bioavailability

BIOAVAILABILITY

• Availability of drug to the biological system

• The extent to which the active ingredient in a dosage form intended for extravascular administration becomes available for absorption.

FACTORS AFFECTING DRUG ABSORPTION

1. Physicochemical properties of the drug substance 

2. Method of manufacture of the dosage form 

3. Manufacturing aides used in the fabrication of the dosage form

Intravenous route

• completely available to the biological system

• Absolute BA

Extravascular routes

may or may not be completely available

Factors

1. Incomplete absorption of the drug dose

2. Inactivation of part of the administered dose

3. Metabolism of part of the dose at the absorption site

Incomplete absorption of the drug dose

• Not all of the drug is absorbed

• % eliminated of the drug may be more than absorbed
  

Inactivation of part of the administered dose

• Commonly in inactivated or easily oxidized drugs 

• Drugs exposed to sunlight may have its active components be deactivated
  

Metabolism of part of the dose at the absorption site

First pass effect

BIOAVAILABILITY is the result of __

interaction between the drug substance & receptors

Unavailability of a portion of the administered drug from the dosage form may result in

variation in the expected therapeutic response

Unavailability of a portion of the administered drug from the dosage form may result in variation in the expected therapeutic response

• may result in ↓ clinical effect

• Clinical effect is not instantaneous since desired concentration in the blood has to be achieved.

The rate at which and extent to which the active drug ingredient is absorbed from a drug product and

becomes available at the site of drug action

APPROACHES TO CORRELATE CONCENTRATION OF DRUG AT THE SITE OF ACTION:

1. Concentration of drug in the blood or plasma

2. Excretion rate of drug [in] the urine

Concentration of drug in the blood or plasma

• If there’s higher concentration available in the target site, the availability or therapeutic concentration in the blood or plasma [can be obtained]

Excretion rate of drug [in] the urine

• Late excretion = drug activity & half-life are longer

APPLICATIONS OF DATA GATHERED FROM BIOAVAILABILITY STUDIES

1. Determination of extent of absorption

2. Determination of rate of absorption of the drug

3. Determination of duration of the presence of drug in the biological fluid

4. Correlation between concentration of drug in the plasma and clinical response 

5. Comparison of systemic availability of drug from different production batches of the dosage form

6. Determination of duration of activity of drug

7. Comparison of systemic availability of drug from different dosage forms of the same drug manufactured by the same manufacturer

8. Comparison of systemic availability of drug from the same dosage form produced by different manufacturers

9. Determination of plasma concentration of drug at which toxicity occurs

10. Determination of the design of the proper dosage regimen for the patient

DETERMINATION OF BIOAVAILABILITY

• Clinical evaluation of therapeutic effectiveness of drug

• Blood or plasma, urine

Clinical evaluation of therapeutic effectiveness of drug

• Example: lowering of BP, reducing blood glucose level

• May be difficult if therapeutic efficacy is difficult to quantify; if subjective

Blood or plasma, urine

• Less costly and more time-saving

• Can provide a quantifiable and highly reliable evaluation of pharmacokinetic parameters of the drug product

BLOOD OR PLASMA

• Most commonly used body fluid to correlate concentration of drug at the receptor site

• Also referred to as systemic availability

Most drugs reach site of action through

systemic circulation

The venous and arterial blood is considered

systemic circulation (blood in the portal vein is excluded)

Blood samples are collected at

predetermined time intervals after extravascular administration of the drug dose

Drug concentration in each blood sample is determined using

suitable assay method and these concentrations are plotted as a function of time on a suitable graph paper

BLOOD OR PLASMA

adv

if the study is well designed and executed properly, it can provide a quantifiable and highly reliable evaluation of pharmacokinetic parameters of the drug product

BLOOD OR PLASMA

disadv

subjects participating in the study have to be under medical supervision and blood samples must be withdrawn by qualified individuals

URINE

• Since the rate of excretion of drug in the urine depends on the concentration of drug in blood, it follows that:

• the rate of urinary excretion of drug is representative of the rate of absorption; and

• cumulative amount of drug excreted in the urine is representative of the extent of drug absorption

rate of excretion of drug in the urine depends

on the concentration of drug in blood,

URINE

• The drug dose is administered by

an extravascular route and the patient is asked to void their bladder or urinate at frequent time intervals.

URINE

adv

simpler, less troublesome, and least painful (catheter instead of needle) to patients

URINE

disadv

Collection of urine samples is limited due to an individual’s ability to void bladder at frequent intervals. This approach is generally limited to only those drugs with at least 10% of the drug is excreted unchanged in the urine

PARAMETERS OF BIOAVAILABILITY

• The rate at which and extent to which the active drug ingredient is absorbed from a drug product and becomes available at the site of drug action

PARAMETERS OF BIOAVAILABILITY

data derived from:

plasma conc

urine

WHEN PLASMA CONCENTRATION DATA ARE USED TO ESTIMATE BIOAVAILABILITY, THE PARAMETERS ARE:

• Peak plasma concentration (Cmax)

• Time of peak plasma concentration (Tmax)

• Area under the plasma concentration versus time curve (AUC)

RATE OF ABSORPTION

• The higher the Cmax,

the faster the rate of drug absorption 

RATE OF ABSORPTION

• The sooner the drug attains Tmax,

the faster the rate of drug absorption

EXTENT OF DRUG ABSORPTION

• Signifies the fraction of administered dose that is actually absorbed and appears in the systemic circulation 

• Applies only to extravascular drug administration 

• If IV, the extent of absorption is 100%, so everything under the curve is shaded.

Determination of Area Under the Curve using this graph: 

• AUC is divided into lines/boxes and each has its own concentration

• Tedious because you have to get each concentration to obtain the total AUC

DETERMINATION OF AREA UNDER THE CURVE

1. Planimeter

2. Counting squares 

3. Cutting and weighing 

4. Trapezoidal rule

PLANIMETER

• Getting the plane

• Instrument that mechanically measures area of plane figures

PLANIMETER

consist of

arm attached to a rotating wheel, which moves a dial with the movement of the arm

PLANIMETER

the dial is equipped with

•  Vernier calipers to ensure accurate reading 

PLANIMETER

the reading on the dial

• is then converted to AUC by using a factor obtained by tracing the arm over a square or circle of known area

PLANIMETER

is considered __

as the simplest and most reliable but not in common use

COUNTING SQUARES

• The total number of squares enclosed by the plasma concentration versus time curve are counted.

COUNTING SQUARES

Only the ___ are counted

whole squares and squares that are covered 50% or more than 50%

COUNTING SQUARES

accuracy depends on:

• The number of squares per linear inch on graphing paper (smaller squares will provide more accurate AUC)

• The investigator counting the squares may be subjective due to eye strains

COUNTING SQUARES: STEPS

1. Plot plasma concentration as a function of time on a rectilinear graphing paper

2. Draw a smooth curve to join data points

3. Draw a straight line to connect last concentration data point with the corresponding time point on the x-axis

4. Count the squares enclosed within the bounded curve

5. Determine area of each square using:

Area=height (in units of conc.)widths (in time)

6. calculate AUC using:

AUC= # of squaresarea of one square

CUTTING & WEIGHING

• Involves plotting the plasma profile on a graph paper and then cutting and weighing the plasma profile

CUTTING & WEIGHING

•  Involves the use of two graphs: 

• one contains plotted data

• other is used as a reference

CUTTING & WEIGHING

frequently used to

• compare AUC of two or more formulations

• Same AUC, different Cmax and Tmax

• Same extent of absorption, different rates of absorption

TRAPEZOIDAL RULE

• The total area under the curve from the time the drug appears in systemic circulation to the time that the drug is virtually eliminated from the systemic circulation.

INTRAVENOUS ADMINISTRATION

• When the drug is administered intravenously, the entire drug dose is placed into the systemic circulation

The amount of drug absorbed from an IV dose is considered to be

equal to the amount of drug administered

RELATIVE BIOAVAILABILITY

• Bioavailability in relation to a given standard 

• May exceed the value of 1 or 100% as compared to a reference drug product 

• Important in generic drug studies

RELATIVE BIOAVAILABILITY

• = 1 or 100%

• Same drug BA (same route of administration)

• Does not indicated completeness of systemic drug absorption

ABSOLUTE BIOAVAILABILITY

• Systemic availability after extravascular administration, compared to IV dosing 

• Measure of the extent of drug absorption 

• May not exceed 100%