Advance Biopharmaceutics & Pharmacokinetics_IMP_By_ADIKAKAD.pdf

Aditya S. Kakad
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Advanced Biopharmaceutics &
Pharmacokinetics
1) Drug absorption. Various routes from which absorption of
drug is necessary for Pharmacological action
Drug absorption is the movement of a drug into the bloodstream
after administration. (See also Introduction to Administration and
Kinetics of Drugs.) A drug product is the actual dosage form of a drug—a
tablet, capsule, suppository, transdermal patch, or solution.
Routes from which absorption of drug is necessary for
Pharmacological action
Drug absorption is a critical step in achieving the desired
pharmacological action, as it determines the amount of drug that
reaches systemic circulation and subsequently its target site. Here are
the primary routes through which drug absorption is necessary for
pharmacological action:
1. Oral Route:
 Gastrointestinal Absorption:
 Drugs are absorbed from the stomach and small intestine into the
systemic circulation.
 Factors influencing absorption include pH of the GI tract, presence of
food, GI motility, and the drug's physicochemical properties.
2. Sublingual and Buccal Routes:
 Sublingual (Under the Tongue):
 Drugs placed under the tongue dissolve and are absorbed directly into
the bloodstream through the mucous membranes.
 Bypasses the first-pass metabolism in the liver, leading to rapid onset of
action.
 Buccal (Cheek):
 Drugs held in the buccal pouch dissolve and are absorbed through the
mucous membranes into the bloodstream.
 Also avoids first-pass metabolism.
3. Rectal Route:
 Suppositories:
 Drugs administered rectally can be absorbed through the rectal mucosa
into the systemic circulation.
 Partial avoidance of first-pass metabolism depending on the location of
absorption within the rectum.

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4. Inhalation Route:
 Pulmonary Absorption:
 Drugs inhaled as aerosols or gases are absorbed through the alveolar
membranes in the lungs.
 Provides rapid absorption and onset of action due to the large surface
area and rich blood supply of the lungs.
5. Transdermal Route:
 Transdermal Patches:
 Drugs are delivered across the skin and absorbed into the systemic
circulation.
 Provides sustained release of the drug over an extended period and
avoids first-pass metabolism.
6. Intranasal Route:
 Nasal Sprays:
 Drugs administered through the nasal cavity are absorbed through the
nasal mucosa.
 Provides a rapid onset of action and partially avoids first-pass
metabolism.
7. Intravenous Route (IV):
 Direct Injection into the Bloodstream:
 Drugs administered intravenously are directly introduced into the
systemic circulation.
 Provides immediate pharmacological action with 100% bioavailability.
8. Intramuscular Route (IM):
 Injection into Muscle Tissue:
 Drugs are absorbed from the muscle tissue into the bloodstream.
 Generally provides a slower and more sustained release compared to IV
administration.
9. Subcutaneous Route (SC):
 Injection into Subcutaneous Tissue:
 Drugs are absorbed from the subcutaneous tissue into the bloodstream.
 Absorption rate can vary depending on the drug formulation and injection
site.
10. Other Routes:
 Ocular (Eye Drops):
 For local absorption in the eye, but some systemic absorption can occur
through the conjunctival sac and nasal mucosa.
 Otic (Ear Drops):
 Primarily for local absorption within the ear, minimal systemic
absorption.
 Vaginal Route:
 Drugs administered vaginally can be absorbed through the vaginal
mucosa into the systemic circulation.

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Factors Affecting Drug Absorption Across Different Routes:
1. Physicochemical Properties of the Drug:
 Solubility, ionization state, molecular size, and stability.
2. Formulation Factors:
 Dosage form, presence of excipients, and drug release mechanisms.
3. Biological Factors:
 Blood flow to the absorption site, surface area for absorption, and the
presence of enzymes or transport proteins.
4. Route-Specific Factors:
 For oral route, factors include GI pH, gastric emptying time, and intestinal
transit time.
 For transdermal route, factors include skin permeability and presence of
stratum corneum.
 For inhalation route, factors include particle size and lung capacity.
2) Mechanism of drug absorption
 Absorption of drug
The movement of unchanged drug from the site of administration
to systemic circulation.
 Pharmacokinetics Process
a) Administration
b) Absorption
c) Distribution
d) Metabolism
e) Excretion
f) Removal
 Trans cellular / Intracellular transport
 Passive transport process.
a) Passive diffusion
b) Pore transport
c) Ion pair transfer
d) Facilitated or mediated
diffusion.
 Active transport Process
a) Primary active transport b) Secondary active transport
 Para cellular / Intracellular transport
Para cellular transport refers to the transfer of substances
across an epithelium by passing through the intercellular space
between the cells. It is in contrast to Tran’s cellular transport, where
the substances travel through the cell, passing through both the
apical membrane and basolateral membrane.
 Vesicular transport.
Vesicular transport is thus a major cellular activity, responsible
for molecular traffic between a variety of specific membrane-
enclosed compartments. The selectivity of such transport is therefore
key to maintaining the functional organization of the cell.

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3) Factors affecting drug absorption
 Physiological factors
 Disease
 Genetics
 Age
 Various Formulation factor
 Dosage Form and Design
 Particle Size and Surface Area
 Solubility and Dissolution Rate
 Excipients
 Lipid-Based Formulations
 Polymers
 Drug Stability
 Prodrugs
 Complexation
 Route of Administration
 Physicochemical Properties of
the Drug
 Gastrointestinal Residence
Time
 Physiochemical factor
 Drug solubility and dissolution
rate
 Particle size and effective
surface area
 Polymorphism and amorphism
 Salt form of the drug
 lipophilicity of the drug
 Drug Stability
 Pka of drug and
gastrointestinal PH
 Pharmaceutical factor
 Disintegration time (tablet /
Capsule)
 Dissolution time
 Manufacturing Variables.
 Pharmaceutical ingredients
 Nature and type of dosage
form.
 Product age and storage
Condition.
 Patient related factor
 Age
 Gastric emptying time
 Intestinal transit time
 Gastrointestinal pH
 Diseased States
 Blood flow through the GIT
 Gastro intestinal Contents -
other drugs, food, fluids, other
normal GI content
 Pre-systemic metabolism by-
 Luminal enzymes
 Gut wall enzymes
 Bacterial enzymes
 Hepatic enzymes.
4) Noyes_Whitney Equation
 Noyes-Whitney equation
The Noyes-Whitney equation describes the rate of dissolution of a
solid substance into a solvent. It is a fundamental equation in the field of
pharmaceutics and is particularly important in understanding the
dissolution behavior of drugs in the gastrointestinal tract.
dC/dt =DAKw/o (Cs-Cb)/Vh

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where,
 D= diffusion coefficient of drug.
This is a measure of how quickly molecules move through the solvent. It depends on the
temperature, solvent viscosity, and size of the solute molecules.
 A= surface area of dissolving solid.
The surface area of the solid that is in contact with the solvent. Increasing the surface
area (e.g., by reducing particle size) enhances the dissolution rate.
 Kw/o= water/oil partition coefficient of drug.
 V= volume of dissolution medium.
 h= thickness of stagnant layer.
 (Cs-Cb)= conc. gradient for diffusion of drug.
 Saturation Concentration (C_s):
The maximum concentration of the solute that can dissolve in the solvent at a given
temperature and pressure. Beyond this concentration, the solute will not dissolve
further.
5) Role of dosage form in Dissolution & Absorption
The dosage form of a drug plays a crucial role in its dissolution and
absorption, directly influencing its bioavailability and therapeutic
efficacy. Here's a detailed look at how different aspects of the dosage
form impact these processes:
1. Solid Dosage Forms:
Tablets and Capsules:
 Disintegration:
o The rate at which a tablet or capsule disintegrates into smaller particles affects the
dissolution rate. Faster disintegration usually enhances dissolution and absorption.
 Coating:
o Enteric coatings protect the drug from stomach acid, allowing it to dissolve in the
more neutral pH of the intestines, which is crucial for acid-sensitive drugs.
o Film coatings can also control the release rate of the drug.
 Fillers and Binders:
o These excipients can influence the porosity and hardness of the tablet, affecting the
rate at which the drug is released and dissolved.
 Release Mechanisms:
o Immediate-release formulations allow rapid dissolution and absorption.
o Controlled-release (CR), sustained-release (SR), and extended-release (ER)
formulations are designed to dissolve slowly over time, providing a prolonged
therapeutic effect.
Powders and Granules:
 Particle Size:
o Smaller particles have a larger surface area to volume ratio, enhancing the
dissolution rate.
 Wetting Agents:
o Surfactants added to powders can improve wettability and dissolution.

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2. Liquid Dosage Forms:
Solutions:
 Homogeneity:
o Drugs are already dissolved in the solvent, ensuring uniform distribution and rapid
absorption.
 pH Adjustments:
o Solutions can be formulated to maintain the drug in its ionized or non-ionized form,
optimizing solubility and absorption.
Suspensions:
 Particle Size:
o Smaller, well-dispersed particles dissolve more rapidly.
 Viscosity:
o The viscosity of the suspension medium can affect the rate of dissolution.
3. Semi-Solid Dosage Forms:
Gels and Creams:
 Drug Release:
o The matrix or base used in gels and creams can control the rate at which the drug is
released and absorbed through the skin or mucous membranes.
4. Specialized Dosage Forms:
Transdermal Patches:
 Permeation Enhancers:
o Ingredients in the patch can enhance skin permeability, improving drug absorption.
 Controlled Release:
o Designed to provide a steady release of drug over an extended period, ensuring
sustained plasma levels.
Inhalers and Aerosols:
 Particle Size:
o Optimal particle size (1-5 microns) is crucial for deep lung penetration and efficient
absorption.
 Propellants and Carriers:
o These can affect the dispersion and deposition of the drug in the respiratory tract.
5. Factors Influencing Dissolution and Absorption Based on Dosage Form:
Disintegration Time:
 Rapid disintegration increases the surface area available for dissolution, leading to faster
absorption.
Wettability:
 Enhancers like surfactants in the dosage form can improve the wettability of the drug
particles, increasing dissolution rate.
Polymorphic Form:
 Different polymorphs of a drug can have different dissolution rates; selecting the
appropriate polymorph is essential for optimal absorption.
Excipients:
 Excipients can enhance or retard dissolution. For example, disintegrants promote faster
dissolution, while hydrophobic excipients might slow it down.
pH Modifiers:
 These can help maintain the drug in its most soluble form throughout the GI tract, enhancing
dissolution and absorption.
Osmotic Systems:
 Used in controlled-release formulations, osmotic systems can provide a consistent drug
release rate over time.

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6) pH partition Hypothesis
The pH partition hypothesis is a fundamental concept in advanced
biopharmaceutics and pharmaceutics, particularly in understanding drug
absorption across biological membranes. This hypothesis explains how the
pH of the environment and the pKa of the drug influence the drug's
absorption and distribution within the body.
 pH Partition Hypothesis:
The pH partition hypothesis suggests that the degree of ionization of a drug
affects its ability to cross biological membranes. Biological membranes are typically
lipid bilayers that allow the passage of non-ionized, lipophilic (fat-soluble) molecules
more readily than ionized, hydrophilic (water-soluble) ones. The hypothesis can be
summarized as follows:
1. Non-ionized (uncharged) drugs: These are more lipophilic and can diffuse across cell
membranes more easily.
2. Ionized (charged) drugs: These are more hydrophilic and have difficulty crossing lipid
membranes.
 Key Concepts of the pH Partition Hypothesis:
1. Drug Ionization:
o The degree of ionization of a drug depends on its pKa (the pH at which the
drug is 50% ionized) and the pH of the surrounding environment.
o Weak acids tend to be non-ionized in acidic environments (pH < pKa) and
ionized in basic environments (pH > pKa).
o Weak bases tend to be non-ionized in basic environments (pH > pKa) and
ionized in acidic environments (pH < pKa).
2. Membrane Permeability:
o Non-ionized forms of drugs are more lipid-soluble and can passively diffuse
across lipid membranes.
o Ionized forms of drugs are less lipid-soluble and are generally unable to
passively diffuse through the lipid bilayer.
3. Absorption Sites:
o The gastrointestinal (GI) tract has varying pH levels: the stomach is highly
acidic (pH 1-3), while the intestines are more alkaline (pH 5-8).
o Drugs absorbed in the stomach are usually weak acids, as they remain non-
ionized in the acidic environment.
o Drugs absorbed in the intestines are often weak bases, as they remain non-
ionized in the alkaline environment.
 Applications of the pH Partition Hypothesis:
1. Drug Formulation:
o Understanding the pH partition hypothesis helps in designing drug
formulations that optimize absorption. For instance, enteric coatings protect
acid-labile drugs from the stomach's acidic environment and allow them to
be released in the more alkaline intestines.
2. Drug Absorption:
o Predicting where in the GI tract a drug will be absorbed helps in determining
the appropriate dosage form and route of administration.

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3. Drug Distribution:
o The distribution of drugs within the body can be influenced by the pH of
various tissues and fluids, affecting the drug's pharmacokinetics and
pharmacodynamics.
4. Drug Excretion:
o The ionization state of drugs also affects their excretion. For instance, weak
acids are more readily excreted in alkaline urine, and weak bases are more
readily excreted in acidic urine. This principle is used in managing drug
overdose by altering urinary pH to enhance drug elimination.
 Limitations of the pH Partition Hypothesis:
While the pH partition hypothesis provides a useful framework, it has limitations and does
not account for all factors influencing drug absorption and distribution:
1. Transport Proteins:
o Active and facilitated transport mechanisms can transport ionized drugs
across membranes, bypassing the limitations suggested by the hypothesis.
2. Physiological Factors:
o Factors such as blood flow, membrane surface area, and the presence of food
or other substances can also influence drug absorption and distribution.
3. Drug Properties:
o The hypothesis does not fully account for the influence of molecular size,
shape, and specific chemical interactions with membrane components.
7) Carrier mediated transport mechanism for drug absorption
Carrier-mediated transport mechanisms are crucial for the
absorption of many drugs, especially those that cannot passively diffuse
through biological membranes due to their size, polarity, or specific
chemical properties. Understanding these mechanisms is vital in
advanced biopharmaceutics and pharmaceutics to optimize drug design
and delivery. Here, we discuss the different types of carrier-mediated
transport, their characteristics, and their implications for drug
absorption.
 Types of Carrier-Mediated Transport
1. Facilitated (Passive) Diffusion:
o Mechanism: Facilitated diffusion involves carrier proteins that transport drugs
across the cell membrane down their concentration gradient, without the use of
energy (ATP).
o Characteristics:
 Saturable: There is a maximum rate of transport (Vmax) due to the limited
number of carrier proteins.
 Selective: Specific carrier proteins will only transport specific drugs or
molecules.
 No Energy Required: Transport occurs passively down the concentration
gradient.
o Examples: Glucose transporters (GLUT) facilitate the transport of glucose across cell
membranes.

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2. Active Transport:
o Mechanism: Active transport involves carrier proteins that move drugs against their
concentration gradient, requiring energy usually in the form of ATP.
o Characteristics:
 Saturable: Similar to facilitated diffusion, there is a maximum rate of
transport due to a finite number of carrier proteins.
 Selective: Transporters are specific for certain drugs or molecules.
 Energy-Dependent: Requires energy to move substances against their
concentration gradient.
o Examples: P-glycoprotein (P-gp) and the sodium-potassium pump (Na+/K+ ATPase)
are examples of active transport mechanisms.
3. Secondary Active Transport:
o Mechanism: This type of transport uses the energy generated from the movement
of one substance down its concentration gradient to drive the movement of another
substance against its gradient. This is usually coupled with the movement of ions like
sodium or hydrogen.
o Characteristics:
 Cotransport: Two substances are transported together, either in the same
direction (symport) or in opposite directions (antiport).
 Energy Indirectly Required: While ATP is not directly used, the process relies
on ion gradients established by primary active transport.
o Examples: The sodium-glucose cotransporter (SGLT) transports glucose into cells
using the sodium gradient established by the Na+/K+ ATPase.
 Role in Drug Absorption
Intestinal Absorption:
 Peptide Transporters: Drugs that mimic natural peptides can be absorbed through peptide
transporters like PepT1.
 Nutrient Transporters: Some drugs are designed to exploit nutrient transporters such as
amino acid or glucose transporters for improved absorption.
Blood-Brain Barrier:
 Efflux Transporters: P-glycoprotein and other efflux transporters at the blood-brain barrier
can limit drug penetration into the brain, affecting drug distribution and efficacy.
 Inhibiting Efflux: Strategies to inhibit these efflux transporters can enhance the central
nervous system (CNS) availability of certain drugs.
Renal Excretion:
 Reabsorption and Secretion: Carrier-mediated transport is also involved in the renal
reabsorption and secretion of drugs, impacting drug clearance and half-life.
 Factors Influencing Carrier-Mediated Transport
1. Drug Structure:
o Structural similarity to the transporter’s natural substrate can enhance carrier-
mediated absorption.
o Modifications to drug molecules can either enhance or reduce their affinity for
specific transporters.
2. Concentration Gradient:
o For facilitated diffusion, a higher concentration gradient increases the rate of
transport until the carriers are saturated.
o For active transport, the concentration gradient of ions like Na+ influences
secondary active transport.

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3. Carrier Protein Expression:
o The expression levels of carrier proteins in different tissues can significantly impact
the absorption, distribution, and excretion of drugs.
o Genetic polymorphisms in transporter genes can lead to inter-individual variability in
drug response.
4. Inhibition and Competition:
o Drugs that are substrates for the same transporter can compete for absorption,
leading to reduced bioavailability.
o Inhibitors of transporters can affect the absorption and clearance of co-administered
drugs.
 Implications for Drug Development
1. Targeting Specific Transporters:
o Designing drugs that can utilize specific transporters can improve oral bioavailability
and targeted delivery.
o Prodrugs that are activated upon transporter-mediated uptake are a common
strategy.
2. Avoiding Efflux Transporters:
o Developing drugs that are poor substrates for efflux transporters like P-glycoprotein
can enhance absorption and CNS penetration.
3. Formulation Strategies:
o Co-administration of transporter inhibitors can be used to increase the
bioavailability of certain drugs.
o Nanoparticle formulations and drug delivery systems can be designed to target
specific transport mechanisms.
8) Characteristics of Passive diffusion
1. Concentration Gradient-Driven:
 Passive diffusion occurs from an area of higher concentration to an area of lower
concentration until equilibrium is reached.
2. No Energy Requirement:
 It is an energy-independent process, meaning it does not require ATP or any other
form of cellular energy.
3. Non-Saturable Process:
 Unlike carrier-mediated transport, passive diffusion does not involve transport
proteins and therefore does not become saturated. The rate of diffusion increases
linearly with the concentration gradient.
4. Rate of Diffusion:
5. Lipid Solubility:
 Drugs that are more lipophilic (fat-soluble) diffuse more easily through the lipid
bilayer of cell membranes. The partition coefficient (log P) is often used to describe
the lipid solubility of a drug.
6. Molecular Size and Shape:
 Smaller molecules diffuse more rapidly than larger ones. The molecular size and
shape affect the ability of the drug to permeate through the cell membrane.
7. Membrane Thickness:
 Thinner membranes facilitate faster diffusion compared to thicker membranes, as
the distance the drug must travel is shorter.

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8. Degree of Ionization:
 Non-ionized (uncharged) forms of the drug diffuse more readily across biological
membranes compared to ionized (charged) forms. The degree of ionization depends
on the pH of the environment and the pKa of the drug, described by the Henderson-
Hasselbalch equation.
9. Partition Coefficient:
 The partition coefficient (P) is a measure of a drug's solubility in lipid versus aqueous
environments. Drugs with higher partition coefficients diffuse more readily through
lipid membranes.
10. Presence of Biological Barriers:
 Biological barriers like the blood-brain barrier (BBB) can affect passive diffusion. The
BBB, for instance, has tight junctions and a high degree of lipid content, which
selectively allows the passage of lipid-soluble substances while restricting hydrophilic
substances.
11. Temperature:
 Higher temperatures can increase the kinetic energy of drug molecules, enhancing
the rate of passive diffusion.
12. Aqueous Solubility:
 While lipid solubility is crucial for crossing lipid membranes, adequate aqueous
solubility is also necessary for the drug to be in solution form in the biological fluids,
which is a prerequisite for diffusion
9) In-vitro dissolution & Drug release testing.
 In-Vitro Dissolution Testing:
Definition: In-vitro dissolution testing measures the rate and extent to which a drug
dissolves in a liquid medium under standardized conditions.
Purpose:
 To predict how the drug will dissolve in the gastrointestinal (GI) tract after oral
administration.
 To ensure batch-to-batch consistency in drug manufacturing.
 To assess the impact of formulation changes on drug release.
Procedure:
 A drug dosage form (like a tablet or capsule) is placed in a dissolution apparatus
containing a specific dissolution medium (e.g., simulated gastric or intestinal fluid).
 The apparatus maintains a controlled temperature (usually 37°C) and agitation.
 Samples of the dissolution medium are taken at predetermined time intervals.
 The amount of drug dissolved in the medium is measured using techniques like UV
spectrophotometry or high-performance liquid chromatography (HPLC).
 Drug Release Testing:
Definition: Drug release testing measures how a drug is released from its dosage form into
a release medium over time.
Purpose:
 To understand the drug release profile and mechanism.
 To ensure the drug will release at the intended rate and duration for therapeutic
effectiveness.
 To compare different formulations or dosage forms.

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Procedure:
 Similar to dissolution testing, the dosage form is placed in a release apparatus with a
release medium.
 Conditions (temperature, agitation, etc.) are controlled to simulate the intended
environment (e.g., skin, GI tract).
 Samples are taken at various time points.
 The concentration of the drug in the release medium is analyzed to determine the
release rate and total amount released.
10)In vitro-In vivo correlation
 General principles of In vitro-In vivo correlation:
IVIVE should be developed using two or more formulations with
different release rate.
only one the release rate is sufficient if dissolution is condition
Independent
In vitro dissolution profile should be generated using an appropriate
dissolution methodology
Dissolution method used should be same for all the formulation
A bioavailability study should be conducted to determine the in-vivo
plasma concentration time profiles for each of the formulation
In Vivo absorption profile is plotted against the in vitro dissolution
profile to obtain a correlation
 Levels of correlation
1. Level A
2. Level B
3. Level C
4. Multiple level C
 Parameters For Correlation
In Vitro In Vivo
Dissolution rate Absorption rate or (absorption time)
Percent of drug dissolve Percent of drug absorbed
Percent of drug dissolve Max Plasma Conc. (C max)
Percent of drug dissolved Serum drug Conc.
 Approaches
1. By establishing a relationship, usually linear, between in Vitro
dissolution and in in-vivo bioavailability Parameters
2. Modifying the dissolution methodology on the basis of existing
bioavailability and clinical data.

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 Application
1. Providing process Control and quality assurance
2. Determining Consistent release characteristics of the product over
time.
3. To ensure batch to batch Consistency in the physiological
performance of a drug product by use of such in vitro Values.
4. To serve as a tool in the development of a new dosage form with
desired in vivo performance.
5. To assist in Validating or setting dissolution specification.
11) Role of Drug product stability consideration in the design of a
drug.
 Drug product stability
Drug Stability is defined as the ability of the Pharmaceutical dosage
from to maintain the physical, chemical, therapeutic and microbial
properties during the time of storage and usage by patient.
 Objective of drug product Stability
1. To provide Knowledge of the physical-chemical principles and
terminology used in discussing stability problems.
2. To create awareness of the general problem of drug Stability so that
expiration dates and other special Storage requirements will have
more Meaning
3. To show how drug stability may be predicted
4. To assist in prediction of incompatibility.
5. To show how stability of drugs in View many influences their
therapeutic effects.
6. Maintenance of quality until the time of usage or until their
expiration date.
 Need
1. quality Varies with time
2. Shelf life of drug product
3. Storage Condition
4. Prevention of expense
5. Essential quality attributes
 Factors influencing drug stability
1. Temperature
2. pH
3. Moisture
4. Light
5. Pharmaceutical dosage form
6. Concentration
7. Drug incompatibility
8. Oxygen
9. Environmental other factor.

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 Biopharmaceutics Considerations in Drug product Design.
1. Pharmacodynamic Consideration
2. Drug Consideration
3. Drug Product Consideration
4. Patient Considerations
5. Manufacturing Considerations.
12)Pharmacokinetic models
Pharmacokinetic modeling is a mathematical modeling technique for
predicting the
absorption, distribution, metabolism and excretion (ADME) of
synthetic or natural chemical substances in humans and other animal
species.
 TYPES OF PHARMACOKINETIC
MODELS:-
1. Compartment models
• Empirical models
2. Physiological models
• Realistic models
3. Distributed parameter models
• Realistic models
 APPILICATIONS OF PHARMACOKINETIC MODELS:-
 Characterizing the behavior of drugs in patients.
 Correlating plasma drug concentration with pharmacological
response.
 Evaluating the bioequivalence bioinequivalence between
different formulations of the same drugs.
 Determining the influence of altered physiologydisease state on
drugs ADME
 Explaining drugs interaction.
13) One compartment (open) model IV-bolus
In a one-compartment open model for IV-bolus, the drug is given
directly into the bloodstream all at once. Here's a simple breakdown:
1. Instant Distribution: The drug quickly mixes throughout the
bloodstream and tissues.

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2. Single Compartment: The body is viewed as a single unit where the drug
distributes.
3. Exponential Decline: The concentration of the drug in the blood
decreases exponentially over time as it's metabolized and eliminated.
4. Key Parameters: The main parameters are the initial concentration (C0),
elimination rate constant (k), and half-life (t1/2).
5. Equation: The drug concentration at any time (Ct) is given
by
In short, the one-compartment model with IV-bolus administration
assumes the drug spreads instantly and uniformly, and its concentration
decreases at a constant rate over time.
14) Non-linear Pharmacokinetics: cause of non-linearity
Non-linear pharmacokinetics occurs when the rate of drug absorption,
distribution, metabolism, or excretion doesn't follow a simple proportional
relationship with the dose.
 Main causes of non-linearity:
1. Saturation of Enzymes: Enzymes that metabolize drugs can become
saturated at higher doses, slowing down drug metabolism.
2. Carrier Saturation: Transport proteins that move drugs across cell
membranes can also become saturated, affecting absorption and
distribution.
3. Binding Sites: Limited binding sites for the drug on proteins in the blood
can become fully occupied.
4. Changes in Blood Flow: High drug concentrations can alter blood flow,
affecting how the drug is distributed and eliminated.
5. Auto-Induction: Some drugs can increase the production of enzymes
that metabolize them, changing the rate of metabolism over time.
In summary, non-linear pharmacokinetics arises when the body's processes for
handling a drug become saturated or are otherwise altered, leading to a non-
proportional relationship between dose and drug levels in the body.
15) Michaelis – Menten equation. Estimation of kmax & Vmax
The Michaelis-Menten equation describes how the rate of drug metabolism
depends on drug concentration. It's especially useful for understanding
enzyme kinetics when the enzyme that metabolizes the drug becomes
saturated. Here's the equation and how to estimate the parameters Vmax & Km:

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Michaelis-Menten Equation:
Where:
 V = Rate of metabolism
 Vmax = Maximum rate of metabolism when the enzyme is saturated
 [S] = Drug concentration (substrate concentration)
 Km = Drug concentration at which the metabolism rate is half of Vmax
Estimation of Vmax and Km:
1. Conduct Experiments: Measure the rate of metabolism at different drug
concentrations.
2. Plot Data: Plot the drug concentration ([S]) on the x-axis and the rate of
metabolism (V) on the y-axis.
3. Lineweaver-Burk Plot (Double Reciprocal Plot): To make estimation
easier, transform the Michaelis-Menten equation into its double
reciprocal form:
4. Calculate Vmax and Km: From the Lineweaver-Burk plot, use the intercept
and slope to calculate Vmax and Km.
Simplified Steps:
In short, VmaxV_{max}Vmax is the maximum metabolism rate,
and Km is the drug concentration at half of Vmax . Use experimental data
and plots to estimate these values.

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16) Drug Interaction & pharmacokinetic interaction with e.g.
Drug Interaction: This occurs when one drug affects the activity, effectiveness,
or side effects of another drug. These interactions can change how drugs are
absorbed, distributed, metabolized, or excreted in the body.
Types of Pharmacokinetic Interactions:
1. Absorption: One drug can change how another drug is absorbed in the
gut.
2. Distribution: Drugs can compete for binding sites on proteins in the
blood.
3. Metabolism: One drug can affect the enzymes that break down another
drug.
4. Excretion: Drugs can affect the kidneys' ability to remove other drugs
from the body.
Example: Grapefruit Juice and Statins
Interaction: Grapefruit juice is known to interact with statins, a class of drugs
used to lower cholesterol.
1. Mechanism: Grapefruit juice inhibits an enzyme called CYP3A4 in the
small intestine. This enzyme is responsible for metabolizing many drugs,
including statins.
2. Effect on Absorption: When CYP3A4 is inhibited by grapefruit juice, less
of the statin is broken down in the intestine.
3. Increased Drug Levels: As a result, more of the statin enters the
bloodstream, leading to higher levels of the drug in the body than
expected.
4. Risk of Side Effects: Elevated levels of statins can increase the risk of
side effects such as muscle pain or, in severe cases, muscle damage
(rhabdomyolysis).
17)Bioavailability. Relative & absolute availability. Methods for
assessment of bioavailability
Bioavailability: Relative & Absolute Availability
Bioavailability refers to the fraction of a drug that reaches systemic circulation
unchanged after administration, thus determining the extent and rate of drug
absorption. There are two types:
1. Absolute Bioavailability: This measures the percentage of the
administered dose of a drug that reaches systemic circulation when
compared to an intravenous (IV) dose, which is considered 100%
bioavailable since it bypasses absorption processes. It gives a direct
measure of how much of the drug actually gets into the bloodstream.

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18
2. Relative Bioavailability: This compares the bioavailability of a drug from
one formulation or route of administration to another. For example,
comparing a tablet form to a capsule form of the same drug. It helps in
evaluating differences in formulation, route of administration, or dosage
forms.
Methods for Assessment of Bioavailability:
1. Pharmacokinetic Studies: These involve measuring drug concentrations
in blood or plasma over time after administration. Key parameters such
as area under the curve (AUC), peak plasma concentration (Cmax), and
time to reach peak concentration (Tmax) are used to assess
bioavailability.
2. Bioequivalence Studies: These compare the bioavailability of a test
formulation (generic or modified formulation) to a reference
formulation (typically the original branded drug). If the test
formulation's bioavailability falls within a predefined range of the
reference formulation, they are considered bioequivalent.
3. In vitro Studies: These involve studying drug dissolution and release
from dosage forms using dissolution testing apparatus. Dissolution
testing helps predict how well a drug will be absorbed in vivo based on
its ability to dissolve in simulated gastric and intestinal fluids.
4. In vivo Imaging Techniques: Advanced imaging techniques like positron
emission tomography (PET) or magnetic resonance imaging (MRI) can
provide real-time visualization and quantification of drug distribution in
the body, aiding in assessing bioavailability.
5. Urinary Excretion Studies: Measurement of drug and its metabolites in
urine provides information about drug absorption, metabolism, and
excretion, helping in determining bioavailability.
By employing these methods, researchers and pharmaceutical companies
can assess the bioavailability of drugs accurately, ensuring efficacy and safety
in clinical use.
18)Crossover study design
A crossover study design is a type of clinical trial where each participant
receives multiple treatments or interventions, with a "crossover" from one
treatment to another during the study.
 Here's a simple breakdown:
1. Participants: Participants in a crossover study receive each treatment or
intervention at different times during the study period. They act as their
own control group, which helps reduce variability between participants.

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19
2. Sequence: Participants are randomly assigned to different sequences of
treatments. For example, one group might receive Treatment A first,
followed by Treatment B, while another group receives Treatment B
first, followed by Treatment A.
3. Washout Period: Between each treatment period, there is a "washout"
period where participants are allowed to return to their baseline
condition or clear the effects of the previous treatment. This helps
ensure that the effects of one treatment do not carry over into the next.
4. Comparison: By comparing each participant's response to different
treatments within the same study, researchers can evaluate the relative
efficacy, safety, and tolerability of the treatments.
5. Advantages: Crossover studies are efficient because they require fewer
participants to achieve statistical power, and they control for individual
differences in response to treatments. They are particularly useful for
studying chronic conditions where participants serve as their own
controls.
6. Disadvantages: There may be carryover effects from one treatment to
another despite the washout period, and the design may not be suitable
for treatments with long-lasting effects or irreversible outcomes.
In summary, a crossover study design allows researchers to compare the
effects of different treatments within the same group of participants, providing
valuable insights into treatment efficacy and safety.
19)Biopharmaceutics classification system (BSC) with suitable e.g.
 DEFINITION
The Biopharmaceutical Classification System is a scientific framework
for classifying a drug substance based on its aqueous solubility &
intestinal permeability & dissolution rate.
 CLASSIFICATIAON
A. CLASS I
1. High Permeability and high Solubility.
2. These are well absorbed and their absorption rate is usually higher
than excretion.
3. Example - Metoprolol.
B. CLASS II
1. High Permeability and Low Solubility.
2. Bioavailability is limited by their solvation rate.
3. Example- Glibenclmide.

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C. CLASS III
1. Low Permeability and High Solublity.
2. The absorption is limited by the permeation rate but drug is solvated
very fast.
3. Example- Cimetidine.
D. CLASS IV
4. Low Permeability And High Solubility.
5. Poor bioavailability and Not well absorbed over the intestinal
mucosa.
6. Example- Hydrochlorothiazide.
20) Clinical Significance of Bioequivalence studies
Bioequivalence studies are crucial in advanced biopharmaceutics and
pharmaceutics because they ensure that different formulations of the same
drug produce similar therapeutic effects in patients. Here’s a short and simple
explanation of their clinical significance:
Clinical Significance of Bioequivalence Studies:
Definition:
 Bioequivalence studies compare the bioavailability (rate and extent of
absorption) of the same active pharmaceutical ingredient from different
formulations, typically a generic version versus a brand-name drug.
Purpose:
 To ensure that the generic drug is therapeutically equivalent to the brand-
name drug.
Key Points:
1. Ensures Therapeutic Effectiveness:
o Confirms that the generic drug will have the same clinical effect and
safety profile as the brand-name drug.
2. Promotes Drug Interchangeability:
o Allows healthcare providers to substitute brand-name drugs with
generics confidently, ensuring patients receive the same therapeutic
benefits.
3. Cost-Effective Treatment:
o Encourages the use of more affordable generic drugs, reducing
healthcare costs for patients and the healthcare system.
4. Regulatory Approval:
o Required by regulatory agencies like the FDA to approve generic drugs,
ensuring they meet strict standards of quality and efficacy.
5. Patient Compliance:
o Improves patient access to essential medications by providing cost-
effective alternatives, leading to better adherence to treatment
regimens.

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21)Generic Substitution
Drug product selection &generic drug product substitution are
major responsibilities for physicians, pharmacists and others who
prescribe dispense or purchase drugs.
 To facilitate that FDA published, Approved Drug Products with
Therapeutic Equivalence Evaluations
Orange book which identifies drug products approved on the basis of
safety and effectiveness.
 They serve as public information and advice to health agencies,
prescribers and pharmacists to promote public education in the area
of drug product selection.
 To contain drug costs, most state have adopted generic substitution
laws to allow pharmacist to dispense a generic drug product for a
brand- name drug product that has been prescribed.
 Some states have adopted positive formulary which lists
therapeutically equivalent or interchangeable drug product that
pharmacist may dispense.
 Others use a negative formulary, which lists drug products that are
not therapeutically equivalent, or interchange of which is prohibited.
 And if the drug is not negative formulary, the unlisted generic drug
products are assumed to be therapeutically equivalent and may not
be interchanged.
 Approved Drug Products With Therapeutic Equivalence Evaluation
 Orange book contains therapeutic equivalence evaluations for
approved drug products made by various manufacturers.
 The concept of therapeutic equivalence as used to develop the
Orange Book applies only to drug products containing the same
active ingredient.
 And does not encompass a comparison of different therapeutic
agents used for same condition.
 Eg: propoxyphene HCL versus pentazocine HCL for treatment of pain.

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22
22)Targeted Drug Delivery System
A targeted drug delivery system is like a special courier service for
medicine in the body. Instead of just sending medicine everywhere, it delivers
it directly to where it's needed most, like a specific organ or even a particular
type of cell.
 Here's how it works:
1. Precision Delivery: Instead of taking a pill that spreads medicine all over
your body, targeted drug delivery systems are designed to release medicine
only where it's needed. This can reduce side effects because it minimizes
the exposure of healthy tissues to the drug.
2. Different Approaches: There are different ways to target drugs. Some
systems use tiny particles or capsules that can carry the medicine to the
right place. Others use special coatings that only dissolve when they reach
the target area.
3. Smart Technology: Some targeted drug delivery systems are really smart.
They can be programmed to release the medicine slowly over time or in
response to specific signals in the body, like changes in pH or temperature.
4. Examples: One example is using nanoparticles to deliver chemotherapy
drugs directly to cancer cells while sparing healthy tissues. Another
example is using targeted drug delivery to treat diseases like diabetes by
delivering insulin directly to the bloodstream.
In summary, targeted drug delivery systems are like precision medicine for
your body. They deliver medicine directly to where it's needed most, which can
make treatments more effective and reduce side effects.
23)Physical & Chemical properties of drug substance importance
in designing of drug for (i) Nasal Administration (ii) Ocular Administration
When designing drugs for nasal and ocular administration, considering
their physical and chemical properties is crucial for effectiveness and safety.
 Nasal Administration:
1. Solubility: The drug should be soluble in nasal fluids to ensure proper
absorption through the nasal mucosa.
2. Particle Size: Small particle size enhances nasal absorption, as larger
particles might get trapped in mucus or be too irritating.
3. Permeability: Drugs with good permeability across nasal membranes are
preferred for efficient absorption into the bloodstream.
4. Stability: The drug should remain stable in nasal fluids to maintain its
potency until absorbed.
5. Irritation Potential: Avoiding drugs that cause irritation or discomfort in
the nasal cavity enhances patient compliance.

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23
 Ocular Administration:
1. Solubility: Drugs should be soluble in tear fluids to ensure uniform distribution over
the eye's surface.
2. Osmolarity: Maintaining isotonicity with tears prevents irritation to the delicate eye
tissues.
3. Viscosity: Proper viscosity ensures adequate retention on the ocular surface without
rapid drainage or discomfort.
4. Sterility: Ocular drugs must be sterile to prevent infection or irritation.
5. Preservative Compatibility: Preservatives, if used, should be compatible with ocular
tissues to avoid irritation or damage.
In both cases, the physical and chemical properties of the drug substance play
a vital role in ensuring optimal drug delivery, absorption, and therapeutic effect
while minimizing adverse effects or discomfort to the patient.
24)Biotechnological Product
A biotechnological product is a type of medicine or therapeutic substance made
using biotechnology methods. Instead of traditional chemical synthesis,
biotechnological products are produced by harnessing living organisms, cells, or
biological systems.
Here's a simple breakdown:
1. Biotechnology: This field involves using living organisms, cells, or biological
systems to develop products or technologies. In the case of biotechnological
products, this usually means using genetic engineering or other biotech
methods to create therapeutic substances.
2. Examples: Biotechnological products include things like recombinant proteins,
antibodies, vaccines, and gene therapies. These can be used to treat a wide
range of diseases, from cancer to genetic disorders.
3. Production Process: To make a biotechnological product, scientists first
identify the gene or genes responsible for producing the desired substance.
They then insert these genes into host organisms, such as bacteria, yeast, or
mammalian cells, which act as tiny factories to produce the therapeutic
substance.
4. Advantages: Biotechnological products often have advantages over traditional
drugs, such as greater specificity, reduced side effects, and the ability to target
specific diseases or conditions more effectively.
5. Regulation: Because biotechnological products are made using living
organisms or cells, they are subject to strict regulations to ensure safety,
efficacy, and quality. Regulatory agencies like the FDA (in the United States)
closely oversee the development, manufacturing, and marketing of biotech
products.
In summary, biotechnological products are medicines or therapeutic substances
produced using biotechnology methods, such as genetic engineering. They offer
innovative solutions for treating diseases and disorders, often with improved
specificity and effectiveness compared to traditional drugs.

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24
25)Pharmacokinetics & Pharmacodynamics of biotechnology
drugs
 Pharmacokinetics:
1. Absorption: Biotechnology drugs can be absorbed differently depending
on how they're administered. For example, some may be injected
directly into the bloodstream (intravenous), while others may be given
as injections under the skin (subcutaneous) or into muscles
(intramuscular).
2. Distribution: Once in the bloodstream, biotechnology drugs travel to
target tissues or organs where they exert their therapeutic effects. Their
distribution can be influenced by factors such as molecular size, charge,
and binding to proteins in the blood.
3. Metabolism: Biotechnology drugs may undergo metabolism in the body,
typically by enzymes, which can affect their effectiveness and duration
of action. However, many biotech drugs are designed to be structurally
similar to naturally occurring proteins, reducing the likelihood of
metabolism.
4. Excretion: Biotechnology drugs are often eliminated from the body
through mechanisms such as renal excretion (in urine) or hepatic
clearance (through the liver). The rate of excretion can impact the
duration of drug action and the need for dosing adjustments in patients
with impaired kidney or liver function.
 Pharmacodynamics:
1. Mechanism of Action: Biotechnology drugs work by interacting with
specific targets in the body, such as receptors, enzymes, or signaling
molecules. Understanding their mechanism of action is essential for
predicting their effects and potential side effects.
2. Dose-Response Relationship: Like traditional drugs, biotechnology drugs
exhibit dose-response relationships, meaning their effects vary with the
dose administered. Finding the right dose is critical for achieving
therapeutic benefits while minimizing adverse effects.
3. Onset and Duration of Action: The onset of action refers to how quickly
a drug begins to produce its effects, while the duration of action refers
to how long those effects last. These factors depend on the drug's
pharmacokinetics and pharmacodynamics.
4. Variability in Response: Individual patients may respond differently to
biotechnology drugs due to factors such as genetic differences, disease
severity, and concurrent medications. Understanding this variability is
important for personalized medicine approaches.

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25
26)Protein & Peptides
Proteins and peptides are molecules that play crucial roles in the body's
functions and are also used in biopharmaceutics for therapeutic purposes.
 Proteins:
1. Definition: Proteins are large, complex molecules made up of chains of
amino acids. They serve various functions in the body, including
structural support, enzyme activity, and signaling.
2. Examples: Examples of proteins include hormones like insulin and
growth factors like erythropoietin. These proteins are essential for
regulating processes such as metabolism, growth, and immune function.
3. Biopharmaceuticals: Proteins are used in biopharmaceutics to develop
therapeutic drugs. These drugs can mimic natural proteins in the body or
act on specific targets to treat diseases like diabetes, cancer, and
autoimmune disorders.
4. Challenges: One challenge with protein-based drugs is that they can be
broken down or deactivated in the digestive tract if taken orally.
Therefore, many protein drugs are administered through injections,
either subcutaneously, intramuscularly, or intravenously.
 Peptides:
1. Definition: Peptides are smaller molecules than proteins, consisting of
shorter chains of amino acids. They can also have various biological
functions, similar to proteins.
2. Examples: Peptides include molecules like hormones (e.g., glucagon),
neurotransmitters (e.g., endorphins), and antimicrobial peptides (e.g.,
defensins). These molecules play important roles in regulating bodily
functions and defending against pathogens.
3. Therapeutic Applications: Peptides have become increasingly important
in biopharmaceutics for their therapeutic potential. They can be used as
drugs to treat conditions such as diabetes (e.g., GLP-1 analogs) or as
targeting agents for drug delivery systems.
4. Administration: Like proteins, peptides face challenges with oral
administration due to degradation in the digestive tract. Therefore,
many peptide drugs are administered through injections, nasal sprays, or
patches to ensure their effectiveness.
 Summary:
Proteins and peptides are important molecules in
biopharmaceutics, both as natural regulators in the body and as
therapeutic agents for treating various diseases. Understanding their
structures, functions, and methods of administration is crucial for
developing effective protein and peptide-based drugs.

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26
27)Monoclonal Antibodies
Monoclonal antibodies (mAbs) are a type of protein designed to
recognize and bind to specific targets in the body, such as viruses, bacteria, or
abnormal cells.
1. Origin: Monoclonal antibodies are made in the lab by cloning a single
type of immune cell, called a B cell, to produce identical copies of a
specific antibody. These antibodies are then purified and used as drugs.
2. Target Specificity: Each monoclonal antibody is designed to target a
specific molecule or structure in the body, known as an antigen. This
specificity allows them to selectively bind to their target with high
affinity.
3. Therapeutic Applications: Monoclonal antibodies have a wide range of
therapeutic applications. They can be used to treat various diseases,
including cancer, autoimmune disorders, infectious diseases, and
inflammatory conditions.
4. Mechanism of Action: Once bound to their target, monoclonal
antibodies can exert their effects in several ways. They may stimulate
the immune system to attack target cells, block receptors to prevent
signaling, or deliver drugs or toxins directly to target cells.
5. Administration: Monoclonal antibodies are typically administered by
injection, either subcutaneously or intravenously. Some may also be
given as infusions over a period of time.
6. Examples: Some well-known examples of monoclonal antibodies include
rituximab, which is used to treat certain types of cancer and
autoimmune diseases, and trastuzumab, which is used to treat HER2-
positive breast cancer.
Monoclonal antibodies are engineered proteins designed to target
specific molecules in the body for therapeutic purposes. They have
revolutionized the treatment of various diseases and continue to be an
important class of biopharmaceuticals.
28)Calculation of Maintainance Dose.
Calculating the maintenance dose of a drug involves figuring out
how much medicine a person needs to take regularly to keep a stable
level of the drug in their body.
1. Therapeutic Goal: First, you need to determine the desired level of the
drug in the body to achieve the desired therapeutic effect. This is often
based on factors like the patient's condition, age, weight, and kidney or
liver function.

Aditya S. Kakad
27
2. Pharmacokinetics: You'll consider the drug's pharmacokinetic
properties, such as its half-life (how long it stays in the body) and
clearance rate (how quickly the body removes it). These factors help
determine how often the drug needs to be dosed to maintain a steady
level in the body.
3. Maintenance Dose Formula: The maintenance dose can be calculated
using the following formula:
Maintenance Dose = (Desired Plasma Concentration) × (Clearance Rate)
× (Dosing Interval)
This formula takes into account the desired drug concentration, how
quickly the drug is removed from the body, and how often the drug is
given.
4. Adjustments: The maintenance dose may need to be adjusted based on
individual factors like kidney or liver function, age, or changes in the
patient's condition. Doctors may also monitor drug levels in the blood
and adjust the dose accordingly.
5. Example: For example, if a patient needs a drug with a desired plasma
concentration of 10 mg/L, and the drug has a clearance rate of 2 L/hour
and is dosed every 8 hours, the maintenance dose would be:
Maintenance Dose = 10 mg/L × 2 L/hour × 8 hours = 160 mg
So, the patient would need to take 160 mg of the drug every 8 hours to
maintain the desired plasma concentration.
Calculating the maintenance dose involves considering the
therapeutic goal, the drug's pharmacokinetic properties, and individual
patient factors to ensure the drug remains at the right level in the body
for optimal treatment.

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