Clinical pharmacokinetics

Basic principles and its

applications

S. M. Habibur Rahman
Department of Pharmaceutics
PSG College of Pharmacy
 Clinical Pharmacokinetics

• The science of the rate of movement of

drugs within biological systems, as
affected by the absorption, distribution,
metabolism, and elimination of
medications
Why Study Pharmacokinetics (PK)
and Pharmacodynamics (PD)?
• Individualize patient drug therapy
• Monitor medications with a narrow
therapeutic index
• Decrease the risk of adverse effects while
maximizing pharmacologic response of
medications
• Evaluate PK/PD as a diagnostic tool for
underlying disease states
 Organization of Workshop
• PK basic principles
• ADME factors
• Half life, Elimination Rate and AUC
• Models
• Hands on Experience
 Clinical (Human) Testing

Preclinical testing

Population PK/PD
Dose response trials
characteristics in
large efficacy trials

PK-guided Post-
Efficacy
Dose marketing
PK/PD in
escalation surveillance
In vitro PK/PD Special
Dosage selection populations
Animal PK/PD Safety
Assessment Patient variables
Toxicity

Animal Phase I Phase II Phase III

testing
 Significance
• Once the target enzyme or receptor is identified,
medicinal chemists use a variety of empirical and
semiempirical structure-activity relationships to modify
the chemical structure of a compound to maximize its in
vitro activity.

• However, good in vitro activity cannot be extrapolated to

good in vivo activity unless a drug has good
bioavailability and a desirable duration of action.

• Key role- Pharmacokinetics and drug metabolism -has

led many drug companies to PK and drug properties as
part of their screening processes in the selection of drug
candidates.
 Absorption
• Able to get medications into the patient’s
body
• Drug characteristics that affect absorption:
– Molecular weight, ionization, solubility, &
formulation
• Factors affecting drug absorption related
to patients:
– Route of administration, gastric pH, contents
of GI tract
Physicochemical properties
 Transport
• Bickel (1994) have shown initial uptake of
drugs into adipose tissue is related to their
lipophilicity, the degree of adipose tissue
storage does not correlate with their
lipophilicity.
• Factors such as drug binding to plasma
and tissue proteins also play a significant
role in drug storage in adipose tissues.
 Pgp transport
• P-glycoprotein, located on the apical surface of
the endothelial cells of the brain capillaries
toward the vascular lumen (Tew et al., 1993;
Pardridge, 1991), is believed to be responsible
for the poor BBB penetration of some highly
lipophilic drugs.

• The poor BBB penetration of drugs may be

related to the efflux function of p-glycoprotein.
 Distribution
• Membrane permeability
– cross membranes to site of action
• Plasma protein binding
– bound drugs do not cross membranes
– malnutrition = albumin =  free drug
• Lipophilicity of drug
– lipophilic drugs accumulate in adipose tissue
• Volume of distribution
 Metabolism
• Drugs and toxins are seen as foreign to
patients bodies
• Drugs can undergo metabolism in the
lungs, blood, and liver
• Body works to convert drugs to less active
forms and increase water solubility to
enhance elimination
 Metabolism
• Liver - primary route of drug metabolism
• Liver may be used to convert pro-drugs
(inactive) to an active state
• Types of reactions
– Phase I (Cytochrome P450 system)
– Phase II
 Elimination
• Pulmonary = expired in the air
• Bile = excreted in feces
– enterohepatic circulation
• Renal
– glomerular filtration
– tubular reabsorption
– tubular secretion
 Pharmacokinetic principles
• Steady State: the amount of drug
administered is equal to the amount of
drug eliminated within one dosing interval
resulting in a plateau or constant serum
drug level
• Drugs with short half-life reach steady
state rapidly; drugs with long half-life take
days to weeks to reach steady state
 Steady State Pharmacokinetics
• Half-life = time
required for serum 100
90
plasma 80
70
concentrations to % 60
decrease by one-half steady 50
state 40
(50%) 30
20
• 4-5 half-lives to reach 10
0
steady state 1 2 3 4 5
Half-life
 Loading Doses
• Loading doses allow
40
rapid achievement of
35
therapeutic serum
30
levels
25 w/ bolus
• Same loading dose 20
w/o
used regardless of 15 bolus
metabolism/eliminatio 10
n dysfunction 5
0
 Linear Pharmacokinetics
• Linear = rate of
120
elimination is
100
proportional to

concentration
80
amount of drug
present 60
40
• Dosage increases
20
result in proportional
increase in plasma 0

drug levels dose

 Nonlinear Pharmacokinetics
• Nonlinear = rate of
50
elimination is constant 45
regardless of amount 40
35

concentration
of drug present 30
• Dosage increases 25
20
saturate binding sites 15
and result in non- 10
5
proportional 0
increase/decrease in dose
drug levels
 Michaelis-Menten Kinetics
• Follows linear kinetics
30
until enzymes
25
become saturated

concentration
20
• Enzymes responsible 15
for metabolism 10

/elimination become 5
0
saturated resulting in
non-proportional dose
increase in drug phenytoin
levels
 Special Patient Populations
• Renal Disease: same hepatic metabolism,
same/increased volume of distribution and
prolonged elimination   dosing interval
• Hepatic Disease: same renal elimination,
same/increased volume of distribution,
slower rate of enzyme metabolism  
dosage,  dosing interval
• Cystic Fibrosis Patients: increased
metabolism/ elimination, and larger volume
of distribution   dosage,  dosage interval
Pharmacologist role
 Clinical Pharmacokinetics
• Application of pharmacokinetic methods in drug
therapy
• Optimized dosing strategies based on
– Patient disease state
– Patient specific consideration
• Influence of disease on drug disposition
– Not adequately studied
• Age, Gender, genetic & ethnic factors
– Pharmacokinetic difference
• Population approach
• TDM
Pharmacokinetics in drug development
Stage of development
Initial PK studies in Humans (decision Phase)
– emphasis on safety and tolerance
• Number of subjects limited but intensive
• Descriptive evaluation of pharmacokinetics
• Look for first evidence of concentration-effect
relationships

Goal: First-Time Knowledge About PK of the Drug

Pharmacokinetics in drug development
• Later PK Studies in Humans (Registration Phase)
– Emphases on Expansion and Depth of Knowledge
• Use number of subjects necessary to be definitive
• Define concentration-effect relationships
• Expand studies to wider population (gender, age, ethnic
origin)
• Link data to target population (population PK)
Goal: Broaden Understanding, Special Populations

• Therapeutic drug monitoring (Commercialization Phase)

Key Pharmacokinetic Descriptive Variables
Half-Life, T½
CL = V X 0.693 / T½
Clearance, CL
Volume of Distribution, V

Primary Pharmacokinetic Measurements

– Concentration (mass per volume), Cp
– Rate constants (time-1), ka ke k12 λ β
– Amount of Drug (mass), A Ae Dose
– Area Under the Curve (integration of time and
mass per volume), AUC
 Why estimate pharmacokinetics
• "Need to know" versus "Nice to know“

•FDA and other regulatory hurdles

•Absolute Bioavailability
- Dosage form design
- Bioavailability problems (F=5% or 95%)
- Intersubject Variability (absorption vs DME)

•Estimate Rate Processes

– Distinguish rate process from rate constant
Why estimate pharmacokinetics
• Characterize drug exposure
– time duration
– degree of exposure
• Predict dosage requirements
– how much, how often
• Assess changes in dosage requirement
– special populations
– drug interactions
 Why estimate pharmacokinetics

• Pharmacokinetic – Pharmacodymamic Relationships

– Concentration effect relationships

– Use PK to provide concentration when PD
measurement is performed
– Establish safety margins and efficacy
characteristics

• Efficient and safe drug utilization

 Interrelationship
Key Pharmacokinetic factors
 Biopharmaceutics & Pharmacokinetics

Dynamic relationship
Drug, Drug Product & pharmacologic effect

Drug release and Drug in systemic

Drug in Tissue
dissolution circulation

Excretion and Pharmacologic or

metabolism clinical effect
 Biopharmaceutical factors –
Dosage form
• Protection of activity of drug within the
drug product
• Release of drug
• Rate of dissolution
• Systemic absorption
Drug Disposition- drug interaction in body
Volatile
BLOOD
drug in
Oral Adipose Effector expired air
Ingestion Tissue tissue
Storage drug receptor Lung
binding
Peripheral
DRUG DRUG tissues
metabolism

Liver Kidney
Drug - Plasma Drug
Protein Complex Metabolism Drugs and
metabolites
Bile in urine
INTESTINE Intestinal Drugs and
reabsorption metabolites
in stools
 Hard drugs
• Nonmetabolizable drugs.
• Not only does it solve the problem of
toxicity due to reactive intermediates or
active metabolites, but the
pharmacokinetics also are simplified
because the drugs are excreted primarily
through either the bile or kidney.
• Eg. ACE inhibitors and bisphosphonates
 Soft drugs
• A soft drug is pharmacologically active as such,
and it undergoes a predictable and controllable
metabolism to nontoxic and inactive metabolites.

• The main concept of soft drug design is to avoid

oxidative metabolism as much as possible and
to use hydrolytic enzymes to achieve predictable
and controllable drug metabolism.
Eg. Atracurium
 Drug Disposition
• BCS – system
• BDDS
– Metabolism
– Solubility
– Permeability
 BCS & its Application
• The Biopharmaceutical Classification System
(BCS) is based on solubility tests, correlating for
drugs with their bioavailability in human body.
• It is widely used in design and development of
innovation drugs
• New dosage forms (permeability amplifiers)
• In clinical pharmacology (drug-drug, drug-food
interaction)
• Regulation agencies of several countries as the
scientific approach, for testing of waiver on
bioavailability.
 PHARMACOKINETIC CHARACTERISTICS
OF BIOAVAILABILITY
Bioavailability is based on the physiological
process of absorption, which include three stages
• Transfer a substance through apical plasma
membrane inside cells
• Intracellular transport of substances followed
by their possible metabolism
• Transfer of the transported and transformed
substance from cells into blood or lymph
 Characteristics of absorption & bioavailability
processes
Absorption Bioavailability
Strictly corresponds Corresponds to an API dose
to API dose and clearance value

In some cases corresponds Strictly corresponds

to a therapeutic effect to therapeutic effect
Depends on permeability Depends on both API
of corresponding bio entrance to blood circulation
membranes and elimination from it
(enterocytes)
The effect of food on API absorption
BCS The effect of food Action mechanism
class on bioavailability
parameters
I Reduction of rate Decrease of GIT
but not duration evacuation
2 Reduction of rate Decrease of solubility
(Bases) but not duration due to the increase
of gastric pH
2 (Acids) Increase of the rate Increase of solubility
and possibly due to the increase
duration of gastric pH
3 The effect is not
observed
The ratio of solubility/permeability
parameters in BCS classes
Measurement of Drug Concentration
• Milk ▪ Saliva
• Plasma ▪ Urine

Sampling of biological specimens

• Invasive Method
– Sampling Blood, Spinal Fluid, synovial
fluid, Tissue biopsy
• Non invasive Method
– Sampling urine, saliva, feces, expired air
 Pharmacokinetic Model

• Quantity study of various kinetic process

of drug disposition in the body

• Biological nature of drug distribution and

disposition is complex and drug events
often happen simultaneously
 Steps in modeling
• Model development
• Model characterization, i.e. methods to describe
how consistent the model is with biology;
strengths and limitations of available model and
data, such as sensitivity analyses,
• Model documentation,
• Model evaluation, i.e. independent review
 Basic pharmacokinetic model
• Various mathematical model can devised to
simulate the rate process of drug ADE
• development of equations useful in describing
drug concentration in the body as a function of
time
• Predictive capability of model lies in the proper
selection & development of mathematical
function (s) that parameterize the essential
factors governing the kinetic process
 Variables in model
• Key parameters in a process is commonly
estimated by fitting the model to the
experimental data
• Pharmacokinetic function relates an
independent variable (time) to a dependent
variable (response)

• Types of model
– Empirical or Physiological
• Empirical models are practical but not very useful
in explaining the mechanism of the actual process
of ADME in the body is not possible
 Pharmacokinetics
Pictorial and Graphical
Understanding of the
Shapes of Concentration Time
Profiles

Mathematical Models that describe

and track these time profiles
Concentration profile depends - On
• Route of Administration
– Intravenous (bolus, infusion)
– Extravascular (oral, IM, SQ)
– Specialized

• Disposition of the drug (ADME)

– distribution
– metabolism
– elimination
Pharmacokinetic Variability
Compartment models
 Compartment Models
• Well stirred model
• Based on assumption using linear
differential equation
• Provides simple way of grouping all the
tissues into one or more compartments
Types
• Mammilary Model and catenary model
IV Bolus One Compartment
IV Bolus Two Compartment
Oral One Compartment
Oral One Compartment
Compartmental Model
Oral Two Compartment
Oral Two Compartment
 compartment model
One compartment open model IV Injection
Central Ke
compartment

One compartment open model with

first order absorption
Ka Central K
compartment
 Multi compartment model
Two compartment open model IV Injection
K12
Central Tissue
compartment compartment
K21
k

Two compartment open model with

first order absorption
K12
ka Central Tissue
compartment compartment
K21
k
 Functions of Drawing Models
• To write differential equations to describe
drug concentration changes in each
compartment
• Visual representation of rate process
• Shows how many pharmacokinetic
constants are necessary to describe the
process adequately
Deficiencies of compartmental analysis
• Lack of meaningful physiological basis for derived
parameters
• Lack of rigorous criteria to determine No of
compartments necessary to describe disposition.
• Lack of ability to elucidate organ specific elimination
• Inability to relate derived parameters to quantifiable
physiological parameters
• Inability to predict impact of pathophysiology
• Inability to provide insight into mechanism of drug-drug
and drug-nutrient interactions
• Highly sensitive to sampling frequency
 Physiological compartment Model
• Blood flow or perfusion model
• Describes the data with the consideration
that blood flow is responsible for
distributing drug to various part of body
• Uptake of drug into organs is determined
by the binding of drug in these tissues
• Tissue volume describes the drug
concentration
 PBPK
• Experimentally difficult
• In spite of this limitation the PBPK model does
describe much better insight into hoe physiologic
factor may change drug distribution from one
animal species to another
• No data fitting is required
• Drug concentration is predicted by organ tissue
size, blood flow & tissue – blood ratio (partition)
• The above facts may vary due to
Pathophysiologic condition
Physiologic pharmacokinetic model
(Flow Model)

From: Rowland M, Tozer TN. Clinical

Pharmacokinetics – Concepts and
Applications, 3rd edition, Williams
and Wilkins, 1995, p. 12.
 Models in Toxicokinetics
• There is no single method or model that
can extrapolate the toxicity from animals to
humans (Boxenbaum et al., 1988), the
species differences in toxicity often can be
explained by pharmacokinetic or
pharmacodynamic effects of drugs.