Bioavailability,

and
Bioequivalence

UNIVERSITY OF HEALTH
Doris Kumadoh, PhD AND ALLIED SCIENCES
1
School of Pharmacy
 • Outline
• Bioavailability and Bioequivalence
• Bioavailability
• Methods of assessment of oral bioavailability
• Bioequivalence
• Objective
• To understand and be able to explain bioavailability,
bioequivalence, and their practical implications
• Recommended reference books
• Pharmaceutics: The Science of Dosage Form Design
• Modern Pharmaceutics
• Remington: Essentials of Pharmaceutics
• Applied Biopharmaceutics & Pharmacokinetics

UNIVERSITY OF HEALTH
2 AND ALLIED SCIENCES
School of Pharmacy
 Bioavailability

UNIVERSITY OF HEALTH
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• Bioavailability (F) -- The rate and extent of drug absorption

• It is the amount of drug from an administered dosage form that

enters systemic circulation intact and rate at which this occurs.
• 100% oral bioavailability -- entire dose must enter systemic
circulation
• bioavailability study design depends on the objectives of the
study including;
• ability to analyze the drug (and metabolites) in biological fluids,
• pharmacodynamics of the drug substance,
• route of drug administration,
• the nature of the drug product.

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 Methods of assessing the oral bioavailability of a drug
involves using:
• In-vivo methods including;
❑Drug concentration in blood plasma
▪ After a single dose of a drug is administered orally to a patient,
blood samples are withdrawn at specific periods and assayed --
A plasma concentration-time curve can then be constructed
▪ Pharmacokinetic parameters can be estimated from the curve
❑Drug concentration in urine
❑Pharmacological effects (including pharmacodynamic and clinical
observational studies)

❑In-vitro methods (including comparative drug

release/dissolution) UNIVERSITY OF HEALTH
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 Plasma concentration time curve

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 Plasma Drug Concentration-Time Curve Data
• Minimum effective concentration (MEC): Minimum drug concentration
needed to produce the desired pharmacological effect
• Minimum toxic concentration (MTC): Minimum drug concentration
needed to produce a toxic effect
• Therapeutic range or window: Range of plasma drug concentrations
over which the desired response is produced without toxic effects.
• Onset time: The time required for the drug to reach the MEC.
• Duration of action: Difference between onset time and the time drug
concentration declines back to the MEC (i.e., conc. > MEC)
• Cmax: Maximum plasma drug concentration
• Tmax: Time at which Cmax is observed in plasma (∝ rate of drug
absorption)
• Area under the plasma concentration-time curve (AUC): ≅
bioavailability UNIVERSITY OF HEALTH
7 AND ALLIED SCIENCES
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 After peroral administration of a single dose of a tablet containing drug X

Absorption Elimination Elimination

Absorption Elimination Phase
Phase Phase
Phase Phase
Plasma concentration of drug X (mg/mL)

Maximum Safe Concentration/

MaximumToxic
Minimum SafeConcentration
Concentration/
Minimum Toxic Concentration
c

Toic cn Rate Rate ofinput

of drug drug input
= Rate = Rate
of drug of drug output
output
Toic

Minimum Effective
Therapeutic
b c Concentration
window
(range)
Minimum Effective
Minimum Effective
Concentration
Concentration

Onset
of Half-life
action

d
a aa
ag Hjjjj\
J j jjj h
Time (hours)
4 half lives, elimination = 94% complete UNIVERSITY OF HEALTH
8 7 half lives, elimination = 99% complete AND ALLIED SCIENCES
School of Pharmacy
Plasma Drug Concentration-Time Curve Data
• The AUC reflects the total amount of active drug that reaches the systemic
circulation.
• The AUC is the area under the drug plasma level–time curve from t = 0 to t = ∞,
• It is the amount of unchanged drug reaching the general circulation divided by the
clearance.

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 • F = fraction of dose absorbed,
• D0 = dose,
• k = elimination rate constant, and
• VD = volume of distribution.
• The AUC is independent of the route of administration and processes of
drug elimination as long as the elimination processes do not change.
• The units for AUC are concentration × time (eg, μg h/mL).
• Generally, the AUC is directly proportional to dose. For instance, if a single
dose of a drug is increased from 250 to 1000 mg, the AUC may also show a
fourfold increase

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 A: 250 mg dose
B: 500 mg dose
C: 1000 mg dose

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 Plasma Drug Concentration-Time Curve Data

The T1/2 is the time it takes for blood levels of a drug to decrease to
half of what it was at equilibrium

• Distribution T½ life?

• Elimination T½ life?

• Which of the two is normally used to determine dosing?

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 Reminder

• Factors Affecting GI Absorption of Drugs

• Pharmaceutical Factors

• Physicochemical properties of the API

• Pharmaceutical ingredients/excipients

• Formulation factors

• Patient-Related Factors

• Including factors relating to the anatomical,

physiological, and pathological characteristics of the
patient
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 Dosage Form Factors
• Pharmaceutical ingredients (excipients/adjuvants). E.g., diluents, vehicles,
disintegrants, suspending agents, coating agents, etc.
• Dosage form type (e.g., tablet, capsule, solution, suspension, suppository, etc.)
• Factors affecting dissolution of drug from different dosage forms
• Disintegration time (tablets/capsules)
• Dissolution time
• Product age and storage conditions
• Manufacturing variables/processes
• E.g., granulation method, direct compression
• Drug release rate depends on complexity of the dosage form
• Therefore, selection of the most appropriate dosage form is important.
• Solution? Emulsion? Suspension? Powder? Capsule?
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 • Drug elimination -- irreversible removal of drugs from the body
(amount of drug cleared from blood per time). It involves:

▪ excretion (intact drug)

▪ biotransformation (metabolism) -- drug is chemically converted to

a metabolite; Usually an enzymatic process → mainly in the liver

• Major route of elimination – Renal

▪ Dependent on glomerular filtration rate (GFR) and blood flow

• Pulmonary --- gaseous, volatile drugs -- via lungs into expired air

• Other routes: liver (biliary – faecal), breast milk, hair, sweat, saliva

• Clearance (CL) – related term -- volume of plasma cleared of drug

from the body per unit time (unit: mL/min or L/h) UNIVERSITY OF HEALTH
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 ❑Cumulative urinary drug excretion curves
• The amounts of the principal metabolite(s) of a drug or the intact drug plus
its metabolite(s) in urine -- an index of bioavailability.
• Assumption -- appearance of the drug and/or its metabolites in urine is a
function of the rate/extent of absorption
• Measurements involving metabolite levels in urine are only valid when the
drug in question is not subject to presystemic metabolism.
• A cumulative urinary excretion curve is obtained by collecting urine
samples (total emptying of bladder) at intervals after a single dose is
administered.
• Urine is collected until all the drug and/or its metabolites is excreted
(indicated by the curve becoming parallel to the abscissa).
• Total amount of intact drug excreted is related to total amount absorbed.

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 UNIVERSITY OF HEALTH
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 Absolute and Relative Bioavailability
❑Absolute bioavailability
• Compare the total AUCs obtained following the administration of
equivalent doses of the drug via a particular absorption site (abs, e.g., oral
route) and via the intravenous route (same subject, different occasions).
AUCT abs
• Absolute Bioavailability =
AUCT iv

AUCT abs
ൗDose abs
• If different dose sizes, Absolute Bioavailability = AUCT ൗDose iv
iv

• Using urinary excretion data, compare the cumulative amounts of

unchanged drug excreted in urine following administration of the drug via
an absorption site and the IV route (bolus injection).
XU abs
• Absolute Bioavailability = (for dose correction?)
XU iv

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❑Relative bioavailability
• When a drug cannot be administered by IV bolus injection, the relative
bioavailability is determined instead.
• Used to assess the effects of dosage form differences on bioavailability
• The bioavailability of a drug from a test dosage form is compared to that of
the same drug administered in a standard dosage form, which is either an
orally administered solution (from which the drug is well absorbed) or an
established commercial (i.e. clinically proven) preparation of proven clinical
effectiveness.
• NB: Same route of administration, Same subject, Different occasions !!
AUCT test
• Relative Bioavailability =
AUCT standard

• Dose correction?
• Using urinary drug excretion data?

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 Bioequivalence
• Bioequivalence is established if;
• the in vivo bioavailability of a test drug product does not differ
significantly from that of the reference listed drug product.
• The two drug products can then be said to be bioequivalent.
• Bioequivalence studies compare;
• the bioavailability of the same active pharmaceutical ingredient
from one drug product (test/generic) to a second drug product
(reference/innovator).
• Bioequivalence is determined based on the relative
bioavailability of the innovator medicine versus the
generic medicine.

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 Bioequivalence
• in vitro biomarkers and in vitro binding studies may
be used to establish bioequivalence.
• Eg.,bioequivalence of cholestyramine resin determine by
equilibrium and kinetic binding studies of the resin to bile
acid salts

UNIVERSITY OF HEALTH
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 Assignment

• What are the advantages and disadvantages of the

various methods of determination of bioavailabilty
of a drug product? (at least 3 each)

• Give 2 reasons why bioequivalence studies on

pharmaceutical products are necessary

• Check published work on the bioequivalence studies

of any (one) popular drug product and assess results
obtained.
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