Advances in Biopharmaceutics and

Pharmacokinetics

Dr. Muzaffar Abbas

Pharmacokinetics
•Pharmacokinetics refers to what the body does to a
drug. It deals with absorption, distribution,
metabolism and excretion of drugs
Biopharmaceutics
Biopharmaceutics is the science that examines this
interrelationship of the physicochemical properties of
the drug, the dosage form in which the drug is given,
and the route of administration on the rate and extent
of systemic drug absorption. Thus, biopharmaceutics
involves factors that influence
(1) the stability of the drug within the drug product,
(2) the release of the drug from the drug product,
(3) the rate of dissolution/release of the drug at the
absorption site, and
(4) the systemic absorption of the drug.
Pharmacokinetics
After a drug is released from its dosage form, the
drug is absorbed into the surrounding tissue, the
body, or both.
Pharmacokinetics is the science of the kinetics of
drug absorption, distribution, and elimination (ie,
excretion and metabolism).
The description of drug distribution and elimination
is often termed drug disposition. Characterization of
drug disposition is an important prerequisite for
determination or modification of dosing regimens for
individuals and groups of patients.
 The study of pharmacokinetics involves both
experimental and theoretical approaches.
 The experimental aspect of pharmacokinetics
involves the development of biologic sampling
techniques, analytical methods for the
measurement of drugs and metabolites, and
procedures that facilitate data collection and
manipulation.
 The theoretical aspect of pharmacokinetics
involves the development of pharmacokinetic
models that predict drug disposition after drug
administration. The application of statistics is an
integral part of pharmacokinetic studies.
Clinical Pharmacokinetics
During the drug development process, large
numbers of patients are tested to determine optimum
dosing regimens, which are then recommended by
the manufacturer to produce the desired
pharmacologic response in the majority of the
anticipated patient population.
However, intra- and interindividual variations will
frequently result in either a subtherapeutic (drug
concentration below the MEC) or toxic response
(drug concentrations above the minimum toxic
concentration, MTC), which may then require
adjustment to the dosing regimen.
Clinical pharmacokinetics is the application of
pharmacokinetic methods to drug therapy. Clinical
pharmacokinetics involves a multidisciplinary
approach to individually optimized dosing strategies
based on the patient's disease state and patient-
specific considerations.
The study of pharmacokinetic differences of drugs
in various population groups is termed population
pharmacokinetics.
Pharmacokinetics is also applied to therapeutic drug
monitoring (TDM) for very potent drugs such as
those with a narrow therapeutic range, in order to
optimize efficacy and to prevent any adverse toxicity.
For these drugs, it is necessary to monitor the patient,
either by monitoring plasma drug
concentrations (eg, theophylline) or by monitoring a
specific pharmacodynamic endpoint such as
prothrombin clotting time (eg, warfarin).
Some drugs frequently monitored are the
aminoglycosides and anticonvulsants. Other drugs
closely monitored are those used in cancer
chemotherapy, in order to minimize adverse side
effects.
Potency
•Potency refers to the concentration (EC50) or dose
(ED50) of a drug required to produce 50% of that
drug’s maximal effect.
•Pharmacologic potency of drug A is less than that of
drug B, a partial agonist because the EC50 of A is
greater than the EC50 of B.
•Drugs A and B are said to be more potent than drugs
C and D because of the relative positions of their
dose response curves along the dose axis.
•For therapeutic purposes, the potency of a drug
should be stated in dosage units, usually in terms of a
particular therapeutic end point (eg, 50 mg for mild
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sedation, 1 mcg/kg/min for an increase in heart rate
of 25 bpm). Relative potency, the ratio of equi-
effective doses (0.2, 10, etc), may be used in
comparing one drug with another.
Potency of a drug depends in part on the affinity
(Kd) of receptors for binding the drug and in part on
the efficiency with which drug-receptor interaction is
coupled to response.

Figure: Graded dose-response curves for four drugs 11

Figure: The effect of dose on the magnitude of pharmacologic response. Panel A is a linear
graph. Panel B is a semilogarithmic plot of the same data. EC50 = drug dose causing 50% of
maximal response. 12
Maximal efficacy
Efficacy is the magnitude of response a drug causes
when it interacts with a receptor.
Efficacy is dependent on the number of drug–
receptor complexes formed and the intrinsic activity
of the drug (its ability to activate the receptor and
cause a cellular response).
Maximal efficacy of a drug (Emax) assumes that all
receptors are occupied by the drug, and no increase in
response is observed if a higher concentration of drug
is obtained.
 The maximal response differs between full and
partial agonists, even when 100% of the receptors are
occupied by the drug. 13
 Similarly, even though an antagonist occupies
100% of the receptor sites, no receptor activation
results and Emax is zero.
 Efficacy is a more clinically useful characteristic
than is drug potency, since a drug with greater
efficacy is more therapeutically beneficial than is
one that is more potent.

Figure: Typical dose–response curve for drugs

showing differences in potency and efficacy.
EC50 = drug dose that shows 50% of maximal
14
response.
Quantal Dose-Effect Curves
Quantal dose-response relationship describes a drug
effect which is binary (either present or absent).
A quantal response to a drug is observed in a
population, and is either present or absent in any
single individual such as prevention of convulsions,
arrhythmia, relief of headache, or death.

Quantal dose-effect plots.

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 Quantal dose–response relationship can be
determined in a population for the
antihypertensive drug atenolol. A positive
response is defined as a fall of at least 5 mm Hg in
diastolic blood pressure.
• Median effective dose: The dose of a drug
required to produce a specified effect in 50% of
the population is the median effective dose
(ED50).
• Median toxic dose: In clinical studies, dose
required to produce a particular toxic effect in
50% of population is called the median toxic dose
(TD50).
• Median lethal Dose: Dose that causes death in 16
LD50
If the ED50s of two drugs for producing a specified
quantal effect are 5 and 500 mg, respectively, then
the first drug can be said to be 100 times more potent
than the second for that particular effect.
The index of the selectivity of a drug’s action can be
obtained by comparing its ED50s for two different
quantal effects in a population (eg, cough suppression
versus sedation for opioid drugs).

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Therapeutic index
The therapeutic index (TI) of a drug is the ratio of the
dose that produces death in half the population
(TD50) to the dose that produces a desired or
effective response (ED50) in half the population:
TI = TD50/ ED50
The TI is a measure of a drug’s safety, because a
larger value indicates a wide margin between doses
that are effective and doses that are toxic.
Clinical therapeutic index
The therapeutic index (TI) of a drug is the ratio of the
dose that produces toxicity in half the population
(TD50) to the dose that produces a clinically desired
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or effective response (ED50) in half the population:
TI = TD50/ ED50
Drugs with low Therapeutic index:
Digoxin, Propranolol, morphine and adrenaline. A
small increase in dose of such drugs may lead to
toxicity.
Drugs with High Therapeutic index:
Diazepam, Sulphonamides, Procainamide and
Chlorpromazine. A large increase in dose of such
drugs may lead to no toxicity

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Quantal dose–effect curves. Animals were injected with varying doses of sedative-hypnotic,
and the responses were determined and plotted. The calculation of the therapeutic index, the
ratio of the LD50 to the ED50, is an indication of how selective a drug is in producing its
desired effects relative to its toxicity. 20
Cumulative percentage of patients responding to plasma levels of warfarin and penicillin.
21
Therapeutic window
The range between the minimum toxic dose and the
minimum therapeutic dose is called the therapeutic
window and is of greater practical value in choosing
the dose for a patient.
Or
The range of plasma levels between that required for
efficacy and that at which toxicity occurs for a given
individual is designated the therapeutic window.

Figure: The relation of the therapeutic window of

drug concentrations to the therapeutic and adverse
effects in the population. Ordinate is linear; abcissa is
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logarithmic.
Figure: Temporal characteristics of drug effect and relationship to the therapeutic
window (e.g., single dose, oral administration) 23
Pharmacodynamics
Pharmacodynamics refers to the relationship
between the drug concentration at the site of action
(receptor) and pharmacologic response, including
biochemical and physiologic effects that influence
the interaction of drug with the receptor.
The interaction of a drug molecule with a receptor
causes the initiation of a sequence of molecular
events resulting in a pharmacologic or toxic response.
Pharmacokinetic-pharmacodynamic models are
constructed to relate plasma drug level to drug
concentration in the site of action and establish the
intensity and time course of the drug.
Receptor
Any biologic molecule to which a drug binds and
produces a measurable response.

Receptor Families
Ionotropic Receptors (Receptors associated ion
channels)
Metabotropic receptors (G Protein–Coupled
Receptors
Enzyme-linked receptors(Receptors linked with
tyrosine kinase & Receptors linked with JAK-STAT
Pathways)
Intracellular receptors
Figure: Transmembrane signaling mechanisms. A. Ligand binds to the extracellular domain of
a ligand-gated channel. B. Ligand binds to a domain of a transmembrane receptor, which is
coupled to a G protein. C. Ligand binds to the extracellular domain of a receptor that activates a
kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact with its
intracellular receptor. R = inactive protein.
1. Ionotropic Receptors (Receptors associated ion
channels)
The extracellular portion of ligand-gated ion channels
usually contains the ligand binding site linked with
ion channel
 Nicotinic acetylcholine receptor
 γ-aminobutyric acid (GABA) receptor
Receptors associated Voltage-gated ion channels
Receptors for glutamate, aspartate, and glycine

The nicotinic acetylcholine (ACh) receptor, a

ligandgated ion channel.
2. Metabotropic receptors (G protein–coupled
receptors)
•The extracellular domain of this receptor contains
the ligand-binding area, and the intracellular domain
interacts (when activated) with a G protein.
•There are many kinds of G proteins (for example,
Gs, Gi, and Gq), but they all are composed of three
protein subunits.
•The α subunit binds guanosine triphosphate (GTP),
and the β and γ subunits anchor the G protein in the
cell membrane.
Figure: The recognition of chemical signals by G protein–coupled membrane receptors affects
the activity of adenylyl cyclase. PPi = inorganic pyrophosphate.
Figure: G proteins and their receptors and effectors.
 3. Enzyme-linked receptors
(Receptor linked with tyrosine kinase
& Receptor linked JAK-STAT Pathways)
A. Receptor linked with tyrosine kinase
Receptor has both extracellular and intracellular
domain.
The intracellular domain has intrinsic enzymatic
activity (tyrosine kinase enzyme) that become
activated on ligand binding, receptor dimerizing and
receptor auto-phosphorylation.
The tyrosine kinase enzyme activates downstream
signaling proteins.
Examples: Receptors for insulin, epidermal growth
factor (EGF), platelet-derived growth factor (PDGF),
atrial natriuretic peptide (ANP), transforming growth
factor-β (TGF-β), and many other trophic hormones.
 Mechanism of activation of the epidermal growth factor
(EGF) receptor, a representative receptor tyrosine kinase.

Insulin receptor.
B. Cytokine Receptors
•Receptor has both extracellular and intracellular
domain.
•JAK is bound to intracellular domain covalently.
•Receptor dimerizes upon ligand binding, JAK
becomes activated and causes receptor
phosphorylation.
•The bound STATs are themselves phosphorylated
by the JAKs and travel to the nucleus, where they
regulate transcription.
•Examples Growth hormone, erythropoietin, several
kinds of interferon, Cytokines etc.
Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains
and form dimers. However, after activation by an appropriate ligand, separate mobile protein
tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal
transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the
nucleus, where they regulate transcription.
4. Intracellular receptors
Intracellular receptors
•The receptor is entirely intracellular.
•The ligand must diffuse into the cell to interact with
the receptor. In order to move across the target cell
membrane, the ligand must have sufficient lipid
solubility.
•Receptors as Transcription Factors ( e.g receptors
for steroid hormones, thyroid hormone, vitamin D),
structural proteins, enzymes, calcium release
receptors, DNA, RNA and ribosomes.
Figure: Mechanism of glucocorticoid action. The glucocorticoid receptor polypeptide i
schematically depicted as a protein with three distinct domains. A heat-shock protein, hsp90, bind
to the receptor in the absence of hormone and prevents folding into the active conformation of th
receptor. Binding of a hormone ligand (steroid) causes dissociation of the hsp90 stabilizer and
permits conversion to the active configuration.
• Tubulin is the target of antineoplastic agents such
as paclitaxel and colchicine.
• The enzyme dihydrofolate reductase is the target
of antimicrobials such as trimethoprim and
antineoplastic drug methotrexate; 3-hydroxy-3-
methylglutaryl–coenzyme A (HMG-CoA)
reductase, the receptor for statins; and various
protein and lipid kinases.
• 50S subunit of the bacterial ribosome is the target
of macrolide antibiotics such as erythromycin.
• Calcium release receptors on endoplasmic
reticulum for IP3.
5. Others
Transport proteins can be useful drug targets e.g.
Na+/K+-ATPase, the membrane receptor for
cardioactive digitalis glycosides;
Norepinephrine and serotonin transporter proteins
that are membrane receptors for antidepressant drugs;
Dopamine transporters that are membrane receptors
for cocaine and a number of other psychostimulants.
Structural motifs of physiological receptors and their relationships to signaling pathways.
Actions of Drugs Not Mediated by Receptors
Some drug effects do not occur via macromolecular
receptors, such as
•Therapeutic neutralization of gastric acid by a base
(antacid).
•Mannitol act according to colligative properties,
increasing the osmolarity of various body fluids and
causing changes in the distribution of water to
promote diuresis,
•Oral Cholesterol-binding agents such as
cholestyramine resin) can be used to decrease dietary
cholesterol absorption.
Spare receptors
•Receptors are said to be “spare” for a given
pharmacologic response if it is possible to produce a
maximal biologic response at a concentration of
agonist that does not result in occupancy of all of the
available receptors.
•In human heart, only about 5% to 10% of the total β-
adrenoceptors are spare while 99% of Insulin
receptors are “spare.”
•One explanation for the existence of spare receptors
is that any one agonist–receptor binding event can
lead to the activation of many more cellular response
elements. Thus, only a small fraction of the total
receptors need to be bound to.
produce a maximum cellular response
Toxicokinetics and Clinical Toxicology
Toxicokinetics is the application of pharmacokinetic
principles to the design, conduct, and interpretation
of drug safety evaluation studies and in validating
dose-related exposure in animals.
Toxicokinetic data aids in the interpretation of
toxicologic findings in animals and extrapolation of
the resulting data to humans.
Toxicokinetic studies are performed in animals
during preclinical drug development and may
continue after the drug has been tested in clinical
trials.
 Clinical toxicology is the study of adverse effects
of drugs and toxic substances (poisons) in the
body.
 The pharmacokinetics of a drug in an
overmedicated (intoxicated) patient may be very
different from the pharmacokinetics of the same
drug given in lower therapeutic doses.
 At very high doses, the drug concentration in the
body may saturate enzymes involved in the
absorption, biotransformation, or active renal
secretion mechanisms, thereby changing the
pharmacokinetics from linear to nonlinear
pharmacokinetics.
 Drugs frequently involved in toxicity cases
include acetaminophen, salicylates, morphine,
and the tricylic antidepressants (TCAs).
Pregnancy category
The pregnancy category of a pharmaceutical agent is
an assessment of the risk of fetal injury due to the
drug.
Categories
Pregnancy Category A
Adequate and well-controlled studies have failed to
demonstrate a risk to the fetus in the first trimester of
pregnancy (and there is no evidence of risk in later
trimesters).
Pregnancy Category B
Animal-reproduction studies have not demonstrated
a fetal risk but there are no controlled studies in 48
pregnant women.
OR
Animal-reproduction studies have shown an adverse
effect that was not confirmed in controlled studies in
women in the first trimester (and there is no
evidence of a risk in later)
Pregnancy Category C
Studies in animals have revealed adverse effects on
the fetus (teratogenic or embryocidal or other) and
there are no controlled studies in women
OR
Studies in women and animals are not available.
Drugs should be given only if the potential 49
benefit justifies the potential risk to the fetus.
Pregnancy Category D
There is positive evidence of human fetal risk, but the
benefits from use in pregnant women may be
acceptable despite the risk (e.g., if the drug is needed
in a life-threatening situation or for a serious disease
for which safer drugs cannot be used or are
ineffective).
Category X
Studies in animals or human beings have
demonstrated fetal abnormalities, or there is evidence
of fetal risk based on human experience or both, and
the risk of the use of the drug in pregnant women 50
clearly outweighs any possible benefit. The drug is
contraindicated in women who are or may become
pregnant.

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Category A drugs
Folic acid, Thyroid harmone
Category B drugs
Acetaminophen/Paracetamol, Amoxicillin,
Amoxicillin with clavulanic acid, Cefotaxime,
Loperamide, Zidovudine
Category C drugs
Diclofenac, Rifampicin, Theophylline,
Triamcinolone (skin), Aspirin
Category D drugs
Tetracycline, Paroxetine, Phenytoin, Ache inhibitors
(2nd and 3rd trimester due to renal defects),
Benenzodiazepines (Neanal withdrawal and 52
respiratory problems) Angiotensin receptor blockers
(2nd and 3rd trimester ), Lithium, NSAIDS (Inhibit
labor), Selective serotonin reuptake inhibitors,
Phenobarbital, Warfarin
Category X drugs
Isotretinoin, Leflunomide, Thalidomide, HMG-CoA
reductase inhibitors, Oral contraceptives
(Controversial), Ergotamine, Alcohol, Methotrexate,
Raloxifene, High dose Vit.A (Lipid soluble)
Avoid during Lactation
Tetracyclines, Metronidazole, Quinolone antibiotics.
Drugs that inhibit lactation
Estrogens, Progesterone, Thiazide diuretics 53