Biopharmaceutics

Dr Keng Wooi Ng

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Learning outcomes
• By the end of this lecture, you should be able to:
– Understand the basic principles of biopharmaceutics and
the adsorption process.
– Understand basic pharmacokinetic principles as a means of
rationalising the therapeutic action of drugs.

Do understand the concepts

Don’t memorise the equations

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Biopharmaceutics
• ‘The study of how the physicochemical properties of drugs,
dosage forms and routes of administration affect the rate and
extent of drug absorption.’

—Aulton’s Pharmaceutics, 5th ed.

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Importance
• Dosage form design has implications on drug absorption, thus
therapeutic efficacy and safety.
• API selection—poor candidates are removed early.
• Formulation optimisation:
– Assess absorption at predicted efficacious dose.
– Excipient selection.
• In vitro-in vivo correlations.
• Bioequivalence.

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Pharmacokinetics (PK)

What the body does to the drug

Absorption
ADME
Distribution Metabolism Excretion
Uptake into Transfer into Transform into Remove from
systemic body fluids and metabolites body
circulation tissue

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PK: ADME
Systemic administration
Drug

IV dosage form
Oral dosage form

Drug release and Absorption Drug in systemic Distribution

Drug in tissues
dissolution circulation

Elimination

Inter-patient variability
• Genetic polymorphism Excretion and Pharmacological and
(pharmacogenomics) metabolism clinical effect
• Age (children, elderly)
• Disease (liver or kidney Drug-body interactions
dysfunction)
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Plasma concentration
Measurements of drug in the body usually limited to blood or
plasma.
Assumption

↑ Drug concentration in plasma

↑ Drug concentration at target site

↑ Pharmacological/clinical effect

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IV administration

Cmax = C0 Toxic range

Plasma concentration, C
(No absorption phase) Minimum toxic
concentration

Therapeutic window

Minimum
effective
Sub-therapeutic concentration
range

Time, t
Tmax = 0
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Plasma half life, t½

Formulation with
Plasma concentration, C

shorter t½ drops out

of therapeutic
window sooner, has
Therapeutic window shorter duration of
action (x1 < x2),
Longer requires more
t½ frequent dosing

x
x 2 Shorter
1 t½
Time, t
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IV administration

Plasma concentration, C

Therapeutic window

Exposure (AUC)

Duration of
action

Time, t
Onset time
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Volume of distribution, Vd
IV dose (mg)

Initial plasma concentration (mg L-1)

• Theoretical fluid volume needed to contain the drug at the

same concentration as that found in the plasma.
• Affected by drug binding to plasma proteins.

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Plasma protein binding

Drug in Drug in plasma Drug out

Confined to plasma Bound drug Unbound drug Can be distributed

⇌ into tissues
fraction, fb fraction, fu

High fb increases C, lowers Vd

Tissue

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Plasma half life, t½
Time taken for the plasma concentration of a drug to fall by 50%.

Plasma concentration, C
Elimination rate
t½ = t2 – t 1 constant (h-1)

C1

C2 = ½ C1

t1 t2 Time, t
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Why is t½ constant?
First-order kinetics
Drug concentration at any given time is
proportional to initial concentration.

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Clearance, CL
Volume of plasma from which the drug is eliminated per unit time
(L·h-1).

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IV administration

Cumulative concentration
1st bolus st nd

Plasma concentration, C
1 bolus remaining + 2 bolus

2nd bolus

Therapeutic window

Dosing interval Time, t

(τ) 16
IV administration

Aim: Keep plasma concentration within therapeutic window

Dose and dosing frequency are important considerations

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 Oral drug absorption
Stomach
• pH 1–2 (fasted); pH 4–5 (fed)
• Surface area: 0.053 m2
• Fluid volume: ~50 mL
• Transit time: 0–3 h

Small intestine
• pH 5–7
• Surface area: 200 m2
• Fluid volume: 120–350 mL
• Transit time: 3–4 h

Large intestine
• pH 6–7.5
• Fluid volume varies along GI tract but • Surface area: 0.35 m2
commonly assumed to be 250 mL • Fluid volume: 10–200 mL
• Transit time: Highly variable
• GI motility follows diurnal rhythm and is
affected by food.
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Oral drug absorption
• Diffusion-driven absorption shows first-order kinetics under
sink conditions.
• Absorption rate may be limited by:
– Permeability
Depends on lipophilicity, size, pH/ionisation, etc.
– Solubility Solubility may affect dissolution rate.

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Oral administration
Absorption phase Elimination phase
Absorption > elimination Elimination > absorption

Plasma concentration, C
Cmax

Exposure (AUC)

Time, t
tmax
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Oral administration
IR Tablet

Toxic range
Plasma concentration, C

Therapeutic window

Sub-therapeutic
Duration of
range
action
Time, t
Onset time
Bioavailability, F
• Fraction (often as %) of dose that reaches systemic circulation.
• IV administration: F = 1 (or 100%).
• Oral administration: F < 1 due to pre-systemic effects.

Absolute bioavailability:
Ref = IV administration.
Relative bioavailability:
Ref = non-IV administration.

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Bioavailability, F
Oral dose
Pre-systemic effects

Intestinal Liver Systemic

Intestinal lumen fa wall fg fh circulation

fa= 70% fi = 80% fh = 50%

F = 28%

15% 20% 50%

Degradation Intestinal First-pass hepatic
15% metabolism metabolism
Excretion
(faeces)
F = absolute bioavailability
fa = fraction absorbed
fi = fraction escaping intestinal metabolism
fh = fraction escaping first-pass hepatic metabolism
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Food effects
Food may affect drug stability, dissolution and absorption.

Fed

• Food components.
Fasted
• Bile salts.
• Gastric retention.
• Enzyme activity.

https://doi.org/10.1002/j.1552-4604.1995.tb04095.x
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Oral administration
Elimination phase
Elimination > absorption

Plasma concentration, C
Terminal elimination phase

Absorption complete

t½ = t2 – t1 = 0.69/kel
C1
C2 = ½ C1
t1 t2
Time, t
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Oral administration

1st IR tablet 2nd IR tablet

Plasma concentration, C

Dosing interval Time, t

(τ) 26
Bioequivalence
• Equivalent rate and extent of absorption between formulations.
• AUC, Cmax and tmax must all fall within 80–125% between
comparators to be considered bioequivalent.
• Implications for efficacy, safety and regulatory compliance.

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Summary
• Biopharmaceutics depicts the relationship between dosage
form design and pharmacokinetics.
• ADME (absorption, distribution, metabolism, excretion) depicts
drug disposition in the body.
• Metabolism and excretion both contribute to drug elimination.
• Pharmacokinetic parameters are usually determined from drug
concentration in the plasma.
• IV drug administration produces 100% bioavailability.
• Oral drug administration products <100% absolute
bioavailability due to pre-systemic effects.
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Recommended reading
• Aulton ME, Taylor KMG (2018) Aulton’s Pharmaceutics: The Design and
Manufacture of Medicines, 5th ed. Elsevier, Edinburgh
– Chapter 18: Introduction to Biopharmaceutics, p. 296–299
– Chapter 19: Gastrointestinal tract – physiology and drug absorption, p. 300–318
– Chapter 20: Bioavailability – physicochemical and dosage form factors, p. 319–
338

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