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Pharmacokinetics - Mathematical Fundamentals

The document covers pharmacokinetics, focusing on mathematical concepts, definitions of variables, constants, and parameters, as well as the relationships between slope, rate, and derivatives in drug absorption, distribution, metabolism, and excretion (ADME). It explains zero-order and first-order processes in drug elimination, including their equations and applications. Additionally, it discusses the components of dose-response relationships, particularly the salt factor and bioavailability of drugs.

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58 views48 pages

Pharmacokinetics - Mathematical Fundamentals

The document covers pharmacokinetics, focusing on mathematical concepts, definitions of variables, constants, and parameters, as well as the relationships between slope, rate, and derivatives in drug absorption, distribution, metabolism, and excretion (ADME). It explains zero-order and first-order processes in drug elimination, including their equations and applications. Additionally, it discusses the components of dose-response relationships, particularly the salt factor and bioavailability of drugs.

Uploaded by

lunguernest29
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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Pharmacokinetics

Mathematical concepts review

Pharmaceutics III
Year 4
Baxter Kachingwe (PhD)
Outcomes
• Define and differentiate variable, constant and parameter?
• Explain the interrelationship between slope, rate, and derivative
• Sketch pharmacokinetic profiles, illustrating pharmacokinetic
equations
• Understand rate processes as they relate to drug Absorption,
distribution, metabolism and excretion (ADME)
A brief history of pharmacokinetics
A brief history of pharmacokinetics
Variables, constants and parameters
• For purposes of pharmacokinetics:

• A variable - is something that changes over time

• A constant - is time invariant

• A parameter
• A constant that may, in fact, be a variable under a particular set of circumstances
• Is constant for a given individual receiving a particular drug
Variables, constants and parameters
• A parameter may vary for:
• Same subject receiving a different drug

• Different subjects receiving the same drug

• Given subject receiving a particular drug, measured over a long time


period (e.g. months)

• If a disease or drug interaction has occurred since value was last


calculated
Variables and constants
Slopes, rates and derivatives
• Slope
• Straight line – constant (Δy/Δx)
• Curved line – instantaneous slope at each point along the curve (dy/dx)
• Calculated by finding the slope of the tangent to that particular point
Slopes, rates and derivatives
• Simplest pharmacokinetic model

• Intravenous injection of a one-compartment drug eliminated by first-


order process

• Described by: Cp = (Cp)0e-Kt


• Cp = plasma drug concentration at time t
• (Cp)0 = plasma drug concentration immediately after iv
injection
• K = first-order elimination rate constant
Slopes, rates and derivatives
• Cp = (Cp)0e-Kt when graphed on rectilinear co-ordinates
Slopes, rates and derivatives
• ln of each side of Cp = (Cp)0e-Kt, yields, In Cp = (Cp)0 – Kt
• Conforms to equation of a straight line
y = mx + b
Slopes, rates and derivatives
By rules of logarithms and exponents
• In Cp = (Cp)0 – Kt equal to:
Kt
• Cp = (Cp)0 10– 2.303 ,
• Log of each side
Kt
•  log Cp = log (Cp)0 – 2.303
Slopes, rates and derivatives
• Log of each side
Kt
•  log Cp = log (Cp)0 – 2.303
Slopes, rates and derivatives
Kt
• Plot “log Cp = log (Cp)0 – 2.303 "
semilogarithmic paper
Time expressions
Construction of pharmacokinetic sketches
(profiles)
Construction of pharmacokinetic sketches
(profiles)
Construction of pharmacokinetic
sketches (profiles)
ADME rate processes
• Control concentration of drug at ‘‘site of action’’
• Affect onset of action, as well as duration and intensity of
pharmacological response
• Knowledge of these rate processes essential for better
understanding of observed pharmacological activity
Rate processes
• Y as some function which changes with time (t)
• (Y dependent variable and time (t) independent variable)
• where Y is either mass of drug in body (X), mass of drug in urine (Xu)
or concentration of drug in plasma or serum (Cp or Cs, respectively)
Rate processes
• Small changes in Y over small time intervals will be given by:

𝑑𝑌 𝑌2−𝑌1
• =
𝑑𝑡 𝑡2−𝑡1

• where dY/dt is instantaneous rate of change in function Y with


respect to an infinitesimal time interval (dt)
Order of a process
• Given equation
𝑑𝑌
• 𝑑𝑡
= KYn

• The numerical value (n) of exponent is the order of process

• Orders and types of process


• Zero-order
• First-order
• Second-order
• Third-order
• Zero-and first-order processes are most useful in pharmacokinetics
Zero-order process
Derivation of equation for a zero-order
elimination process
−𝑑𝑌
• = K0Y0
𝑑𝑡

where K0 =zero-order rate constant, minus sign = negative change over


time (elimination)

• Since Y0 = 1,

−𝑑𝑌
• Then, = K0
𝑑𝑡
Derivation of equation for a zero-order
elimination process
−𝑑𝑌
• Integration of = K0 ,
𝑑𝑡

yields: Y = Y0 - K0t

• Similar to y = b – mx

• Where b is vertical axis


intercept and – m is negative
slope of line
Applications of zero-order processes
• Administration of drug as an intravenous infusion
• Formulation and administration of drug through controlled
release dosage forms
• Administration of drugs through transdermal drug delivery
systems
Rate constant (K0) for zero-order
elimination
−dX
• Substitute X (mass of drug in body at time t) for Y in = K0
dt
−dX
• = K0
dt

• Integrated  X = X0 - K0t or K0t = X0 - X

• Since dX in Eq. 1.10 has units of mass and dt has units of time, K0
must have units of mass/time (e.g. mg/h)

X0 −X
• Therefore, K0t = = mg/h
t−t0
First-order process
Derivation of equation for a first-order
elimination process
−dY
• Equation = KY1
dt

• Where:
• Y = mass of a substance under-going change or transfer
• K is first-order elimination rate constant

• However, since by definition Y1= Y


−dY
• Then, = KY
dt
Derivation of equation for a first-order
elimination process
−dY ln is logarithm to base e = 2.718
• Integration of = KY,
dt

yields: Y = Y0e -Kt ,


or In Y = In Y0 - Kt
or Iog Y = Iog Y0 - Kt /2.303

•
Unit for first-order rate constant, K
−dY
• Substitute X (mass of drug in body at time t) for Y in = KY
dt

−dX −dX
• Gives = KX or X=K
dt dt

mg/h 1
• Units are: =
mg h
Comparing zero- and first-order processes
Comparing zero- and first-order processes
Components of dose-response
relationships
• Pharmacokinetic equations, dose is constant given on
administration
• Effective Dose
• amount of parent drug that reaches systemic circulation
• This may differ from dose administered for two reasons:
• Salt factor (S)
• Bioavailability factor (F)
Components of dose-response
relationships
• Effective Dose

• Where
• S = Salt factor
• F = bioavailability or fraction of dose administered that reaches
systemic circulation
• D = Dose administered
Components of dose-response
relationships
Salt factor
• Many drugs are administered as salts.
• Dose will consist of pure drug and its conjugate acid or base
• For example
• Phenytoin sodium consists of 92% phenytoin and 8% sodium
• Quinidine sulfate consists of 82% quinidine and 18% sulfate
Components of dose-response
relationships
fraction of drug salt made up of pure drug
Salt factor
• Defined as fraction of salt that is made up of pure drug
• To account for fact that only a portion (usually a large portion) of
a dose administered is pure drug
• Dose is adjusted using salt factor (S),
• Thus, phenytoin sodium and quinidine sulfate have salt factors
of 0.92 and 0.82, respectively.
Thank You.

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