PHA6120: Unit 4: Bioavailability

BIOAVAILABILITY

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

• Physicochemical properties of the drug substance
• Method of manufacture of the dosage form
• Manufacturing aides used in the fabrication of the dosage form

FACTORS WHICH ARE KNOWN TO AFFECT DRUG ABSORPTION

Intravenous route

route completely available to the biological system

Extravascular routes

route that may or may not be completely available

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

lack of incomplete availability of drugs administered thru the extravascular route is due to:

BIOAVAILABILITY

Result of interaction between drug substance and receptors

variation in the expected therapeutic response

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

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

1. Concentration of drug in the blood or plasma
2. Excretion rate of drug the urine

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

- Determination of extent of absorption
- Determination of rate of absorption of the drug
- Determination of duration of the presence of drug in the biological fluid
- Correlation between concentration of drug in the plasma and clinical response
- Comparison of systemic availability of drug from different production batches of the dosage form
- Determination of duration of activity of drug
- Comparison of systemic availability of drug from different dosage forms of the same drug manufactured by the same manufacturer
- Comparison of systemic availability of drug from the same dosage form produced by different manufacturers
- Determination of plasma concentration of drug at which toxicity occurs
- Determination of the design of the proper dosage regimen for the patient

Applications of data gathered from bioavailability studies:

lowering of BP, reducing blood glucose level

Clinical evaluation of therapeutic effectiveness of drug examples

Clinical evaluation of therapeutic effectiveness of drug

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

Blood or plasma, urine

way of determination of bioavailability that is Less costly and more time-saving

Blood or plasma, urine

way of determination of bioavailability that 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

venous and arterial blood
exclusion: blood in the portal vein

considered as systemic circulation and what is excluded

systemic availability

bioavailability may also be referred to as:

Blood samples

collected at predetermined time intervals after extravascular administration of the drug dose

function of time

Drug concentration in each blood sample is determined using suitable assay method and these concentrations are plotted as a _______ on a suitable graph paper

Blood or Plasma

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

- Subjects participating in the study have to be under medical supervision
- Blood samples must be withdrawn by qualified individuals

Disadvantage of using blood or plasma

̶ 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

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

Urine

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

- Collection of urine samples is limited due to an individual's ability to void bladder at frequent intervals.

- Limited to only those drugs with at least 10% of the drug is excreted unchanged in the urine

Disadvantages of using urine samples

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

̶ Plasma concentration
̶ Urine

Data used in bioavailability studies is derived from:

1. Peak plasma concentration (Cmax)
2. Time of peak plasma concentration (Tmax)
3. Area under the plasma concentration versus time curve (AUC)

When plasma concentration data are used to estimate bioavailability, the parameters are:

The higher the Cmax, the faster the rate of drug absorption

The _______ the Cmax, the _______ the rate of drug absorption

The sooner the drug attains Tmax, the faster the rate of drug absorption

The _______ the drug attains Tmax, the _______ 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

extravascular

Extent of Drug Absorption applies only to ______ drug administration

100%

If IV, the extent of absorption is _____

Planimeter
Counting squares
Cutting and weighing
Trapezoidal rule

DETERMINATION OF AREA UNDER THE CURVE

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

dial

The ____ of a Planimeter is equipped with Vernier calipers to ensure accurate reading

AUC

The reading on the dial of a planimeter is then converted to _____ by using a factor obtained by tracing the arm over a square or circle of known area

Planimeter

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

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

- Whole squares
- ≥ 50% covered

Which squares are counted in counting squares method?

̶ The number of squares per linear inch on graphing paper
- The investigator counting the squares

Accuracy of counting squares depends on:

more accurate

Counting Squares:

smaller squares will provide _______ AUC

Cutting and Weighing

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

- one that contains plotted data
- reference

Cutting and Weighing involves the use of two graphs:

Cutting and Weighing

Frequently used to compare AUC of two or more formulations

Same extent of absorption, different rates of absorption

Same AUC, different Cmax and Tmax means:

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

Trapezoidal rule

this method is relatively easy, less time consuming, and the most reproducible method in the determination of AUC

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 time _____

True

T/F. Pharmacokinetic studies are seldom carried out long enough to allow the drug to be almost completely
eliminated from the body.

False, usually not available.

T/F. The entire drug concentration versus time curve is usually available for estimating the total AUC

time constraints

Early termination of pharmacokinetic study is partly due to

True

T/F. Very low concentrations of drug in the plasma samples are very difficult to determine accurately

intravenously

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

amount of drug administered

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

RELATIVE BIOAVAILABILITY

Bioavailability in relation to a given standard

̶ Same drug bioavailability
̶ Does not indicated completeness of systemic drug absorption

RELATIVE BIOAVAILABILITY = 1 or 100% means

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%