Biopharmaceutics and Pharmacokinetics

Part 6
(PK)

by
Dr. Tanya Ralli
(M. Pharm., Ph.D.)
 Pharmacokinetics
Plasma Drug Concentration is the concentration of drug in blood plasma in relation to site of absorption, that varies with time. It
is used in evaluating two parameters
1. Pharmacokinetic
2. Pharmacodynamic
Pharmacokinetic Parameters
1. Peak Plasma Concentration (Cmax): It is the maximum
concentration of drug absorbed from the site of absorption into
plasma. Short term side effects arise from Cmax. Factors affecting
Cmax:
• Dose administered
• Extent of absorption
• Rate of absorption and elimination
Units: microgram/ml
2. Time to Peak Concentration (tmax): Time required to achieve
the maximum plasma concentration. Useful in depicting onset of
action and rate of absorption. Units: Hrs.
3. Area Under the Curve (AUC): a measure of bioavailability i.e.,
the rate and extent of absorption (the amount and time required
for the administered drug to reach the blood plasma from
absorption site)
Pharmacodynamic Parameters
• Minimum Effective Concentration (MEC): Minimum concentration
of drug in plasma, required to produce a biological action
• Maximum Safe Concentration (MSC): Maximum concentration of
drug in plasma, that is tolerable
• Onset Time: Time required the drug to produce the required
biological action from the time of administration
• Therapeutic Range: Drug concentration between Minimum
effective concentration (MEC) and maximum safe concentration
(MSC)
• Therapeutic Index: Ratio of the dose of drug that causes toxicity in
50% of subjects (Toxic dose 50, TD50) to the dose that causes
desired pharmacological effect in 50% of subjects (effective dose
50, ED50)
➢ A measure of safety margin of drug.
 Contd…

Rate, Rate Constants and Orders of Reactions

Rate is defined as the velocity at which a reaction or process occurs, while order is defined as factor by which concentration of
drug (or reactants) influences the rate of reaction.
For say: Drug A → Drug B
Rate of forward reaction = -dA/dt or dB/dt
Negative sign indicates that the concentration of drug A decreases with time t, while that of B increases. Rate can be defined as
= -KCn
Where, K = rate constant; n = order of reaction; C = drug concentration
 Contd…
Kinetics order Zero-Order First-Order Kinetics (Linear Kinetics)
Description n = 0, Thus, rate equation n = 1, Thus, rate equation
dC/dt = -Ko dC/dt = -KC
where Ko = zero-order rate constant (in mg/min) where K = first-order rate constant (in mg/min)
Rate independent of concentration of drug or reactants. Rate is directly proportional to the concentration of drug undergoing
Finally, C = Co – Ko t reaction i.e., greater the concentration, faster the reaction and vice
Where, C= concentration at time t, time of reaction; Co = drug versa, hence, the name Linear kinetics.
concentration initially In terms of log, the equation is
Zero-Order Half-Life (t½) is defined the time period required for Log C = log Co – Kt/2.303
the concentration of drug to decrease by one-half of the original
concentration. Other names: Monoexponential rate process.
t1/2 = Co / 2 Ko The process is characterized by logarithmic or exponential kinetics i.e.,
a constant fraction of drug undergoes reaction per unit time.
t1/2 of first order reaction
t1/2 = 0.693/K
The half-life is independent of initial concentration of drug and
remains constant.
Examples • Metabolism Most pharmacokinetic processes, absorption, distribution, and
• Protein-drug binding elimination follow first-order kinetics.
• Administration of a drug at constant rate IV infusion.
• Controlled drug delivery such as from IM implants or osmotic
pumps or controlled release dosage forms
• Enzyme or carrier-mediated transport once saturation is
reached
 Drug modelling
Pharmacokinetic model
Quantitative or mathematic description of the drug's time course, throughout the body, for computing pharmacokinetic
parameters

Various approaches are used to describe the PK parameters

• Model approach
• Model-independent approach (also called as non- compartmental analysis): linear kinetics
1. Model approach
• It uses a hypothesis, employing mathematical terms to concisely describe quantitative relationship
• Model approaches can be compartment models, physiological model based or distributed parameter model. The former is an
empirical model while the latter two are realistic.
.
A) Compartment models
For estimating pharmacokinetics of drug, hypothesis is made that
• The human body is regarded as a series of compartments connected in series or parallel to each other, with reversible
communication
• The compartment is hypothetical, no such real physiologic or anatomic region exists
• The compartment considered are similar though not same in terms of flowability and tissue characteristics
• Every organ, tissue or body fluid that can be equilibrated with the drug is considered as a separate compartment
• Compartmental model is of two types
 Contd…

Mammillary model Catenary model

One central compartment (plasma and highly perfused tissues such as All compartments are connected to one another in series just like a
lungs, liver, kidneys, etc. that equilibrate with the drug, rapidly) train
connected with one or more peripheral compartments (low Rarely used, as this is not observable physiologically/anatomically as
vascularity and poorly perfused). the various organs are directly linked to the blood compartment.
Central compartment features:
• Drug absorbed directly into this compartment (i.e., blood)
• Elimination too occurs from this compartment as chief eliminatory
organs, liver, and kidneys, are involved in this compartment itself
• Highly perfused so drug is directly absorbed in this compartment
Compartments are connected in parallel to central compartments

B) Physiological models: (PB/PK models)

• They are drawn on the basis of known anatomic and physiological data
• Orangs or tissues that have no penetration are excluded
• Organs are divided into rapidly equilibrating tissues (RET) or slowly equilibrating tissues (SET)
C) Distributed parameter model
• Similar to PBPK model but also takes into account variations in blood flow to the organ and variation in drug diffusion in an organ
 Compartmental modeling
Open Compartment models
Open means input (availability) and output (elimination) are unidirectional and drug can be eliminated from the body .

1. One-Compartment (Instantaneous distribution model)

One-compartment open models can be divided on basis of rate of input:
• One-compartment open model, IV bolus administration
• One-compartment open model, continuous IV infusion
• One-compartment open model, EV (oral, rectal) administration, zero-order absorption
• One-compartment open model, EV administration, first-order absorption
 Contd…
(a) IV administration (bolus)
Absorption occurs rapidly, hence, absorption rate in neglected.
Rate of reaction= Rate of absorption - Rate of elimination
dX/dt = -Rate out
dX/dt = -KeX
Ke = elimination rate constant
X = amount of drug in the body at any time t remaining to be eliminated. Negative sign indicates that the drug is being lost
from the body.
• For drugs with one-compartment kinetics and administered as rapid IV injection, the decline in plasma drug concentration is
due to elimination of drug from the body, as absorption occurs rapidly, known as the elimination phase.
Parameters for Elimination phase
• Elimination rate constant
• Elimination half-life
• Clearance
(i) Elimination Rate Constant:
LogX = LogXo–Ket/2.303
LogC = LogCo–Ket/2.303
The elimination rate constant is directly obtained from the slope of the line, and has units of min–1. Linear plot is easier to handle
than the regular curve plot, which can be obtained by using log values of concentration vs time plot.
 Contd…

(ii) Elimination Half-Life:

Another name: Biological half-life
Time taken for the amount of drug in the body as well as plasma to decline by one-half or 50% its initial value. It is expressed in
hours or minutes.
t1/2 = 0.693/Ke
t1/2 = 0.693Vd/Cl
(iii) Clearance:
It is defined as the theoretical volume of body fluid containing drug from which the drug is completely removed in a given
period of time.
Measured in ml/min or liters/hour.
Clearance = Rate of elimination/Plasma drug concentration
Cl= (dX/dt)/C
 Contd…
(b) Intravenous Infusion
• Preferred when rapid I.V. injection is unsuitable, because of drug potential to precipitate toxicity, and when a stable
concentration of drug is required, in body

• Drug is administered at a constant rate (zero-order) by IV infusion, with duration of infusion is longer than the half-life of the
drug
• The rate of change in the amount of drug in the body,
dX/dt= Ro –KeX
Where, rate of drug infusion is Ro
Thus,
C= Ro/Cl (1-e-Ket)
At the start of constant rate infusion, elimination is zero as the amount of drug in the body is zero.
Steady state: The point where infusion rates equal to the rate of elimination. Also known as plateau or infusion equilibrium. At
this point, the rate of change of amount of drug in the body is zero, hence, the equation becomes:
0= Ro- KeX
Hence,
Css= Ro/Cl
Where Css is plasma concentration at steady state
Ke value can be obtained from the slope of straight line obtained after a semilogarithmic plot (log C versus t)
Contd…
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