BIOPHARMACEUTICS & PHARMACOKINETICS

PCT400 (AY 2021-2022)

Ms. Imma Olayan, RPh

UNIT 1
INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS

INTRODUCTION TO 1. Drug in its dosage form is taken by the patient by an oral,

BIOPHARMACEUTICS & PHARMACOKINETICS
BIOPHARMACEUTICS & PHARMACOKINETICS
− examine factors affecting drug product performance
− usually discussed together, esp for conventional DDS
− pertain to LADME system
Drug Product Performance
− release of drug substance from drug product for:
o local drug action
o systemic therapeutic activity
− Drugs are substances intended for use in the diagnosis,
cure, mitigation, treatment or prevention of disease.
Biopharmaceutics
− Examines interrelationship of
o drug physical/chemical properties,
o dosage from (drug product), &
o ROA on rate & extent of systemic drug absorption
intravenous, subcutaneous, transdermal, etc ROA
2. Next, drug is released from dosage form in a predictable &
characterizable manner
3. Then, some drug fraction is absorbed from site of
administration into either the
a. surrounding tissue for local action
b. body (as with oral dosage forms), or both
4. Finally, drug reaches the site of action
Pharmacodynamic Response
− Result when drug concentrations at site of action reaches
or exceeds the minimum effective concentration (MEC)
− suggested dosing regimen (starting dose, maintenance
dose, dosage form, dosing interval) is determined in
clinical trials to provide drug concentrations that are
therapeutically effective in most patients
− This sequence of events is affected by the design of the
o dosage form
o drug physicochemical properties

IN VITRO IN VIVO BIOPHARMACEUTICS INFLUENCING FACTORS

“in glass” “in living” 1. drug product design
Test on lab equipments Test on living organisms
2. drug stability within the drug product
3. manufacture of drug product
DEFINITION OF TERMS
4. drug release from drug product
Drug Product release of drug substance from
5. drug rate of dissolution/release at the absorption site
Performance drug product for local and systemic
activity 6. drug delivery to site of action
Biopharmaceutics Study relationship between: a. targeting drug to localized area (colon - Crohn dx)
• patient’s physiological aspects b. systemic absorption of the drug
• drug physicochemical
properties BIOPHARMACEUTIC CONSIDERATION IN
PharmacoKinetics • what Katawan does to drug DRUG PRODUCT DESIGN
• mathematically describes how
body affects drug after Therapeutic − rapid relief of symptoms
administration through ADME objective − slow extended action given SID
• time relation of drug action − longer for chronic use
PharmacoDynamics • what Drug does to body − local action or systemic action
• MOA of a drug Drug (API) − Physicochemical properties (solubility,
polymorphic form, particle size)
DRUG, DRUG PRODUCT, & PHARMACOLOGIC EFFECT − impurities
RELATIONSHIP Route of − Oral, topical, parenteral, transdermal,
administration inhalation, etc
Drug dosage − Large or small drug dose, frequency of
and dosage doses, patient acceptance of drug
regimen product, patient compliance
Type of drug − Orally disintegrating tablets, immediate
product release tablets, extended release
tablets, transdermal, topical,
parenteral, implant, etc

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Excipients − very little pharmacodynamic activity PHARMACODYNAMICS

− may affect DPP including release of
drug from drug product
Method of − Variables in manufacturing processes
manufacture (weighing accuracy, blending
uniformity, release test, product
sterility for parenterals)
RELATIONSHIP OF DRUG CONCENTRATION TO
DRUG RESPONSE
− Manufacturer or physician’s recommended dosage
regimen dictates dose + frequency of drug
− Due to individual differences in px genetic makeup or
pharmacokinetics, recommended dosage regimen drug
may not provide desired therapeutic outcome
PLASMA DRUG CONCENTRATION
− measured to confirm whether drug dose was
subtherapeutic due to px
o individual pharmacokinetic profile (observed
by low plasma drug concentrations)
o unresponsiveness to drug therapy due to
genetic difference in receptor response
Drug Concentration Range
− relationship between drug concentration at the site of
action (receptor) and pharmacologic response, including:
o biochemical & physiologic effects that influence
interaction of drug with receptor
− interaction of a drug molecule with a receptor causes
initiation of a sequence of molecular events resulting in a
pharmacologic or toxic response
DRUG EXPOSURE VS DRUG RESPONSE
Drug − dose (drug input to body)
EXPOSURE − various measures of acute or integrated
drug concentrations in plasma & other
biological fluid
Drug − direct measure of drug pharmacologic
RESPONSE effect
− includes a broad range of endpoints or
biomarkers:
o clinically remote biomarkers (eg,
receptor occupancy)
o presumed mechanistic effect (eg,
ACE inhibition)
o potential or accepted surrogate (eg,
effects on blood pressure, lipids, or
cardiac output)
o full range of short-term or long-term
clinical effects related to either
efficacy or safety

TOXICOKINETICS VS CLINICAL TOXICOLOGY

Toxicokinetics − application of pharmacokinetic
principles to
o design, conduct, and
interpretation of drug safety
evaluation studies and
o in validating dose-related
exposure in animals
Clinical − Study of adverse effects of drugs and
Toxicology toxic substances in the body

SAMPLE SCENARIOS
− drug conc are in therapeutic range but px don’t respond to
drug tx
− px respond to drug tx at lower drug doses that result in
lower drug conc
− px may need higher drug conc to obtain a therapeutic
effect, which requires higher drug doses

DESIRABLE HIGH Range between MEC & MTC

adverse drug responses occur at drug
concentrations higher relative to the
therapeutic drug concentrations
POTENT drugs LOW Range between MEC & MTC
adverse effects can also occur close to the
same drug concentrations as needed for
the therapeutic effect

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MEASUREMENT OF DRUG CONCENTRATIONS DEFINITION OF TERMS

BIOLOGIC SAMPLES
Biologic Samples: Milk, saliva, plasma, and urine
Methods
1. Sensitive, accurate and precise analytical methods
2. Chromatographic and mass spectrophotometric methods
Minimum Effective Concentration (MEC)
− minimum concentration of drug needed at receptors to
produce the desired pharmacologic effect
Minimum Toxic Concentration (MTC)
− drug concentration needed to barely produce a toxic effect

INVASIVE AND NONINVASIVE METHODS Onset Time

INVASIVE NONINVASIVE
requires parenteral or obtained w/out parenteral or − Time required for the drug to reach the MEC
surgical intervention in px surgical intervention
Intensity
sampling blood, spinal fluid, sampling of urine, saliva, − of the pharmacologic effect
synovial fluid, tissue biopsy feces, expired air − proportional to the number of drug receptors occupied
− reflected in observation that: (up to max)
BLOOD COMPONENTS
How obtained Components o plasma drug conc → pharmacologic response
Whole − venous puncture − All cellular protein
blood − + anticoagulant elements of blood Duration
(heparin or EDTA) − of drug action
Serum − *Liquid − No cellular − dif bet onset time & time for drug to decline back to MEC
− obtained from whole elements,
blood after blood is fibrinogen, or Therapeutic Window
allowed to clot & other clotting
the clot is removed factors − Concentrations between the MEC and the MTC
Plasma − *Liquid, supernatant − noncellular liquid
− obtained after fraction of whole Therapeutic Index
centrifugation of blood − Refers to ratio between toxic & therapeutic doses
non-clotted whole − contains all
blood that contains proteins including
Peak Plasma Level
an anticoagulant albumin
− average rate of drug absorption
SERUM = Whole Blood – Clotting factors
PLASMA = Centrifuged Blood + Clotting factors Time For Peak Plasma Level
− drug dose, absorption rate constant, elimination constant
PLASMA DRUG CONCENTRATION – TIME CURVE
Area Under the Curve
− amount of drug absorbed systematically

DRUG CONCENTRATIONS
Tissues
− Only a small sample of tissue is removed, making drug
concentration measurement difficult

Urine
− an indirect method to ascertain bioavailability of a drug

As the drug reaches the general circulation, plasma drug
concentrations will rise up to a maximum if the drug was given
by an extravascular route.
As the drug is being absorbed into the systemic circulation, the
drug is distributed to all the tissues in the body and is also
simultaneously being eliminated.
Feces
− reflect drug that has not been absorbed after an oral dose
− or may reflect drug that has been expelled by biliary
secretion after systemic absorption
Saliva
− Only free drug diffuses into the saliva

Forensic Drug Measurements

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SIGNIFICANCE OF MEASURING PLASMA DRUG − Assumptions to simplify the complex biologic system
CONCENTRATIONS concerning the movement of drugs within the body
− To measure perfusion − Plasma drug concentration reflects drug concentrations
globally within the body
PHARMACOKINETIC MODELS
− Pharmacokinetic Models: allow more accurate Basis Of Models
interpretation of relationship between plasma drug levels & Empirical − Simply interpolates data & allows an
pharmacologic response empirical formula to estimate drug
− In the absence of PK information, plasma drug levels are level over time
relatively useless for dosage adjustment. Physiological − Sample tissue & monitor blood flow to
o When the sample was drawn? the liver in vivo
o What dose was given? − Based on knowledge of physiologic &
o How it was given? biochemical composition of body
organs
Plasma Drug Concentration Monitoring or
Compartmental − Represent organs as compartments
Pharmacodynamic Response Monitoring
COMPARTMENT MODELS
PHARMACOKINETIC MODELLING − Compartment: Not a real or anatomic region but a tissue
or group of tissues w/ similar blood flow & drug affinity
− Drug distribution & disposition is complex & drug events
often happen simultaneously. − Rate Constants: Used to represent overall rate processes
− The inherent complexity of these events requires use of of drug entry into & exit from the compartment
mathematical models & statistics to:
o estimate drug dosing MAMMILLARY MODEL
o predict time course of drug efficacy for a given dose − Most common compartment model used in
pharmacokinetics
Model − One or more compartments around a central compartment
like a satellite
− A hypothesis using mathematical terms to described
quantitative relationships concisely
CATENARY MODEL
− predictive capability of a model lies in proper selection and
− Consists of compartments joined to one another like the
development of mathematical function(s) that
compartments of a train
parameterizes essential factors governing kinetic process
PHYSIOLOGIC MODEL
VARIABLES: Experimental data
− Blood Flow or Perfusion Model
PK PARAMETER: Drug constant that is estimated from − Actual tissue volume is used
experimental data − Experimentally difficult

Independent variable - (Parameter) → Dependent variable Advantage

1. no data fitting
Models can be devised to simulate rate process of drug ADE to 2. sensitive to pathophysiologic conditions
describe & predict drug concentration in body as a fx of time 3. applied to several species

USE OF PHARMACOKINETIC MODELS PBPK: Physiologic based pharmacokinetic model

1. Predict plasma, tissue, and urine drug levels with any
dosage regiment
2. Calculate the optimum dosage regimen for each patient
individually
3. Estimate the possible accumulation of drugs and/or
metabolites
4. Correlate drug concentrations with pharmacologic or
toxicologic activity
5. Evaluate differences in the rate or extent of availability
between formulations (bioequivalence)
6. Describe how changes in physiologic or disease affect the
ADE of the drug
7. Explain drug interactions
− Organs such as lung, liver, brain and muscle were
individually described by differential equations
LADMER SYSTEM
− Absorption: drug movement from absorption site to
systemic circulation
− Distribution: reversible transfer of drug molecules to
extravascular compartment
− Metabolism: drug elimination due to biotransformation of
drug molecules through enzyme-catalyzed chemical rx
− Excretion: physical removal of drug from the body
ELIMINATION = Metabolism + Excretion
DRUG DISPOSITION = Distribution + Metabolism + Excretion

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ROUTES OF ADMINISTRATION
ROA
− ROA directly affects drug bioavailability, w/c determines
both start & duration of pharmacological effect
DDF CONSIDERATIONS
Some considerations must be taken into account when
designing a drug dosage form:
(1) intended ROA
(2) amount or dose to be administered
(3) anatomical & physiological characteristics of site of
absorption, s.a membrane permeability & blood flow
(4) physicochemical properties of site (pH & osmotic
pressure of physiological fluids) and
(5) potential effect of medication over site of
administration
TWO MAIN ROUTES
When the systemic absorption of a drug is desired,
medications are usually administered by two main routes:
1. Parenteral Route (through skin by injection, avoiding
the digestive system)
2. Enteral Route (directly at some point of GI)
3. Pulmonary (or Respiratory) & Nasal Routes are
employed (To a lesser extent)
Other routes of administration, such as ophthalmic and vaginal,
are not included here because their application is almost
exclusive for local (not systemic) drug administration.
PARENTERAL DRUG ADMINISTRATION
− carried out directly through skin, or towards systemic
circulation
− route of choice for:
o drugs that cannot be absorbed orally
o drugs unstable in GI tract (e.g. insulin, heparin)
o tx of unconscious patients or under circumstances
that require a rapid onset of action
The Three Main Parenteral Routes:
1. intravenous (IV)
2. intramuscular (IM)
3. subcutaneous (SC)
INTRAVASCULAR
Intravenous
− involves introduction of a drug solution through a needle,
directly into a vein
− best way to deliver a dose rapidly & accurately, as drug
enters directly into systemic circulation without delay
associated to absorption processes, achieving its
therapeutic effect faster than by any other route.
− For the same reason, this route presents a bioavailability
of 100%, since pharmaceutical active ingredient usually
reaches site of action without suffering alterations due to
pre-systemic effects
TWO TYPES OF INTRAVENOUS
1. Fast IV injection
2. Slow IV infusion
Intraarterial
− Direct administration to an artery, generally for local
effects over irrigated organs or tissues.
− For ex, antineoplastic injected in surroundings of tumor,
with a decrease of systemic adverse effects
o useful for administration of vasodilators in arterial
embolisms or contrast media for arteriography
Intracardiac
− Direct administration into heart, used only as emergency
route during a cardiac arrest
− (Adrenaline injection into cardiac chambers) due to the
serious injuries that may be caused by the needle
EXTRAVASCULAR
Enteral
A. ORAL
• first choice for drug administration wHen possible,
since it is both convenient & economical
• simple & basic series of instructions allow px to take
medication safely, reducing visits to health centers
• convenient = compliance = successful drug therapy
• some drugs are specially targeted to GI sites of action
o bismuth subsalicylate – heartburn
o ezetimibe - reduction of cholesterol
absorption
• most API exert therapeutic effect outside GI tract
• must be absorbed from GI to gain access to systemic
circulation & reach site of action
• absorption of drugs administered by enteral route is
determined, in part, by:
o GI tract physiological state (diet, hormones,
ANS, pathological states and other drugs)
o drug physicochemical properties
• ++ possibility of losses due to pre-systemic metabolism,
hinders systemic bioavailability
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B. BUCCAL AND SUBLINGUAL C. RECTAL

• for systemic absorption of drugs
• unlike other buccal regions (hard palate, gingiva or Parenteral
dorsal surface of tongue)
• no keratinized epithelia, more favorable drug
absorption
• main characteristic: rapid onset of action
o due to high blood flow & lymphatic flow of
oral cavity
o lack of GI factors that delay absorption
o substances absorbed at this level reach
general circulation without loss due to a first-
pass effect, as the buccal venous drainage
flows directly into the superior vena cava

Advantages of Administering Drugs Through Oral Mucosa

• rapid onset of therapeutic effect is achieved
• Portal circulation is avoided
• avoiding intestinal & first-pass hepatic metabolism
• API is not exposed to aggressive GI medium W/C
degrade it by the GI pH or enzymes
• for px with swallowing difficulties, nausea or
malabsorption syndrome, unconscious
A. SUBCUTANEOUS
• injecting under skin into adipose layer, beneath
Greatest Limitation of Buccal Administration
dermis, also called hypodermic administration
• due to small size of oral cavity, only very potent drugs
• usually performed on:
can be effectively delivered
o external side of arm or thigh
• buccal mucosa offers about 200 cm2 of area for drugs
o anterior face of abdomen
absorption, i.e., ~10,000 times less than duodenum
o generally admits smaller injection volumes
• difficulty in keeping drug in site than IM route
• need for px to refrain from swallowing, talking or
drinking during administration so as not to affect B. INTRAMUSCULAR
residence time in which medication is in direct contact • into muscle tissue, can be done in different areas:
with the mucous membrane
• Upper part of arm:
• not applicable to bitter or bad-tasting drugs bc adds to
o deltoid muscle admits ~2 mL,
px discomfort, generates excessive saliva production o painful for px
which increases risk of swallowing
o rate of absorption
• While absorption may occur by any of paracellular &
• Glutes:
transcellular mechanisms studied, passive diffusion of
o dorsogluteal muscle admits higher volumes
drugs from salivary aqueous phase through
(~7–8 mL)
membranes of oral mucosal cells predominates
o rate of absorption due to amount of
• drugs of intermediate polarity are well absorbed:
adipose tissue
o lipophilicity limits drug dissolution
• External thigh face:
o polarity limits diffusion in cell membranes o vastus lateralis muscle admits ~ 5 mL
• ionized compounds at salivary pH are absorbed o recommended zone for babies & children,
since due to its minor muscle development,
Plasma conc of gluteal zone carries a high risk of nerve
nitroglycerine (NTG) damage
after administration
of a SL tablet of 0.3 Typical plasma
mg NTG (black concentration vs. time
circles), 6.5 mg NTG profiles for the same drug
oral capsule by three different routes:
(asterisks) and a 2% IV bolus (long dashes), IM
ointment, equivalent (dotted line) and oral
to 16 mg of NTG (continuous line)
(black triangles).

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Others ROA OUTLINE

A. PULMONARY 1. Intravascular
• traditionally used for drug administration to a. Intravenous
respiratory tract, in pathologies (chronic obstructive i. Fast IV injection
ii. Slow IV infusion
pulmonary disease (COPD), asthma, cystic fibrosis)
b. Intraarterial
c. Intracardiac
Main Advantages 2. Extravascular
• rapid absorption & rapid onset of action (important for a. Enteral
bronchodilator & anti-inflammatory drugs) i. Oral
• localization of drug activity in lung with minimal ii. Buccal and Sublingual
systemic toxicity, w/c is particularly important in case iii. Rectal
of anti-inflammatory corticosteroids such as b. Parenteral
beclomethasone, budesonide, fluticasone, etc. iv. Subcutaneous
v. Intramuscular
c. Others
vi. Pulmonary
vii. Nasal

To further understand the topics outlined, please watch the following videos:
1. https://youtu.be/IOf-z0D1mHk
2. https://youtu.be/Jiml3iGBs88
3. https://youtu.be/uOcpsXMJcJk
4. https://youtu.be/9mcuIc5O-DE
5. https://youtu.be/URrXh0LJ6JE
6. https://youtu.be/Og5xAdC8EUI
7. https://youtu.be/wbh3SjzydnQ
Modelled data of the regional deposition of monodisperse 8. https://youtu.be/FN3MFhYPWWo
inert particles as a function of particle size, for a healthy ADME SERIES
9. https://youtube.com/playlist?list=PLN4mLNb7L4Vfwy8DeR677YzDjfdmpg0Wh
lung. Inhalation volume: 1,5 L. Left: flow 200 ml/s. Right:
flow of 1000 ml/s.

B. NASAL
• absorption of drugs across nasal mucosa (not
accessing to the respiratory tract)
• can be used for both local & systemic therapies
• presented as an alternative, non-invasive route,
especially useful in case of extensively metabolized or
labile drugs in the GI medium
• limited to very small volumes (25–200 μL)
o only applicable to potent drugs with high
water solubility
• API must have a molecular weight <1 kDa to be
absorbed and should not be irritating or injurious to
the nasal mucosa

Schematic representation of the nasal (columnar, non-

keratinized) epithelium, where the ciliated cells responsible for
the mucociliary clearance mechanism are observed.

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