∑ marked reduction in the dose-level and
∑ effective cost reduction of ‘cyclosporin’ in organ transplantation (viz. kidney, liver, eyes etc.).
Examples
3. Importantly, the metabolic inhibition also renders the subjects to a high risk of toxicity level.
Clinical Pharmacokinetics
281
4.1.4. Interactions Affecting Renal Excretion
It is particularly applicable to most of the water-soluble drug molecules that are duly eliminated via
the following different means:
∑ kidneys,
∑ change in urinary pH profi le,
∑ tubular secretion pattern and
∑ glomerular fi ltration rate (GFR)
and may appreciably alter the quantum of drug substance being excreted from the body.
The above ‘renal excretion’ phenomenon may further be expatiated with the help of some typical examples:
1. Lithium (Li) Excretion: A good number of interactions that are intimately associated with the
lithium-excretion by the kidney give rise to a signifi cant degree of interference being involved.
Thiazide diureties (e.g., Hydrochlorothiazide, Hydrofl umethiazide, Bendrofl umenthiazide,
Trichloromethiazide, Methyclothiazide, Polythiazide, and Cyclothiazide) distinctly enhances the
renal-tubular reabsorption of Li and hence, may cause toxicity profusely. Besides, the NSAIDs (e.g.,
Paracetamol, Ibuprofen, Piroxicam etc.) are found to inhibit the prostaglandins which are known
to maintain the required blood fl ow right inside the renal glomeruli. Obviously, at a reduced rate
in blood fl ow, one may observe relatively lesser quantum of lithium being fi ltered via the glomeruli,
which ultimately enhances the plasma levels.
2. Sodium Citrate: It serves as an alkalinizing agent employed invariably to accomplish two main objectives:
∑ enhancing the pH of urine and
∑ minimizing the symptoms of an urinary tract (UI infection).
In addition, it may exert its action upon the excretion of both basic and acidic drug substances as follows:
1. Basic Drugs, e.g., Amiloride, Cimetidine and Ranitidine—the excretion gets reduced appreciably
perhaps due to the production of more unionized molecules.
2. Acidic Drugs, e.g., Acyclovir, Cephalosporins, Penicillins and Thiazide Diuretic—exertion gets
increased by virtue of the quantum of ionized drug molecules, and corresponding depletion of
tubular reabsorption.
4.2. Pharmacodynamic Interactions
The pharmacodynamic interactions usually take place whenever a drug exerts either an additive or
antagonistic effect upon pharmacological action of another drug. Therefore, a sound and thorough
knowledge in pharmacology actually renders it possible to anticipate/predict a plethora of such phar-
macodynamic interactions. Therefore, in a specifi c situation when the patients are duly subjected to
Theophylline toxicity may be observed frequently in subjects administered with ciprofl oxacin
thereby causing immediate seizures. This untoward behavioural pattern of the drug could be
explained logically due to the ability of inhibiting the metabolism of theophylline in conjunction
with ciprofl oxacin or some other quinolone antibiotics (viz. Cinoxacin, Norfl oxacin, Enoxacin,
Ofl oxacin, Lomefl oxacin) via critical inhibition of CYP1A2 and CYP3A4.
Examples
Essentials of Biopharmaceutics and Pharmacokinetics
282
treatment with a relative number of medicaments (drug products), it would be rather be diffi cult to
interpret the overall interactions justifi ably.
Following are the two cardinal aspects pertaining to the pharmacodynamic interactions, namely:
∑ pharmacological synergism and
∑ pharmacological antagonism,
which will be discussed briefl y in the following.
4.2.1. Pharmacological Synergism
It may be expatiated by citing a typical example when one specifi c drug is being added to another drug
to yield a defi nite and perceptible enhancement in the pharmacological activity observed ultimately.
As to date, an avalanche of so-called ‘drug combinations’ are put in use abundantly for gainful thera-
peutic advantages.
1. Combination of Trimethoprim and Sulfamethoxazole [Septron
®
]—It shows a synergistic
effect against the bacterial infections.
2. Combination of Norfl oxacin and Metronidazole [Norfl ox–MZ
®
], and Norfl oxacin and
Tinidazole [Norfl ox-TZ
®
]—It exhibits a broad spectrum activity in severe diarrhoea due to
food poisoning.
3. Paracetamol and Ibuprofen [Combifl am
®
]—It is used in joint pain.
Examples
4.2.2. Pharmacological Antagonism
This sort of action, i.e., pharmacological antagonism, could be seen when the effect of one drug prevents
the action shown by another drug.
1. Marked reduction in the anti-hypertensive activity of a drug by a thiazide diuretic, e.g.,
Nebicard-H
®
(where H stands for hydrochlorothiazide).
2. A combination of phenytoin and amitriptyline, where former is an anti-epileptic drug and
the latter is a tricyclic anti-depressant drug.
Examples
Suggested Readings
Hardman JG, Limbird LE . Pharmacokinetics: The dynamics of drug absorption, distribution, and elimination, In:
The Pharmacological Basis of Therapeutics, 10th edn. New York: McGraw Hill, 2001.
Levine RJ. Ethics and Regulation of Clinical Research. Baltimore, MD: Urban & Schwarzenberg, 1986.
Notari RE. Biopharmaceutics and Clinical Pharmacokinetics: An Introduction, 4th edn. New York: Marcell Dekker, 1987.
Pratts WB, Taylor P (eds.). Principles of Drug Action: The Basis of Pharmacology, 3rd edn. New York: Churchill
Livingstone, 1990.
Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications, 3rd edn. New York: PA: BI Waverley Pvt.
LTD., 1996.
Veatch RM. The Patient as Partner: A Theory of Human Experimentation Ethics. Bloomington, UK: Indian University
Press, 1987.
SECTION 5
Bioavailability and
Bioequivalence
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5
Bioavailability and Bioequivalence
CHAPTER OUTLINE
1. Introduction
2. Bioavailability
3. Bioequivalence
4. Bioanalytical Method Development and Validation
for Bioavailability and Bioequivalence Studies
1. Introduction
1.1. Preamble
Bioavailability refers to the extent to which a ‘drug’, or other substance, becomes available to the respec-
tive ‘target tissue’ after its due administration.
The modern trend is gaining heat with regard to the tremendous quantum leap towards the devel-
opment of highly improvized ‘drug formulations’ (drug products or dosage forms) so that the active
ingredient reaches the ‘target tissue’ directly thereby giving prompt relief to the patient. Once this goal
is achieved, the manufacturer assigns the ‘drug product’ a ‘brand name’, e.g.,
∑ Travatan
®
: Travopost 0.004% (w/v) ophthalmic solution;
∑ Allergan-P
®
: Brimonidine Tartrate 0.15% (w/v) ophthalmic solution;
∑ Lariago
®
: Chloroquine phosphate tablets (250 mg),
and sells it both within the country and abroad at a defi nitely higher ‘price-level’.
1
In view of the above stark realities, the ‘formulation selected’ and the ‘critical manufacturing method’
of the dosage form may
∑ directly affect the ‘bioavailability’ and
∑ overall stability
of the active ingredient (i.e., drug). Therefore, it has become abundantly clear that the producer of ‘generic
drug’
2
should mandatorily demonstrate that the marketed ‘generic drug product’ proves to be both
1
Since the manufacturer has already spent a lot of money in its development in the Research and Development.
2
Generic Drug: That is, denoting a drug name not protected by a ‘Trademark’.
Essentials of Biopharmaceutics and Pharmacokinetics
286
∑ bioequivalent and
∑ equivalent
pertaining to their therapeutic effi caciousness to the corresponding ‘Branded Drug Product’.
It is worthwhile to mention at this material time that the following authorized professionally quali-
fi ed personnel, such as:
∑ physicians,
∑ pharmacists,
∑ dispensers and
∑ drug buyers,
do share major responsibilities pertaining to
∑ selection of proper ‘dosage form(s)’ and
∑ perfect substituted ‘generic drug products’.
United States-Food and Drug Administration (US-FDA) provides through annual published guide-
lines (both in print and on the Internet) for the Approved Drug Products with Therapeutic Equivalent
Evaluations (also sometimes referred to as the ‘Orange Book’.
3
Website: www.fda.gov/cder/ob/default.htm).
1.2. Definitions
Following are some of the key terminologies related to ‘bioavailability’ and ‘bioequivalence’ as described
under (1) through (18).
3
Orange Book: It specifi cally identifi es complete range of ‘dosage forms’ (i.e.,) drug products duly approved on
the basis of safety and effectiveness by the US-FDA; and also comprises the ‘therapeutic equivalence evaluations’
for approved multi source for prescriptions.
For such drug products which are not meant to be absorbed into the bloodstream directly, the
required ‘bioavailability’ may be determined by such measurement modalities that are intended either
to represent the rate or the degree to which the ‘drug’ is made available at the very site of action.
Note
1. Bioavailability: It may be defi ned as the rate and extent to which the active substance or active
moiety gets duly absorbed from a dosage form (or drug product) and becomes readily available at
the site of action.
2. Bioequivalence Requirement: The bioequivalence requirement as imposed by the US-FDA for
the critical testing of both in vivo and/or in vitro dosage forms, that should be satisfi ed satisfactorily
as a pre-requisite condition for marketing.
3. Bioequivalent Dosage Forms: In a broader perspective, this terminology duly describes both
∑ pharmaceutical equivalents and
∑ pharmaceutical equivalent products,
which explicitly exhibit fairly comparable bioavailability on being subjected to identical experi-
mental parameters.
Systemically absorbed drug substances, such as test (generic) drug and reference (listed) drug may also
be regarded to be ‘bioequivalent’, if one may observe that
Bioavailability and Bioequivalence
287
∑ Rate and degree of absorption of ‘test drug’ fails to display an appreciable difference vis-à-vis rate and
degree of absorption of ‘reference drug’, only when given carefully at the same molar dosage of the
therapeutic ingredient under identical experimental parameters in a single dose, or a multiple doses;
∑ Degree of absorption of ‘test drug’ does not exhibit a signifi cant difference vis-à-vis degree of absorp-
tion of ‘reference drug’ on being administered at the same molar dose of the therapeutic ingredient
almost under identical experimental parameters in
_ a single dose or
_ multiple doses,
whereby, the observed difference from ‘reference drug’ with regard to the rate of absorption of the
‘drug’ essentially remains to be
∑ intentional,
∑ shown in its proposed labelling,
∑ must not attain effective body-drug-dose concentrations on chronic usage and
∑ regarded as medically insignifi cant for the drug substance.
Note
It has been observed that the ‘bioequivalent dosage forms’ may essentially comprise altogether
different inactive ingredients provided the manufacturer clearly identifi es the actual differences, if
any. Besides, the latter provides enough information to this effect that such inherent differences
DO NOT affect either the effi caciousness or safety of the drug product.
4. Chemical Nomenclature: The chemical nomenclature used by the International Union of Pure
and Applied Chemistry (IUPAC) to indicate the chemical structure of the drug.
N-acetyl-p-aminophenol or paracetamol, or acetaminophen.
+2
2
1
+
&+
Example
5. Brand Name: It refers to the ‘trade name’ of the drug product (or dosage form). In fact, this name
is registered and privately owned by the pharmaceutical manufacturer in the country of origin
and is, therefore, used to make a clear-cut distinction of the specifi c drug product from other com-
petitors products, viz. Tylenol
®
(Manufactured in USA by: McNeil Laboratories); Efudex
®
(Roche
Laboratories, Switzerland); Pfi zerpen A
®
(Pfi zer, USA), Kelbeil
®
(Beecham, UK).
6. Drug Product: It means the fi nished dosage form (viz. capsules, tablets, injectables, elixirs, sus-
pensions, inhalers etc.) which solely contains the active drug ingredient, mostly, but not necessarily,
in association with several other inactive ingredients (adjuvants: starch, binders, emulsifi ers etc.).
7. Selection of Drug Product: The critical phenomenon of selecting (or choosing) the most pre-
ferred drug product in a specifi ed ‘dosage form’ available commercially.
Essentials of Biopharmaceutics and Pharmacokinetics
288
8. Drug Substance: A drug substance invariably refers to the ‘active pharmaceutical ingredient’
(API) or component present in the drug product which is solely responsible for providing the
desired pharmacodynamic activity (i.e., pharmacologic activity).
9. Equivalence: The term ‘equivalence’ relates to the prevailing relationship with respect to the fol-
lowing aspects:
∑ Bioavailability,
∑ Therapeutic response and
∑ A set of predetermined/established ‘standards’ of one drug product to another.
10. Generic Nomenclature: It largely refers to the established, recognized, nonproprietary or common
name of an ‘active drug’ in a drug product, viz. acetaminophen (USA) or paracetamol (UK/India).
11. Generic Substitution: The generic substitution usually means the typical process of
∑ dispensing an altogether different brand or
∑ an unbranded drug product
instead of the originally prescribed dosage form (or drug product). Nevertheless, the ‘substituted
drug product’ mainly comprises the
∑ same active ingredients,
∑ therapeutic moiety and
∑ present as same salt/ester
usually present in the same drug product, but is obviously made by an altogether different manufacturer.
A prescription for Glaxo Smith Kline Pharmaceutical Ltd. brand [Calpol
®
] paracetamol tab-
lets might be dispensed by the pharmacist with either Genmole
®
by Cadila Pharmaceuticals or
Magadol
®
by Novocare Pharmaceuticals or if the generic substitution is duly permitted and indi-
cated by respective physician.
Example
12. Pharmaceutical Alternatives: Dosage forms which prominently consist of the same therapeutic
moiety, but actually present as complexes, salts or esters.
Preparations available as ‘Testosterone’ active drug:
∑ Andractim
®
—Chemech Laboratories: Dihydrotestosterone;
∑ Nuvir
®
—Infar Laboratories: Testosterone Undecanoate;
∑ Sustanon-100
®
—Infar Laboratories; Testosterone Propionate.
Examples
Remarks: Following two important remarks may be noted:
(a) Drug product variants having different strengths within a product line produced by a ‘single
manufacturer’ are usually considered as pharmaceutical alternatives, such as:
∑ a sustained-release dosage form and
∑ a standard immediate-release drug product.
(b) US-FDA Requirements: It critically examines and considers a ‘tablet’ or ‘capsule’ essentially
comprising the ‘same active ingredient’ present duly in the ‘same dosage strength’ as in the alter-
native pharmaceuticals (or drug products).