Pharmacokinetic models

By
Silvano
Study of pharmacokinetics involves:
a)Experimental aspects involves dev’t of:
• biologic sampling techniques
• analytical methods for the measurement of drugs and metabolites
• procedures that facilitate data collection and manipulation

b)Theoretical aspect of involves dev’t of:

• P.k models that predict drug disposition after drug administration.
PHARMACOKINETIC MODEL.
• A Model is a hypothesis using mathematical terms to describe quantitative
relationships

• MODELING REQUIRES:
• Thorough knowledge of anatomy & physiology
• Understanding concepts & limitations of mathematical models.
• Assumptions are made for simplicity

• OUTCOME
• Development of equations to describe drug concentrations in the body as a function of time.
• PHARMACOKINETIC MODEL cont’d.
• One of the approaches to study drug pharmacokinetics
• Has no physiologic meaning, but can be described mathematically.

Types of PK Models
1- Physiologic (Perfusion) Models
2- Compartmental Models
PHYSILOGIC PK MODELS
• based on known physiologic and anatomic data.
• Blood flow is responsible for distributing drug to various parts of the body.
• Each tissue volume must be obtained and its drug concentration described.
• Predict realistic tissue drug concentration
• Applied only to animal species & human data can be extrapolated.
• Can study how physiologic factors may change drug distribution from one animal species to
another
• applied to several species, and, for some drugs, human data may be extrapolated.
COMPARTMENTAL MODELS
• The body is represented by a series of compartments that communicate reversibly with each other.

k12
1 k21 2

1 2 3

• A compartment is not a real physiologic or anatomic region, but it is a tissue or group of tissues having similar blood flow
and drug affinity.

• Within each compartment the drug is considered to be uniformly distributed & Drug moves in and out of compartments

• Extrapolation from animal data is not possible b’se the volume is not a true volume but is a mathematical concept.
Characteristics of pharmacokinetic compartments
1. Are not real physiological or anatomical regions.
2. Grouping of a set of tissues in a compartment is based on similar blood flow and drug affinity.
3. Input and output into these compartments are defined in form of 1st order kinetics.
4. In each compartment drug is considered to be rapidly and uniformly distributed.
5. rate constants are used to represent overall rate processes of the drug entry into and exist
from the compartments.
Types of compartment model
1. One compartment model
2. Two compartment model
3. Three compartment model
One Compartment Open Model: I.V Administration

• When the drug is administered i.v. in a single

rapid injection (i.v bolous), absorption
process of is bypassed

• Does not predict actual drug levels in the

tissues, but does imply that changes in the
plasma levels of a drug will result in
proportional changes in tissue drug levels.
 One Compartment Open Model: Iv Administration
• Assumptions:
• Drug is injected all at once into a box, or compartment
• Drug distributes instantaneously & homogenously throughout the compartment.
• Drug elimination occurs from the compartment immediately after injection.

• Uptake of drugs by various tissue organs depends on:

• Blood flow to the tissue
• Lipophilicity of the drug
• Molecular weight of the drug
• Binding affinity of the drug for the tissue mass.

Two pharmacokinetic parameters of one-compartment model

1) apparent volume of distribution (VD): governs plasma concentration of the drug after a given
dose.
2) elimination rate constant (k): governs rate at which the drug concentration in the body declines
Elimination Rate Constant(k)
• Rate of elimination 4 most drugs from the body is a first-order process.
• k is a first-order elimination rate constant with units of time– 1 (e.g., hr– 1 ).
• Elimination of the parent drug is effected by metabolism & excretion. i.e. k = km + ke

dD B
Recall that: = - kD B
dt

• Integrating above equation gives:

- kt
log D B = + log D B0
2.3
D B = drug in the body at time t and D B 0 = drug in the body at t = 0.
Volume of Distribution (VD)
• Relates amount of drug in the body to the plasma concentration

Dose D0B
VD = 0
= 0
Cp Cp

DB = VDCp

• The calculated parameter for the VD has no direct physical equivalent; therefore denoted apparent VD

• EXAMPLE: Exactly 1 g of a drug is dissolved in an unknown volume of water. Upon assay, the
concentration of this solution is 1 mg/mL. What is the original volume of this solution?
Significance of the Apparent VD
Drugs can have VD =, < or > body mass
• Drugs with small VD are usually confined to the central compartment or
highly bound to plasma proteins
• Drugs with large VD are usually confined in the tissue. Drugs that are
highly lipid soluble, such as digoxin ( VD = 600 liters), have a very high VD.
• VD can also be expressed as % of body mass and compared to true
anatomic volume
• 4 a given drug, VD is constant but can change due to pathological
conditions or with age
Clearance (Cl )
• Drug clearance refers to the volume of plasma fluid that is cleared of drug per unit time.
• Clearance for a first-order process is constant regardless of the drug concn. b’se clearance is
expressed in volume/unit time rather than drug amount per unit time
• Mathematically:
dD B
Recall that: = - kVDCp
dt

dD B / dt - kVDCp
=
Cp Cp
dD B / dt
= - kVD= - Cl
Cp

k = Cl/VD
TWO COMPARTMENT MODEL
• A.k.a delayed distribution model
• body is considered to be comprised of 2 compartments
① Compartment 1 (central compartment):
• Comprises of blood, extra cellular fluid & highly perfused tissues.

②Compartment 2 (Tissue or peripheral compartment):

• contains tissues that equilibrate more slowly with the drug.
• does not represent a specific tissue.

• Plasma drug conc. declines biexponentially as the sum of two first-order processes—
distribution and elimination.
TWO COMPARTMENT MODEL
•k12 & k21: first-order rate transfer constants 4 mov’t of drug from:
• Compartment 1 to compartment 2 (k12)
• Compartment 2 to compartment 1 (k21).

•k12 & k21 are sometimes termed microconstants.

•Drug elimination is presumed to occur from the central compartment
•Plasma level–time curve for a drug that follows a two-compartment model is
divided into two parts:
• Distribution phase
• Elimination phase

•After an IV bolus injection, drug equilibrates rapidly in the central compartment.

• concentration in central & tissue compartments
• At t=0, no drug is in the tissue compartment.
• drug is rapidly transferred into tissue compart & blood or plasma level
declines rapidly due to both transfer of drug out of central comp. into
various tissues & elimination of drug.
• The tissue drug level eventually peaks & then starts to decline.

• Drug conc. in tissue comp. represents average drug conc. in a group of

tissues rather than drug conc. in any real anatomic tissue.
• Drug Distribution
• Drug concentration in plasma & highly perfused tissues decline
rapidly due to distribution of drug from central compart into
other more slowly perfused tissue.
• This rapid decline represents the distribution phase of curve
and is represented by a or α .

• When drug attains equilibrium b/w the central & Tissue

compartment, after this loss of drug from CC appears due to
elimination process & the curve becomes log linear.
• Drug Distribution & Elimination
• This is the elimination phase and is represented by b or β.
• Drug elimination is presumed to occur from the central
compartment b’se the eliminating organs are located in the CC.
• Fraction of drug in the tissue compart during distribution phase↑
up to a maximum in a given tissue, whose value may be greater
or less than the plasma drug concentration.
• Equations in two comp. model
• first-order rate constants (k12 & k21) govern rate of drug change in & out of the tissues:
dCt
= k12CP - K 21Ct
dt
• Conc. of drug in each compart. is shown by:
DP Dt
• Plasma: CP = and tissue: Ct =
VP Vt

• Dp = amount of drug in CC, Dt = amount of drug in TC, Vp = vol. of drug in CC, & Vt = vol. of drug TC

dCP Dt DP DP
= k21 - k12 - k
dt Vt VP VP

dCt D D
= k12 P - k21 t
dt VP Vt
 Equations in two comp. model
• Solving the last Equations in previous slide gives:

• D 0p = dose given i.V, t = time after administration of dose, and a and b are constants that depend solely on k12, k21, and k.
The amount of drug remaining in the plasma and tissue compartment at any time may be described by the last two
Equations.
• Equations in two comp. model
• Microconstants relate to amount of drug being transferred/unit time from one compart. to the other.
• values 4 these microconstants cannot be determined by direct measurement but can be estimated
by a graphic method.
a + b = k12 + k21 + k
ab = k21k

• a & b are hybrid first-order rate constants 4 distribution phase & elimination phase, respectively.

CP = Ae- at + Be- bt
• constants A & B are intercepts on y axis, are obtained graphically by the method of residuals or by
computer & do not have actual physiologic significance.

D0 (a - k21 ) D0 (k21 - b)
A= and B =
VP (a - b) VP (a - b)
Equations in two comp. model
ab( A + B )
k=
Ab + Ba

AB (b - a ) 2
k12 =
( A + B )( Ab + Ba )

Ab + Ba
k21 =
A+ B
• VP = D0/A+B
• Vt = (VPK12)/K21

• The method of residuals

• A.k.a feathering or peeling
• is a useful procedure for fitting a curve to the experimental data of a
drug when the drug does not clearly follow a one-compartment model.
• Method of Residuals
• As shown in the biexponential curve , the decline in the initial distribution phase is more rapid
than the elimination phase.
• The rapid distribution phase is confirmed with the constant a being larger than the rate constant
b.
• There4, at some later time the term Ae–at will approach zero, while Be–bt will still have a value. At
this later time Equation will reduce to

CP = Be- bt
- bt
log CP = + log B
2.3

0.693
t1/2 =
b
HOME WORK: 100 mg of a drug was administered by rapid IV
injection to a 70-kg, healthy adult male. Blood samples were taken
periodically after the administration of drug, and the plasma
fraction of each sample was assayed for drug. The following data
were obtained: Give the equation for the curve
Park and associates (1983) studied the pharma- cokinetics of amrinone after
a single IV bolus injection (75 mg) in 14 healthy adult male volunteers. The
pharmacokinetics of this drug followed a two-compartment open model and
fit the following equation: Cp = Ae−αt + Be−βt
Where
A = 4.62 ± 12.0 mg/mL
B = 0.64 ± 0.17 mg/mL
α = 8.94 ± 13 h−1
β = 0.19 ± 0.06 h−1
From these data, calculate:
a) The transfer constants k12 and k21
b) The volume of the central compartment
c) The volume of the tissue compartment
d) The elimination rate constant from the central compartment
END