Clinical pharmacokinetics

1. Clinical pharmacokinetics

2. BASIC CONCEPTS
• PK
• PK vs PD
• Clinical PK
• Bioavailability
• Ka
• Vd
• Protein binding
• CL
• Ke
• T1/2

3. Conc. Vs time
– Oral
– Parenteral
– Cont. iv
• AUC, t max Cmax
• Linear and nonlinear PK
• PK models
– One compartment
– Two compartment

4. • Derived from Ancient Greek pharmakon
"drug" and kinetikos "moving, putting in
motion"
• It is a branch of pharmacology dedicated to
determining the fate of substances
administered externally to a living organism.
• The substances of interest include
pharmaceutical agents, hormones, nutrients,
and toxins.

5. • Syn= Applied PK
• It is the application of pharmacokinetic
principles to the safe and effective therapeutic
management of drugs in an individual patient.
• Primary goals of clinical pharmacokinetics
include enhancing efficacy and decreasing
toxicity of a patient's drug therapy.

6. PHARMACOKINETIC PROCESSES
• Absorption
– Bioavailability (F)
• The percentage of the administered dose that reaches
the systemic circulation.
– Absorption Rate (Ka)
• The speed of input into the systemic circulation.
• Distribution
– Volume of Distribution (Vd)
• The apparent volume into which the drug distributes
within the body.
– Protein Binding
• The percentage of drug binds to the plasma protein

7. • Elimination
– Clearance (CL)
• The volume of drug cleared per unit time.
– Elimination Rate Constant (Ke)
• The proportion of drug in the body eliminated per unit
time.
– Elimination Half-life (t½)
• The time taken for the concentration to fall to half the
previous value

8. Vd
• It is also known as apparent volume of
distribution.
• It is defined as the distribution of a
medication between plasma and the rest of
the body after oral or parenteral dosing.

10. • The VD of a drug represents the degree to which
a drug is distributed in body tissue rather than
the plasma.
• VD is directly correlated with the amount of drug
distributed into tissue; a higher VD indicates a
greater amount of tissue distribution.
• A VD greater than the total volume of body water
(approximately 42 liters in humans) is possible,
and would indicate that the drug is highly
distributed into tissue.

11. • In rough terms, drugs with a high lipid solubility
(non-polar drugs), low rates of ionization, or low
plasma binding capabilities have higher Vd than
drugs which are more polar, more highly ionized
or exhibit high plasma binding in the body's
environment.
• Vd may be increased by renal failure (due to fluid
retention) and liver failure (due to altered body
fluid and plasma protein binding).

12. • Conversely it may be decreased in
dehydration.

13. CL
• It is a pharmacokinetic measurement of the
volume of plasma that is completely cleared
off a substance per unit time.
• Unit: mL/min.
• The total body clearance will be equal to the
renal clearance + hepatic clearance + lung
clearance.
• Clearance= Vd X Ke

14. • Cmax= The peak plasma concentration of a
drug after administration.
• Tmax= Time to reach Cmax
• Cmin= The lowest (trough) concentration
that a drug reaches before the next dose is
administered.

15. • Concentration= Amount of drug in a given
volume of plasma.
• AUC= The integral of the concentration-time
curve (after a single dose or in steady state).
• Formula= C x dt

16. CONCENTRATION VS TIME PROFILE
(Oral Administration)
Cp
t
A
A+D D+E
E
Ka
Ke
Ke

17. CONCENTRATION VS TIME PROFILE
(Parenteral Administration)
Cp
t
D+E
E
Ke
Ke

18. Cp
t
Input > Output
Input = output
CONCENTRATION VS TIME PROFILE
(Continuous Infusion)

19. CONCENTRATION VS TIME PROFILE
(AUC, Cmax, tmax)
Cp
t
Cmax
tmax
AUC

20. Linear/non-linear pharmacokinetics
• When doses are increased for most drugs,
steady-state concentrations increase in a
proportional fashion leading to linear
pharmacokinetics
• When steady-state concentrations change in a
disproportionate fashion after the dose is
altered, drug is said to follow nonlinear
pharmacokinetics

23. Models
• These are the hypothetical , mathematical
terms that describe the quantitative
relationship between drug movements in the
body and various Pk parameters.

24. Uses:
• Prediction of drug conc.
• Calculation of optimum dose and regimen
• Estimation of possible accumulation of drug
&/or metabolites
• Correlate drug conc. With
pharmacological/toxicological activities
• Bioequivalence studies
• To describe Pk changes in diseased state
• To explain drug interaction

26. Compartmental models
• The simple way to describe the PK of drugs
• Not realistic , are based on the group of
tissues having similar blood flow and affinity.
• Mixing within the compartment is rapid and
homogenous
• Compartment models are based on linear
assumptions & linear differential equations.

27. Compartment models
Caternary model Mammilary model

28. • Caternary model:
According to this model the compartments are
linked to each other in a chain pattern like a
train.

29. • Mammilary Models:
• The compartmental model where tissues are
grouped into one or more compartment, where
drug move to and from central compartment.
• Mammilary models are the most commonly used
PK models
• The central compartments considered to be
highly perfused tissues that rapidly equilibrate
with the drug.

31. One compartment model
• The one-compartment open model is the simplest way to describe
the process of drug distribution and elimination in the body.
• This model assumes that the drug can enter or leave the body , and
the entire body acts like a single, uniform compartment.
• The simplest route of drug administration from a modeling
perspective is a rapid intravenous injection (IV bolus).
• The simplest pharmacokinetic model that describes drug
disposition in the body is the IV bolus model where the drug is
injected all at once into a box (the human body) or compartment,
and the drug distributes/equilibrates instantaneously and rapidly
throughout the compartment.
• Drug elimination from the compartment also begins to occur
immediately after the IV bolus injection.

32. • This model is appropriate for drugs that
rapidly and readily distribute between the
plasma and other body tissues.

33. • Because of rapid drug equilibration between the blood
and tissues, drug distribution and elimination occur as
if the dose is all dissolved in a tank of uniform fluid (a
single compartment) from which the drug is
eliminated.
• The volume in which the drug seems to be distributed
is termed the apparent volume of distribution, VD.
• The apparent volume of distribution assumes that the
drug is theoretically rapidly and uniformly distributed
in the body throughout the apparent volume.
• The VD is determined from the injected amount or the
dose and the plasma drug
concentration Cp
0 immediately after injection.
• For simplicity, it is assumed that the injected dose
disperses and distributes instantly. This model is also
termed a well-stirred one-compartment model.

34. • A second pharmacokinetic parameter is the
elimination rate constant, k, which governs
the rate at which the drug concentration in
the body declines over time.

35. • The one-compartment open model does not predict
actual drug levels in the tissues.
• However, the model assumes that changes in the
plasma levels of a drug will result in proportional
changes in tissue drug levels, since their kinetic profile
is consistent with inclusion within the vascular
compartment and the various drug concentrations
within the compartment are in equilibrium.
• The drug in the body, D B, cannot be measured
directly; however, accessible body fluids (such as
blood) can be sampled to determine drug
concentrations.

37. ELIMINATION RATE CONSTANT
• The rate of elimination for most drugs from a tissue or
from the body is a first-order process, in which the rate
of elimination is dependent on the amount or
concentration of drug present.
• The elimination rate constant, k, is a first-order
elimination rate constant with units of time
• Generally, the parent or active drug is measured in the
vascular compartment.
• Total removal or elimination of the parent drug from
this compartment is effected by metabolism
(biotransformation) and excretion

40. The equation can also be written as:

42. Two-compartment model:
• The body is divided into:
• central and peripheral compartment.
• The central compartment (compartment 1)
consists of the plasma and tissues where the
distribution of the drug is practically
instantaneous.
• The peripheral compartment (compartment 2)
consists of tissues where the distribution of the
drug is slower.

44. • The plasma level-time curve for a drug that follows a two
compartment model shows that the plasma drug concentration
declines biexponentially as the sum of two first order processes,
distribution and elimination.
• A drug that follows the pharmacokinetics of a two-compartment
model does not equilibrate rapidly throughout the body, as is assumed
for a one-compartment model.
• In this model, the drug distributes into two compartments, the central
compartment and the tissue, or peripheral compartment. The central
compartment represents the blood, extracellular fluid, and highly
perfused tissues. The drug distributes rapidly and uniformly in the
central compartment.
• A second compartment, known as the tissue or peripheral
compartment, contains tissues in which the drug equilibrates more
slowly. Drug transfer between the two compartments is assumed to
take place by first-order processes.

46. Apparent volume of distribution
• volume of distribution represents a volume that
must be considered in estimating the amount of
drug in the body from the concentration of drug
found in the sampling compartment.
• The volume of distribution is also the apparent
volume (V D) in which the drug is dissolved.
• Because the value of the volume of distribution
does not have a true physiologic meaning in
terms of an anatomic space, the term apparent
volume of distribution is used.

48. • As we know that

50. CLEARANCE
• Clearance is a measure of drug elimination
from the body without identifying the
mechanism or process.
• Clearance (drug clearance, systemic clearance,
total body clearance, Cl T) considers the entire
body as a drug-eliminating system from which
many elimination processes may occur.

51. • Drug Clearance in the One-Compartment Model
• The body is considered as a system of organs perfused by plasma
and body fluids.
• Drug elimination from body is an ongoing process due to both
metabolism (biotransformation) and drug excretion through the
• kidney and other routes.
• The mechanisms of drug elimination are complex, but collectively
drug elimination from the body may be quantitated using the
concept of drug clearance.
• Drug clearance refers to the volume of plasma fluid that is cleared
of drug per unit time.
• Clearance may also be considered as the fraction of drug removed
per unit time multiplied by the V D.

53. DRUG ELIMINATION EXPRESSED AS
VOLUME PER TIME UNIT

54. One-Compartment Model Equation in
Terms of Cl and V D

57. Calculation of k from urinary excretion
data

62. END