Lesson 8. Bioavailability

Bioavailability

Availability of the administered drug dose to the biological system

absorption

Bioavailability is the extent to which the active ingredient in a dosage form intended for extravascular administration becomes available for ___________.

rate

Bioavailability is the a.____ (how fast and how slow it reaches the systemic circulation) at which and b._______ (amount that reaches the systemic circulation) to which the active drug ingredient is absorbed from a drug product and becomes available at the site of drug action.

a = ?

extent

Bioavailability is the a.____ (how fast and how slow it reaches the systemic circulation) at which and b._______ (amount that reaches the systemic circulation) to which the active drug ingredient is absorbed from a drug product and becomes available at the site of drug action.

b = ?

Physicochemical properties of the drug substance

FACTORS WHICH ARE KNOWN TO AFFECT DRUG ABSORPTION

• Such as solubility in water, solubility in lipids, ionization, and polarity of the drug that can affect how well the drug can be released from the drug product

Method of manufacture of the dosage form

FACTORS WHICH ARE KNOWN TO AFFECT DRUG ABSORPTION

• Either by wet granulation or dry granulation methods, direct compression for tablets, and other manufacturing methods available

Manufacturing aides used in the fabrication of the dosage form

FACTORS WHICH ARE KNOWN TO AFFECT DRUG ABSORPTION

• excipients used include bulking agents, binders, lubricants, dyes, and others

Intravenous Routes

EXPECTED BIOAVAILABILITY OF DOSAGE FORMS

• completely available to the biological system because the entire drug dose is administered directly to the bloodstream

Extravascular Routes

EXPECTED BIOAVAILABILITY OF DOSAGE FORMS

• may or may not be completely available

absorption

FACTORS OF EXTRAVASCULAR ROUTES:

1. Incomplete ____________ of the drug dose

2. ______________ of part of the administered dose such as in first-pass effect

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

1 = ?

Inactivation

FACTORS OF EXTRAVASCULAR ROUTES:

1. Incomplete ____________ of the drug dose

2. ______________ of part of the administered dose such as in first-pass effect

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

2 = ?

Metabolism

FACTORS OF EXTRAVASCULAR ROUTES:

1. Incomplete ____________ of the drug dose

2. ______________ of part of the administered dose such as in first-pass effect

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

3 = ?

clinical safety and efficacy

Bioavailability is related to both the pharmacologic or clinical effect and the drug product's adverse effects. Therefore, bioavailability studies are conducted to relate the quality of the drug product to the _______________________.

drug substance and receptors

Biologic response is a result of interaction between _____________________

variation

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

Concentration of drug in the blood or plasma

APPROACHES TO CORRELATE CONCENTRATION OF DRUG AT THE SITE OF ACTION

• indicator of the rate and extent of drug availability at the site of action

• Used since most drugs reach the site of action through the systemic circulation

• reflects the drug concentration at the site of action

Excretion rate of drug the urine

APPROACHES TO CORRELATE CONCENTRATION OF DRUG AT THE SITE OF ACTION

• Utilizes urinary excretion of an unchanged drug as an index of drug concentration in the plasma

extent

APPLICATIONS OF DATA GATHERED FROM BIOAVAILABILITY STUDIES

• Determination of ________ of absorption

rate

APPLICATIONS OF DATA GATHERED FROM BIOAVAILABILITY STUDIES

• Determination of _____ of absorption of the drug

duration

APPLICATIONS OF DATA GATHERED FROM BIOAVAILABILITY STUDIES

• Determination of _______________ of the presence of drug in the biological fluid

Correlation

APPLICATIONS OF DATA GATHERED FROM BIOAVAILABILITY STUDIES

• _____________ between concentration of drug in the plasma and clinical response

production batches

APPLICATIONS OF DATA GATHERED FROM BIOAVAILABILITY STUDIES

• Comparison of systemic availability of drug from different _______________ of the dosage form

activity of drug

APPLICATIONS OF DATA GATHERED FROM BIOAVAILABILITY STUDIES

• Determination of duration of __________________

dosage forms of the same drug

APPLICATIONS OF DATA GATHERED FROM BIOAVAILABILITY STUDIES

• Comparison of systemic availability of drug from different _____________ manufactured by the same manufacturer

different manufacturers

APPLICATIONS OF DATA GATHERED FROM BIOAVAILABILITY STUDIES

• Comparison of systemic availability of drug from the same dosage form produced by ____________________________

toxicity

APPLICATIONS OF DATA GATHERED FROM BIOAVAILABILITY STUDIES

• Determination of plasma concentration of drug at which ________ occurs

dosage regimen

APPLICATIONS OF DATA GATHERED FROM BIOAVAILABILITY STUDIES

• Determination of the design of the proper _______________ for the patient

Clinical evaluation of therapeutic effectiveness of drug

DETERMINATION OF BIOAVAILABILITY

• Ideal method and easier if the effect or response is quantified such as in lowering of BP, reducing blood glucose level

• May be difficult if therapeutic efficacy is difficult to quantify or if subjective such as in evaluation of analgesia (pain)

Blood or plasma

DETERMINATION OF BIOAVAILABILITY

• Most common, collection at predetermined time intervals and assayed to determine drug concentration

Urine

DETERMINATION OF BIOAVAILABILITY

• Indirect Method of determining drug effect (A high drug concentration in the urine can indicate that there is also a high drug concentration in the body).

• Less costly and more time-saving

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

body fluid

BLOOD OR PLASMA

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

systemic circulation

BLOOD OR PLASMA

• Most drugs reach site of action through a.________________________ which is why it is referred to as b._______________________.

a = ?

systemic bioavailability

BLOOD OR PLASMA

• Most drugs reach site of action through a.________________________ which is why it is referred to as b._______________________.

b = ?

venous and arterial blood

BLOOD OR PLASMA

• The a.____________________ is considered systemic circulation (blood in the b.____________ is excluded)

a = ?

portal vein

BLOOD OR PLASMA

• The a.____________________ is considered systemic circulation (blood in the b.____________ is excluded)

b = ?

predetermined time intervals

BLOOD OR PLASMA

• Blood samples are collected at _______________________ after extravascular administration of the drug dose

suitable assay method

BLOOD OR PLASMA

• Drug concentration in each blood sample is determined using a __________, and these concentrations are plotted as a function of time on a suitable graph paper

pharmacokinetic parameters

ADVANTAGES OF BLOOD OR PLASMA

• provide a quantifiable and highly reliable evaluation of the _____________ of the drug product

medical supervision

DISADVANTAGES OF BLOOD OR PLASMA

1. subjects participating in the study have to be under ________________

2. blood samples must be withdrawn by ______________________

1 = ?

qualified individuals

DISADVANTAGES OF BLOOD OR PLASMA

1. subjects participating in the study have to be under ________________

2. blood samples must be withdrawn by ______________________

2 = ?

blood

URINE

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

• The rate of b._________________ of drug is representative of the rate of absorption since active drug is absorbed, it will be excreted

• c.____________________ excreted in the urine is representative of the extent of drug absorption

a = ?

urinary excretion

URINE

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

• The rate of b._________________ of drug is representative of the rate of absorption since active drug is absorbed, it will be excreted

• c.____________________ excreted in the urine is representative of the extent of drug absorption

b = ?

cumulative amount of drug

URINE

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

• The rate of b._________________ of drug is representative of the rate of absorption since active drug is absorbed, it will be excreted

• c.____________________ excreted in the urine is representative of the extent of drug absorption

c = ?

void their bladder

URINE

• The drug dose is administered by an extravascular route and the patient is asked to __________________________ at frequent time intervals

simpler

ADVANTAGES OF URINE:

1. ______

2. less ________________________

3. least _____________ to patients

1 = ?

troublesome

ADVANTAGES OF URINE:

1. ______

2. less ________________________

3. least _____________ to patients

2 = ?

painful

ADVANTAGES OF URINE:

1. ______

2. less ________________________

3. least _____________ to patients

3 = ?

limited

DISADVANTAGES OF URINE:

1. Collection of urine samples is _______ due to an individual’s ability to void bladder at frequent intervals because the subject can void their bladder more frequently at the earlier part of the study, compared to the latter part, giving limited data points that can be obtained via bioavailability studies.

2. This approach is generally limited to only those drugs with at least __________________________________ in the urine because if the drug is excreted in its metabolite form, it will be difficult to use that data to correlate the amount of drug in the site of action

1 = ?

10% of the drug is excreted unchanged

DISADVANTAGES OF URINE:

1. Collection of urine samples is _______ due to an individual’s ability to void bladder at frequent intervals because the subject can void their bladder more frequently at the earlier part of the study, compared to the latter part, giving limited data points that can be obtained via bioavailability studies.

2. This approach is generally limited to only those drugs with at least __________________________________ in the urine because if the drug is excreted in its metabolite form, it will be difficult to use that data to correlate the amount of drug in the site of action

2 = ?

rate and extent of drug availability

When we use plasma concentration to correlate the drug concentration to the site of action, the data that you will get is then plotted in a graphing paper which provides information about the ______________________ from the dosage form

MEC

Reflects the minimum concentration that a drug needs in order to produce a therapeutic effect

MTC

Represents the drug concentration needed to just barely produce a toxic effect

Onset Time

Time required for the drug to reach MEC

Intensity

Proportional to the drug receptors occupied

Duration

Difference between the onset time and the time for the drug to decline below MEC

rate at which and extent to which

PARAMETERS OF BIOAVAILABILITY

• The ______________________ the active drug ingredient is absorbed from a drug product and becomes available at the site of drug action

Plasma concentration and Urine

Data derived from:

Peak Plasma Concentration (Cmax) and Time of Peak Plasma Concentration (Tmax)

PARAMATERS OF BIOAVAILABILITY WHEN PLASMA CONCENTRATION IS USED

• Parameters used to reflect rate of absorption

Area Under the Plasma Concentration Time Curve (AUC)

PARAMATERS OF BIOAVAILABILITY WHEN PLASMA CONCENTRATION IS USED

• Parameters used to reflect extent of absorption

higher

RATE OF ABSORPTION

1. _______ Cmax = faster drug absorption

2. reaches Cmax the ____________ (Tmax) = faster drug absorption

3. if the Tmax of the two drugs are the same, the drug with the higher ______ has a faster drug absorption

1 = ?

fastest

RATE OF ABSORPTION

1. _______ Cmax = faster drug absorption

2. reaches Cmax the ____________ (Tmax) = faster drug absorption

3. if the Tmax of the two drugs are the same, the drug with the higher ______ has a faster drug absorption

2 = ?

Cmax

RATE OF ABSORPTION

1. _______ Cmax = faster drug absorption

2. reaches Cmax the ____________ (Tmax) = faster drug absorption

3. if the Tmax of the two drugs are the same, the drug with the higher ______ has a faster drug absorption

3 = ?

absorbed and appears in the systemic circulation

EXTENT OF DRUG ABSORPTION

• Signifies the fraction of administered dose that is actually _________________________________________

extravascular

EXTENT OF DRUG ABSORPTION

• Applies only to __________________ drug administration

100%

EXTENT OF DRUG ABSORPTION

• If IV, the extent of absorption is _____________

Area Under the Plasma Concentration Time Curve (AUC)

EXTENT OF DRUG ABSORPTION

• To measure the extent of drug absorption for extravascular readministrated drugs, the _____________________________________ is used as indicator.

Planimeter

DETERMINATION OF AREA UNDER THE CURVE

• An instrument that mechanically measures the area of plane figures

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

• The dial is equipped with Vernier calipers to ensure accurate reading

• 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

• Considered as the simplest and most reliable, but not commonly used

Counting Squares

DETERMINATION OF AREA UNDER THE CURVE

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

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

number of squares per linear inch

DETERMINATION OF AREA UNDER THE CURVE

Accuracy of Counting Squares depends on:

1. The ____________________________ on graphing paper (smaller squares will provide more accurate AUC)

2. The _________ counting the squares (may be subject to error due to eyestrain while counting)

1 = ?

investigator

DETERMINATION OF AREA UNDER THE CURVE

Accuracy of Counting Squares depends on:

1. The ____________________________ on graphing paper (smaller squares will provide more accurate AUC)

2. The _________ counting the squares (may be subject to error due to eyestrain while counting)

2 = ?

Cutting and Weighing

DETERMINATION OF AREA UNDER THE CURVE

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

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

• Frequently used to compare AUC of two or more formulations

• Two graphs may contain the same AUC, but different Cmax and Tmax

• Same extent of absorption, different rates of absorption

Trapezoidal Rule

DETERMINATION OF AREA UNDER THE CURVE

• Relatively simple, least time-consuming, and most reproducible method for determining the AUC

• 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 (AUC₁ = average concentration x time interval)

zero

𝐴𝑈𝐶 = since most drugs are absorbed almost immediately 0→∞ after administration of the drug dose, the appearance of the drug in plasma is considered to have taken place at time _____

completely eliminated

Pharmacokinetic studies are seldom carried out long enough to allow the drug to be almost _____________________ from the body

entire drug concentration versus time curve

The _____________________________________ is usually not available for estimating the total AUC

time constraints

Early termination of the pharmacokinetic study is partly due to ______________

Very low concentrations

____________________ of the drug in the plasma samples are very difficult to determine accurately so we use infinity

systemic circulation

INTRAVENOUS ADMINISTRATION

• When the drug is administered intravenously, the entire drug dose is placed into the a.___________________

• The amount of drug absorbed from an IV dose is considered to be equal to the b._____________________________

a = ?

amount of drug administered

INTRAVENOUS ADMINISTRATION

• When the drug is administered intravenously, the entire drug dose is placed into the a.___________________

• The amount of drug absorbed from an IV dose is considered to be equal to the b._____________________________

b = ?

Relative Bioavailability

• Bioavailability in relation to a given standard

• equal to 1 or 100% (Same drug bioavailability and does not indicate completeness of systemic drug absorption)

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

• Important in generic drug studies

Absolute Bioavailability

• Systemic availability after extravascular administration, compared to IV dosing

• Measure of the extent of drug absorption

• May not exceed 100%