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Introduction to Biopharmaceutics and Pharmacokinetics
19
11.2. Uncomplicated Drugs
The uncomplicated drugs invariably refer to the various ‘oral drug product’, duly marketed as the common
conventional formulations, which do not fi nd their place under single or several complicated categories
(Table 1.2).
11.3. Guidelines for Equivalence Studies
It is, however, pertinent to state here that while making or formulating the guidelines for bioequivalence
studies for the actual conduct and careful analysis, the following array of pivotal factors must be consid-
ered, such as:
∑ physicochemical characteristic features,
∑ pharmacokinetics profi le of the drug,
∑ vital and important clinical aspect and
∑ a host of methodological aspects,
for both classifi cation of aforesaid drugs (viz. complicated ones and uncomplicated ones as well).
11.4. Plasma–Drug Concentration Versus Time Curve
The plasma–drug concentration versus time curve is usually obtained by determining precisely the drug
concentration in plasma samples meticulously drawn at predetermined/programmed time interval (in
hours) soon after a drug product is duly administered to a patient.
11.5. Modus Operandi
The various steps that are essentially involved in the preparation of plasma–drug concentration versus
time curve are enumerated as follows:
1. The actual concentration obtained after a single oral dose of a drug product being analyzed in each
plasma sample is duly plotted on a rectangular coordinate graph paper by taking
∑ plasma–drug concentration along y-axis and
∑ time interval
16
(in hours) along x-axis, to obtain a typical curve, as illustrated in Figure 1.5.
2. Figure 1.5 distinctly elaborates the various observed pharmacokinetic and pharmacodynamic
parameters.
16
Time Interval: It refers to the corresponding ‘time’ at which the ‘plasma sample’ was collected duly from the
patient after the administration of the drug product.
The various vital and important aspects of the plasma–drugs concentrated versus time curve are
explained duly as under:
1. Administered drug does have a remarkable tendency to reach the general (systemic) circula-
tion, thereby giving rise to the attainable drug concentration in plasma to a maximum level.
2. Invariably, one may observe critically that the absorption of a drug is found to be more fast
and rapid vis-à-vis its elimination phenomenon.
Explanation
Essentials of Biopharmaceutics and Pharmacokinetics
20
Figure 1.5 Diagrammatic representation of a typical plasma–drug concentration versus time curve, showing
explicitly pharmacokinetics/pharmacodynamic parameter accomplish after oral administration of a single dose
of drug.
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3. Importantly, the drug soon after its absorption right into the systemic circulation gets even-
tually distributed to most of the tissues in the body and ultimately, undergoes elimination
simultaneously.
4. Interestingly, the process of ‘elimination’ may be gainfully accomplished by
∑ excretion,
∑ biotransformation or
∑ a combination of both processes.
5. There are three distinct cut-off points along the y-axis, representing plasma–drug concentra-
tion (C
max
) in Figure 1.5, namely:
MTC: Minimum toxic concentration,
MSC: Maximum safe concentration and
MEC: Minimum effective concentration.
MEC: Such drugs that act specifi cally upon the autonomous nervous system, namely:
∑ norepinephrine—acting on the sympathetic system and
∑ acetylcholine—acting on the parasympathetic system.
It is absolutely necessary and useful to know the actual concentration of ‘drug substance’ which
would just afford a bare minimum level of pharmacologic effect. At this point in time, let us
assume that the prevailing concentration of the drug substance duly presented in the plasma
Introduction to Biopharmaceutics and Pharmacokinetics
21
remains to be in perfect equilibrium status with the tissues; the ensuing MEC duly designates
the minimum concentration of drug required actually at the receptor to exhibit the antici-
pated pharmacologic effect.
MTC: Likewise, MTC designates the prevailing drug concentration required to cause just a bare
minimum extent of toxic effect.
6. The intensity of the pharmacologic effect (as shown in the apex segment of Fig. 1.5) is observed
to be proportional to the number of drug receptor occupied predominantly. Nevertheless, this
specifi c pharmacologic action is distinctly refl ected in the observation that the higher plasma–
drug concentrations do exhibit a greater pharmacologic response up to a maximum degree.
7. The duration of drug action (as shown in the lower segment of AUC in Fig. 1.5) is shown by the
difference between the onset time and the time needed for the drug to decline back to MEC.
8. AUC
17
: In fact, the wisdom and skill of a pharmacokineticist may also elaborate and describe
the respective plasma–drug level concentration versus time curve of the following three phar-
macokinetics terms, namely:
∑ peak plasma level,
∑ time for peak plasma level and
∑ AUC.
9. AUC: It is virtually guided by three cardinal factors
∑ absorption phase,
∑ postabsorption phase and
∑ elimination phase.
10. Average rate of drug absorption: It is represented by the time of peak plasma level vis-à-vis
the time of maximum drug concentration recorded in the plasma.
11. Peak plasma concentration: The peak plasma concentration or maximum drug concentration
is intimately dependent upon the following cardinal factors, such as:
∑ directly related to the dose,
∑ rate constant for absorption and
∑ elimination constant of the drug.
17
AUC: It is related to the actual quantum of drug being absorbed systemically.
Few extra terms you must know!
Dosage regimen: It is the method that should be used to administer the appropriate quantity of
the drug.
Drug disposition: Distribution and elimination play a role in the therapeutic activity of a drug and
are together referred to as drug disposition.
Drug distribution: The relative motion of drug between different compartments of the body
(e.g., blood and extravascular tissue) is known as drug distribution.
Elimination: This is the process in which of drug activity is terminated (through biotransforma-
tion) and drug metabolites are removed from the body (excretion).
ADME: Absorption, distribution, metabolism and excretion.
KADME: Kinetics of ADME or pharmacokinetics.
Essentials of Biopharmaceutics and Pharmacokinetics
22
Suggested Readings
Gibaldi M. Biopharmaceutics and clinical pharmacokinetics. 4th edn. Hyderabad, India: Pharma Books
Syndicate, 2006.
Lutz R, Dedrick R. Physiological pharmacokinetics: relevance to human risk assessment. In: Li AP,
ed. Toxicity testing: new applications and applications in human risk assessment. New York: Raven; 1985:129–149.
Rowland M, Tozor T. Clinical pharmacokinetics: concepts and application. 3rd edn. Philadelphia, PA:
Lea & Febiger, 1995.
Tipnis HP. Bioavailability and bioequivalence. New Delhi, India: New Age International, 1996.
Welling P, Tse F. Pharmacokinetics. New York: Marcel Dekker, 1993.
Winters ME. Basic clinical pharmacokinetics. Vancouver, WA: Applied Therapeutics, 1994.
SECTION 2
Biopharmaceutics
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2
Biopharmaceutics
CHAPTER OUTLINE
1. Introduction
2. Biopharmaceutics Classifi cation System (BCS)
3. In Vitro–In Vivo Correlation (IVIVC): An Introspection
4. Passage of Drugs across Biological Barrier
5. Factors Infl uencing Drug Absorption
6. Mechanisms of Drug Absorption
7. Drug Absorption vs. Bioavailability
1. Introduction
Biopharmaceutics refers to the study of the relationship between physical, chemical and biological
properties of matter specifi cally in relation to drug substances, dosage forms (or drug products), drug
availability in vivo (or bioavailability) and the overall therapeutic actions.
It has been experimentally proven that the occurring ‘therapeutic response of a drug’ is dependent on
the following two important aspects, namely:
∑ suffi cient concentration of the acting drug and
∑ sustained presence of the drug either at a particular site or at several sites of action simultaneously.
In a broader perspective, the ‘drug substances’ which exert their action systematically are consid-
ered to be most preferred for clinical purposes exclusively because there exists a ‘dynamic equilibrium’
between the two under-mentioned entities
∑ critical concentration of drug in circulating blood and
∑ specifi c concentration of drug at its site(s) of action.
In other words, there exists a so-called ‘linear relationship’ between the drug-concentration in blood
and drug-concentration at the site of action. Obviously, one may easily predict the exact and precise
drug- concentration at the site of action based upon the present concentration of drug in the blood.
However, it is pertinent to state now that the actual concentration of drug in plasma water
1
dose serve
as a more reliable index of drug concentration prevailing at the site(s) of action compared to the actual
1
Plasma Water: It refers to the protein-free plasma.
Essentials of Biopharmaceutics and Pharmacokinetics
26
concentration of drug occurring in whole plasma.
2
Hence, it may be concluded that only such drug, which
is unbound, i.e., practically dissolved in plasma–water, may exhibit a tendency to release from plasma via
∑ capillary endothelium and
∑ various adjoining tissues,
and virtually approach other body fl uids and, therefore, gain a viable entry to the site(s) of action
appropriately.
To carry out the precise measurements (i.e., determination) of a specifi c ‘unbound drug substance’ in pro-
tein-free plasma (or plasma water) defi nitely requires a more sensitive and complex assay techniques rather
than estimating the total concentration of both bound and unbound drug substance in the ‘whole plasma’.
1.1. Alternative Distinctness of Biopharmaceutics
Biopharmaceutics may also be defi ned as ‘the intensive and extensive study of various factors that critically
infl uence the rate and amount of drug reaching the systematic circulation; and the subsequent usage of
this extremely valuable information so as to optimize the therapeutic effi caciousness of the drug products
(or dosage forms)’.
1.1.1. Important Modalities Encountered by a Drug
In other words, there are four important modalities which are eventually encountered by a drug inside
a human body, namely:
∑ Absorption: It usually refers to the process of movement of the ‘drug substance’ from its site of
administration to the systemic circulation.
∑ Distribution: It refers to the particular movement of drug substance between one compartment
and the other (viz. blood and extracellular tissues). Nevertheless, as the site of action is strategically
located in the extracellular tissues, the ultimate accomplished onset, intensity and duration of the
action of drug depends exclusively on the behavioural distribution pattern of the drug substance.
∑ Elimination: It may be defi ned as ‘the critical phenomenon during which the body tends to
remove the drug and terminate its action completely’.
In fact, elimination comes into play via two well-recognized processes:
∑ biotransformation (or metabolism)—that normally renders the ‘drug’ inactive, and
∑ excretion—that is responsible for the complete exit of the ‘drug’ or its ‘respective’ metabolites from
the human body.
Earlier it was believed that the therapeutic response of a ‘drug substance’ is attributed to its intrinsic
pharmacologic activity. However, as to date, it is absolutely clear that the ensuing dose–response relation-
ship is accomplished after ‘drug administration’ via different routes, such as:
∑ oral administration and
∑ parenteral administration (viz. IV, IM, SC etc.),
are not found to be of the same level.
Besides, wide variations in drug products may also be noticed predominantly when produced by dif-
ferent manufacturers, which could be caused due to critical factors, such as:
2
Whole Plasma: It contains plasma protein which has a tendency to bind the drug in a reversible manner.
Biopharmaceutics
27
∑ physicochemical characteristics features of the drug substance,
∑ excipients incorporated in the drug product,
∑ formulation technique adopted and
∑ the route of administration engaged.
On the basis of these facts, one has to take cognizance of factual information(s) and data pertaining
to the optimal administration of drugs so as to
∑ fully understand the inherent mechanisms of drug–absorption–distribution–metabolism–and excre-
tion (ADME) and
∑ evaluate the kinetics (rate) at which ADME takes place, i.e., the ‘pharmacokinetics’.
1.2. Pharmacokinetics
Pharmacokinetics may be referred to as ‘the study of the quantitative relationships of the rates of drug
absorption, distribution and elimination processes, i.e., data used to establish dosage amount and fre-
quency for desired therapeutic response’.
In a rather simpler version, pharmacokinetics represents the ensuing kinetics of ADME or more
precisely, KADME.
1.3. Clinical Pharmacokinetics
It refers to the ‘application of pharmacokinetics to the safe and effective therapeutic management of an
individual patient’.
Shargel and Yu (1999)
3
emphasized that ‘biopharmaceutics’ makes use of both quantitative method-
ologies and theoretical models to evaluate the effect of
∑ drug substance,
∑ dosage form,
∑ routes of drug administration upon the therapeutic needs of the ‘drug’ and
∑ critical role of drug products in a typical physiological environment.
Table 2.1 records the various aspects of biopharmaceutic considerations in the specifi c design of drug
product (or dosage form) which is entirely based on the following characteristic features:
∑ physiochemical properties of the ‘active drug’,
∑ desired ‘dosage form’ (or drug product) and
∑ anatomical and physiological considerations of the human body.
Importantly, the meticulous design of an appropriate dosage form requires in-depth knowledge of phar-
macodynamics
4
of the drug substance including the following important criteria:
∑ onset time of drug product,
∑ duration of the drug product exhibiting its action,
3
Shargel L and Yu ABC: Applied Biopharmaceutics and Pharmacokinetics, 4th edn., McGraw Hill Medical Publishing,
New York, 1999.
4
Pharmacodynamics: It refers to the study of absorption, distribution, metabolism and excretion of a drug
substance, besides its mechanism of action and its biochemical and physiological effects.
Essentials of Biopharmaceutics and Pharmacokinetics
28
∑ observed intensity of clinical response and
∑ pharmacokinetics of the drug, e.g., absorption pattern, distribution profi le, elimination mode and the
ultimate target-drug concentration.
Shargel and Yu (1999) put forward a descriptive scheme, as shown in Figure 2.1, demonstrating the ensu-
ing dynamic correlation prevailing among the drug substance, drug product and pharmacologic effect.
Interestingly, biopharmaceutics embraces the factors which infl uence the following aspects:
Table 2.1 Various aspects of biopharmaceutic considerations in the specifi c design of drug product (or dosage form)
S. No.
Various considerations/
factors
Characteristic features Special remarks
1 Active pharmaceu-
tical ingredient
(API)
Stability; solubility; pH and pK
a
; polymorph
(crystalline form; excipient interaction;
compatibility).
Presence of impurities; particle
size; salt form; and complexa-
tion.
2 Dosage form (or
drug product)
Types of secondary pharmaceutical prod-
uct (dosage form), viz. tablet, capsule,
parenterals; immediate or modifi ed drug
release profi le; dosage strength variability;
and bioavailability.
Stability profi le; excipient
variants; and manufacturing
variable criteria.
3 Physiological factors Various routes of administration; permea-
tion of drug across the cell membranes;
and binding of ‘drug’ to macromolecules
(viz. proteins).
Blood-fl ow pattern; surface area;
and biotransformation.
4 Pharmacodynamic
and pharmacoki-
netic factors
Bioavailability; therapeutic aim and objec-
tive; and adverse drug reactions.
Pharmacokinetics; dose; and
toxic effects.
5 Manufacturing
aspects
Production methods; latest technological
adaptation; quality assurance; and raw
material specifi cations.
Cost-effective measures and
product stability testing.
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Figure 2.1 A descriptive scheme showing the dynamic correlation prevailing among drug substance, drug
product and pharmacologic effect.
(Adapted from: Shargel L, Yu ABC. Applied Biopharmaceuties and Pharmacokinetics, 4th edn. New York: McGraw Hill Medical
Publishing, 1999.)