MEASUREMENTS OF DRUG CONCENTRATION

pharmacological testing

The pharmacokinetic principles are used to assess the relationship between the drug concentration and pharmacological activities.

This is important to determine how much and how often the drug should be given

toxicological testing

The pharmacological principles are used to assess tissue accumulation of drug and how it is related to tissue toxicity

evaluation of organ function

The pharmacokinetic principles are used to evaluate the function of eliminating organs. For example, inulin is eliminated entirely by the kidney and the rate of inulin elimination can be used to assess the kidney function

dosage regimen design

The pharmacokinetic principles are used to design the dosing regimen (dose and dosing interval of a specific drug product) that can achieve the maximum therapeutic effect with minimal toxicity

X is the exponent, b is the base, and N represent the number when b is raised to the xth power,

In the expression N=𝒃 𝒙

Common logarithm (log)

The logarithm of a positive number N to a give base B is the exponent (or the power) x to which is base must be raised to equal the number N.

logarithms

logarithm does not have units.

is dimensionless and is considered a real number.

zero

The logarithm of 1 is

negative number

logarithm of a number less than 1 is a

positive number.

The logarithm of a number greater than 1 is a

horizontal line (abscissa x axis)

values of the independent variable __are placed on the line in a plane, or on the (x axis)

vertical line (y ordinate axis)

values of the dependent variable are placed on the ___in the plane, or on the ordinate (__axis), as demonstrated in

increase

the values are usually arranged so that they __from left to right and from bottom to top. The values may be spaced arbitrarily along each axis to optimize any observable relationships between the two variables.

time

pharmacokinetics, __is the independent variable and is plotted on the abscissa (x axis

drug concentration

__ is the dependent variable and is plotted on the ordinate (y axis).

curve fitting

Fitting a curve to the points on a graph implies that there is some sort of relationship between the variables x and y, such as dose of drug versus pharmacologic effect (eg, lowering of blood pressure). Moreover, the relationship is not confined to isolated points but is a continuous function of x and y. In many cases, a hypothesis is made concerning the relationship between the variables x and y. Then, an empirical equation is formed that best describes the hypothesis. This empirical equation must satisfactorily fit the experimental or observed data.

straight lines

Physiological variables are not always linearly related. However, the data may be arranged or transformed to express the relationship between the variables as a . _are very useful for accurately predicting values for which there are no experimental observations.

slope

where m = _

intercept

b = y __

steepness of the curve

The absolute magnitude of m gives some idea of the

horizontal

as the value of m approaches 0, the line becomes more __

larger

As the absolute value of m becomes __, the line slopes farther upward or downward, depending on whether m is positive or negative, respectively.

left to right.

The negative sign indicates that the curve is sloping downward from

1. Peak plasma concentration ( Cmax)

2. Time of peak concentration (Tmax )

3. Area under curve (AUC)

PHARMACOKINETIC PARAMETERS

Peak plasma concentration ( Cmax)

the point at which, maximum concentration of drug in plasma

Units : µg/ml

peak plasma conc units

above MEC but less than MSC

Peak conc. Related to the intensity of pharmacological response, it should be ___

administered dose and rate of absorption and elimination

The peak level depends on__

Time of peak concentration (Tmax)

the time for the drug to reach peak concentration in plasma (after extra vascular administration).

hrs

Tmax Units

Time of peak concentration (Tmax)

Useful in estimating onset of action and rate of absorption.

Time of peak concentration (Tmax)

Important in assessing the efficacy of single dose drugs used to treat acute conditions (pain, insomnia )

Area under curve (AUC)

It represents the total integrated area under the plasma level-time profile and expresses the total amount of the drug that comes into systemic circulation after its administratio

µg/ml x hrs

AUC Units

Area under curve (AUC)

Represents extent of absorption – evaluating the bioavailability of drug from its dosage form.

Area under curve (AUC)

Important for drugs administered repetitively for treatment of chronic conditions (asthma or epilepsy)

1. Minimum effective concentration (MEC)

2. Maximum safe concentration (MSC)

3. Onset time

4. Onset of action

5. Duration of action

6. Intensity of action

7. Therapeutic range

PHARMACODYNAMIC PARAMETERS

Minimum effective concentration (MEC)

Minimum concentration of drug in plasma/receptor site required to produce therapeutic effect.

sub therapeutic level

Concentration below MEC –

Maximum safe concentration (MSC)

Concentration in plasma above which adverse or unwanted effects are precipitated

toxic level

Concentration above MSC –

Onset time

Time required to start producing pharmacological response.

Onset time

Time for plasma concentration to reach MEC after administrating drug

Onset of action

The beginning of pharmacologic response exceeds the required mec

Onset of action

It occurs when plasma drug concentration just exceeds the required mec

Duration of action

The time period for which the plasma concentration of drug remains above MEC level.

Intensity of action

It is the minimum pharmacologic response produced by the peak plasma conc. Of drug

Therapeutic range

the drug conc. Between MEC and MSC

bioavailability

refers to the relative amount of drug from an administered dosage form that enters the systemic circulation.

Drug’s bioavailability factor (F)

which represents the decimal percentage of a drug substance available that can be used to calculate bioavailability. The value of F may be zero to 1

bioequivalence

is a term in pharmacokinetcis used to assess the expected in biological equivalence of two preparations of a drug

bioequivalence

If two products are said to be bioequivalent, it means that they would expected to be, for all intents and purposes, the same or equal.

bioequivalent

if they produces same effect, then they are

Area under the Curve

The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose of the drug and is expressed in mg*h/L

dependent

This area under the curve is __on the rate of elimination of the drug from the body and the dose administered.

Area under the Curve

The total amount of drug eliminated by the body may be assessed by adding up or integrating the amounts eliminated in each time interval, from time zero (time of the administration of the drug) to infinite time. This total amount corresponds to the fraction of the dose administered that reaches the systemic circulation.

directly proportional

The AUC is __to the dose when the drug follows linear kinetics.

inversely proportional

The AUC is__to the clearance of the drug.

higher

That is, the __the clearance, the less time the drug spends in the systemic circulation and the faster the decline in the plasma drug concentration. Therefore, in such situations, the body exposure to the drug and the area under the concentration time curve are smaller.

Integral of the plasma drug concentration-time curve

Clinical implications

During clinical trials, the patient’s plasma drug concentration-time profile can be drawn by measuring the plasma concentration at several time points. The AUC can then be estimated. Knowing the bioavailability and the dose, the clearance of the drug may be calculated by dividing the dose absorbed by the AUC. The clearance calculated is relatively independent on the shape of the concentration-time profile. This method gives precious information on the pharmacokinetic behavior of a drug on trial. It can also be used to study a change in the clearance of a drug in specific clinical conditions, such as disease or concomitant drug administration.

Zero order elimination kinetics

a constant amount of drug is eliminated per unit time

First order elimination kinetics:

a constant proportion ofdrug is eliminated per unit time

ZERO-ORDER PROCESS

The rate of a zero-order process is one that proceeds overtime (t) independent from the concentration of the drug (c).The negative sign for the rate indicates that the concentration of the drug decreases over time.

zero-order kinetics

In chemistry, when doubling the concentration of reagents has no effect on the reaction rate, the increase in rate is by a factor of 0 (i.e. 20). This is __. The relationship of concentration to reaction rate can therefore be plotted as a boring straight line:

FIRST-ORDER PROCESS

This is a logarithmic function. All enzymes and clearance mechanisms are working at well below their maximum capacity, and the rate of drug elimination is directly proportional to drug concentration

FIRST-ORDER PROCESS

The drug concentration halves predictably according to fixed time intervals. When you plot this on a semi-logarithmic scale, the relationship of concentration and time is linear.

FIRST-ORDER PROCESS

The term "first order" actually comes from chemistry, where is has classically been used to describe reaction kinetics. When doubling the concentration of reagents also doubles the reaction rate, the increase in rate is by a factor of 2 (2 to the first power, or 21). That "first power" gives rise to the term "first order

half-life

how much time it takes for blood levels of drug to decrease to half of what it was at equilibrium

“Distribution” ½ life

when plasma levels fall to half what they were at equilibrium due to distribution to/storage in body’s tissue reservoirs

“Elimination” ½ life

when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated..

“Elimination” ½ life

It is usually the __ life that is used to determine dosing

longer

a longer half life obviously means it takes __to lose half of the drug’s activity

• determine the length of drug effect

• drug accumulation occur under multiple dosage regimen

• selection of appropriate dosing interval

• essential to determine and maintain steady state plasma con’c

Clinical implications of determining half life

concentration per unit time (eg, [mg/mL]/h)

or amount per unit time (eg, mg/h)

The units for k0 are

Volume of distribution (Vd)

- reflects the extent of drug that gets into the plasma

Volume of distribution (Vd)

The apparent volume of distribution for a drug is not a “real”volume but rather a hypothetical volume of body fluid that would be required to dissolve the the total amount of drug at the same con’c as that found in the blood.

Volume of distribution (Vd)

It is an indicator of the extent of a drug’s distributionthroughout the body fluids and tissues. This information isuseful in understanding how the body processes anddistributes a given drug substance.

(High Vd -> More distribution to other tissue)

A drug with a high Vd tends to leave the plasma and enter the extravascular compartments of the body, requiring a higher dose of a drug to achieve a given plasma concentration.

(Low Vd -> Less distribution to other tissue)

Conversely, a drug with a low Vd tends to remain in theplasma, requiring a lower dose of a drug achieve a given plasma concentration.

clearance

reflects on how you eliminate the drug

clearance

by definition: volume of plasma that is cleared of drug per unit time

volume/time (mL/min)

clearance unit:

-doesn’t talks about the amount of drug, but rather the volume of plasma that is cleared of drug

Cl

= elimination rate/remaining drug

clearance

-is a proportionality factor used to determine RofE (Rate ofelimination)

high clearance

means that there is high drug lost in urine,and less drug in the body.

low clearance

means that there is low drug lost in urine, and more drug in the body