PHA6120: Bioavailability

BIOAVAILABILITY

Availability of drug to the biological system

BIOAVAILABILITY

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

FACTORS WHICH ARE KNOWN TO AFFECT DRUG ABSORPTION

Physicochemical properties of the drug substance

FACTORS WHICH ARE KNOWN TO AFFECT DRUG ABSORPTION

Method of manufacture of the dosage form

FACTORS WHICH ARE KNOWN TO AFFECT DRUG ABSORPTION

Manufacturing aides used in the fabrication of the dosage form

Intravenous route

completely available to the biological system

Extravascular routes

may or may not be completely available

Factors of Extravascular Routes

Incomplete absorption of the drug dose

Factors of Extravascular Routes

Inactivation of part of the administered dose

Factors of Extravascular Routes

Metabolism of part of the dose at the absorption site

BIOAVAILABILITY

Result of interaction between drug substance and receptors

BIOAVAILABILITY

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

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

Concentration of drug in the blood or plasma

Approaches to correlate concentration of drug at the site of action:

Excretion rate of drug the urine

Approaches to correlate concentration of drug at the site of action:

Applications of data gathered from bioavailability studies:

Determination of extent of absorption

Applications of data gathered from bioavailability studies:

Determination of rate of absorption of the drug

Applications of data gathered from bioavailability studies:

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

Applications of data gathered from bioavailability studies:

Correlation between concentration of drug in the plasma and clinical response

Applications of data gathered from bioavailability studies:

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

Applications of data gathered from bioavailability studies:

Determination of duration of activity of drug

Applications of data gathered from bioavailability studies:

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

Applications of data gathered from bioavailability studies:

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

Applications of data gathered from bioavailability studies:

Determination of plasma concentration of drug at which toxicity occurs

Applications of data gathered from bioavailability studies:

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

Clinical evaluation of therapeutic effectiveness of drug

Determination of Bioavailability
Example: lowering of BP, reducing blood glucose level

Clinical evaluation of therapeutic effectiveness of drug

Determination of Bioavailability

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

Blood or plasma, urine

Determination of Bioavailability

Less costly and more time-saving

Blood or plasma, urine

Determination of Bioavailability

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

Blood or Plasma

Most drugs reach site of action through systemic circulation

Blood or Plasma

Also referred to as systemic availability

systemic circulation

The venous and arterial blood is considered _ (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

Advantage

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

Disadvantage

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

Urine

the rate of excretion of drug in the _ depends on the concentration of drug in blood

representative

the rate of urinary excretion of drug is _ of the rate of absorption

cumulative

_ amount of drug excreted in the urine is representative of the extent of drug absorption

Urine

The drug dose is administered by an extravascular route and the patient is asked to void their bladder at frequent time intervals.

Urine

Volume of xx and concentration of drug in each xx sample is calculated

Amount of drug excreted

(Volume of urine collected) x (Concentration of drug in urine)

Urine

Advantage: simpler, less troublesome, and least painful to patients

Urine

Disadvantages: Collection of urine samples is limited due to an individual’s ability to void bladder at frequent intervals.

Urine

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 concentration ̶Urine

RATE OF ABSORTION

Peak plasma concentration (Cmax)

Time of peak plasma concentration (Tmax)

EXTENT OF ABSORPTION

Area under the plasma concentration versus time curve (AUC)

Extent of Drug Absorption

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

Extent of Drug Absorption

Applies only to extravascular drug administration

Extent of Drug Absorption

If IV, this is 100%

DETERMINATION OF AREA UNDER THE CURVE

1. Planimeter

2. Counting squares

3. Cutting and weighing

4. Trapezoidal rule

Planimeter

• Instrument that mechanically measures area of plane figures

Planimeter

Consists of an 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

Counting Squares

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

Counting Squares

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

2. 2. Draw a smooth curve to join data points

3. 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:

6. Calculate AUC using:

Counting Squares

Only the whole squares and squares that are covered 50% or more than 50% are counted

Accuracy

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

The investigator counting the squares

Cutting and Weighing

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

Cutting and Weighing

• Involves the use of two graphs: one contains plotted data, other is used as a reference

Cutting and Weighing

Frequently used to compare AUC of two or more formulations

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

AUC 1

average concentration x time interval

time zero

Since most drug are absorbed almost immediately after administration of the drug dose, the appearance of drug in plasma is considered to have taken place at _

long enough

Pharmacokinetic studies are seldom carried out _ to allow the drug to be almost completely eliminated from the body

not available

The entire drug concentration versus time curve is usually _ for estimating the total AUC

time constraints

Early termination of pharmacokinetic study is partly due to _

difficult

Very low concentrations of drug in the plasma samples are very _ to determine accurately

INTRAVENOUS ADMINISTRATION

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

INTRAVENOUS ADMINISTRATION

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

RELATIVE BIOAVAILABILITY

= 1 or 100%

RELATIVE BIOAVAILABILITY

Same drug bioavailability ̶

Does not indicated completeness of systemic drug absorption

RELATIVE BIOAVAILABILITY

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

RELATIVE BIOAVAILABILITY

Important in generic drug studies

ABSOLUTE BIOAVAILABILITY

Systemic availability after extravascular administration, compared to IV dosing

ABSOLUTE BIOAVAILABILITY

Measure of the extent of drug absorption

ABSOLUTE BIOAVAILABILITY

May not exceed 100%

F

fraction of the dose that is bioavailable

ABSOLUTE BIOAVAILABILITY

Expressed as fraction or percent (F x 100)