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Biopharmaceu,cs

Dr. Herman J. Woerdenbag

Department of Pharmaceu1cal Technology and Biopharmacy
University of Groningen
The Netherlands
h.j.woerdenbag@rug.nl

2016 H.J.Woerdenbag
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Ques,ons
Why should medicine A be taken only once a day and medicine B four
1mes daily to obtain the desired therapeu1c eect?

Why do some drugs only act aNer injec1on and not when administered
orally, as a tablet?

How can we inuence the func1onality of a medicine by its composi1on

and formula1on?

What can be the reason that an orally given drug does not or hardly work,
despite the fact that it is well absorbed from the gastrointes1nal tract?
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What is a medicine?
A pharmacologically ac1ve substance (drug substance, drug)
manufactured into a suitable dosage form (drug product)

Dosage form consists of ac1ve principle(s) plus excipients

Drug and dosage form determine the biopharmaceu1cal

proper1es
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Biopharmaceu,cs
Describes the fate of a drug product in the body from the
moment of administra1on un1l the moment it exerts its
ac1on and the moment it is eliminated

Links the proper1es of a drug substance and its dosage form

with the ac1on and fate in the living organism

Integrates aspects from physics and chemistry, drug delivery

technology, pharmacokine1cs and pharmacodynamics
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Biopharmacy inuenced by
Drug substance
Content, physicochemical proper1es
Dosage form
Structure (design, excipients) and manufacture determine func1onality
and performance
Route of administa,on
Dosage form relates to administra1on route
The way the body handles the drug
Absorp1on, distribu1on, metabolism, excre1on (ADME)
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Func,onality of a drug product

Produc,on process and process condi,ons
Reliable, robust, reproducible
Quality assurance (GMP)
Technical aspects (quality related)
Uniformity of content (UoC)
Stability
Microbiological quality
Biopharmaceu,cal aspects
Drug release prole
Suitability to be administered via intended route
Ability of drug to reach site of ac1on
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Excipients
Excipients are added to a formula1on to
Facilitate produc1on
Improve quality
Op1mise structure performance Diluent
Increase pa1ent acceptability Filler
Vehicle
Emulsier
Viscosity enhancer
Preserva1ve
An1oxidant
Flavour
Colour
pH correctant
Stabilizer
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Types of ac,on
Systemic
Ac1ve substance reaches its site of ac1on via the blood stream

Local
Ac1ve substance is administered at the site where it exerts its ac1on
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Administra,on routes and dosage forms

Administra,on route Dosage form

Oral Tablet, powder, capsule, granules (solid); solu1on, suspension,

emulsion, gel (liquid)
Rectal Suppository, enema
Vaginal Pessary
Parenteral Injec1on (solu1on, suspension, emulsion)
Dermal Ointment, cream, paste, lo1on, gel, solu1on, dus1ng powder,
transdermal patch
Pulmonary Aerosol (solu1on, suspension, emulsion, powder), inhala1on, spray,
gas
Nasal Drop, spray (solu1on, suspension)
Auricular Drop (solu1on, suspension), ointment, cream
Ocular Drop (solu1on, suspension), ointment, cream
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Major routes of administra,on

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Routes and forms: key points

Dierent dosage forms for one administra1on route
Dierent administra1on routes to obtain a similar systemic
eect

Desired eect (systemic, local, kine1cs) determines the route

of administra1on
Route of administra1on and desired eect determine which
type of dosage form is preferred
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Condera,ons: which route, which form?

Physicochemical proper1es of drug substance
Site of ac1on, mechanism of ac1on
Desired drug plasma concentra1on prole in 1me
Pharmacokine1cs and metabolism
In rela1on to bioavailability, absorp1on, dose frequency
Toxicological proper1es drug substance
Possible risks of varia1on in bioavailability
Compa1bility of drug substance and excipients
Ease and frequency of administra1on
Nature of the disease
Acute, chronic
Abili1es of the pa1ent and pa1ent friendliness
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Time of onset of ac,on

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Dose
How much at a 1me (number, volume)
Frequency
Maximum daily dose (weekly dose)

Determined by
Ac1ve substance (chemical and physical form, ADME)
Dosage form and administra1on route
Pa1ents age and condi1on (child, elderly, organ failure)
Also relevant
Time when taken (before, aNer, during meal)
Contraindica1ons, hypersensi1vity, interac1ons
Chronotherapy
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Chronotherapy

Drug release coincides

with 1me it is required
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Drug disposi,on
Four stages; ADME
Absorp1on
Distribu1on
Metabolism
Excre1on

First: libera1on
LADME
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Pharmacokine,cs and -dynamics

Pharmacokine,cs (PK)
Study and characterisa1on of 1me course ADME
Determined by measuring plasma prole (blood concentra1on)
What the body does with the drug

Pharmacodynamics (PD)
Study of biochemical and physiological eects of the drug in the body
What the drug does to the body
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Availability (systemic ac,on)

Pharmaceu,cal availability
Amount of drug released from the drug product in a dissolved form
- Disintegra1on of the drug product (tablet, capsule)
- Dissolu1on of the drug (solubility in aqueous environment)

Biological availability
Amount of unchanged drug that becomes available in the systemic
circula1on
- Absorp1on (biological membranes)
- Transport to the site of ac1on
- First-pass eect
- By deni1on: 100% (or 1.0) for intravenous administra1on
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Bioavailability (local ac,on)

Dermal, nasal, ocular, pulmonary, rectal, vaginal
administra1on
Local eect is the pharmacotherapeu1c eect
No absorp1on into systemic circula1on desired
Adverse eects may occur due to systemic absorp1on

Determined by the frac1on of drug substance dissolved in

aqueous uid at site of applica1on
Not determined by the amount of drug reaching systemic
circula1on
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ADME
Absorp,on
D
M
E

Absorp,on of drug substance into the systemic circula,on

Preceded by libera1on of the drug from the drug product (release) and
dissolu1on in aqueous environment
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Solubility is important
No dissolu,on in aqueous environment = no bioavailability
Important determinant for dissolu1on rate
Dissolved amount of drug is driving force for diusion driven
transport (concentra1on gradient; Ficks Law of Diusion)
A low amount of dissolved drug limits the driving force for transport
(and the subsequent par11on and absorp1on)
Solubility of poorly water soluble drugs may be limited by the
volume of uid available (gastrointes1nal tract)
Only a minor frac1on of the total dose is dissolved
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Dissolu,on rate and solubility

Not the same
Not necessarily related

In prac1ce
High drug solubility oNen associated with high dissolu1on rate
Excep1ons
HPMC (lm-coa1ng): very water soluble, but it takes hours to hydrate
and to dissolve
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Determinants of solubility, dissolu,on rate

Drug related
Aqueous solubility (molecular structure, salt versus weak acid or base)
Solid state (crystalline, amorphous)
Par1cle size
Wemability
Necessary to understand
Environment related bioavailability!
Volume of water available
pH
Food, fat
Bile salts
Drug product related
Excipients (complex formers, solubilising agents, cosolvents)
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Molecular structure of API

Increased water solubility
Introduc1on of hydrophilic (polar) groups
Sodium salt of weak acid
Hydrochloride of weak base
Solubility can be inuenced
by changing the molecular structure
Decreased water solubility
Esterica1on
- Taste masking
- Protec1on against degrada1on
- Increased ease of gastrointes1nal absorp1on
- Erythromycin propionate
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Nature of solvent
Like dissolves like
Polar substance dissolves in polar solvent
Apolar substance dissolves in apolar solvent

Mixtures of solvents for aqueous systems

Co-solvents (miscible with water)
- Ethanol
- Propylene glycol
- Glycerol
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Solid state form of API

Nearly all drug substances are handled in powder form at
some stage of manufacture process
Amorphous
Crystalline
Anhydrous or hydratated
Solvated

Polymorphism
Many drugs exist in more than one form
Dierent molecular packing arrangements in crystal lapce
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Polymorphs
One form stable
Other forms metastable
Metastable forms convert to stable crystalline form
Dierent physical proper1es
Dissolu1on, solid-state stability
Dierent processing behaviour
Powder ow, compac1on

Polymorphism important for formula,on, stability,

biological ac,vity
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Polymorphism
Crystalline materials generally dissolve slower than
amorphous material
Release of a molecule from crystalline lapce takes more 1me
Most amorphous materials are not stable and will transform
in 1me to the crystalline state
Only applicable for drugs that crystallise very slowly
Dierent crystal forms may have dierent dissolu1on rates
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Modied product performance?

Polymorphic transi1ons
Milling, granula1on, drying, compac1on
Solvate forma1on
Granula1on
Loss hydrate water
Drying
Reversion metastable to stable form
Suspensions: crystal growth during storage

Formulator must be aware that during the formula,on

process these proper,es of an API may change
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Dissolu,on proles

Sulphamethoxydiazine Theophylline Erythromycin

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Par,cle size of solid

Surface area (S) propor1onal to par1cle size
S = 6d (d = diameter cubic par1cle)
2

Increasing solubility with decreasing size

Up to about 1 micrometer
Further decrease in size may reduce solubility
- Due to presence of electrical charges on par1cle?
- Relevant for nanotechnology products

d = 1 cm 10x 0.1 cm 100x 0.01 cm

S = 6 cm2 60 cm2 600 cm2
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pH
Determines propor1on of (un)ionised weak acid or base
Solubility
Absorp1on

Gastrointes1nal tract: pH range (1-8)

Rela1onship pH, pKa and solubility weak acids, weak bases
Henderson-Hasselbalch equa1on
Solubility of acidic and basic drugs is pH-dependent
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Weak acids, weak bases

The ionised form of an acid or base dissolves much bemer in
aqueous solvents than the non-ionised form
An acid dissolves good in basic environment
A base dissolves good in acidic environment

Weak acid Weak base

pKa=5.7

Lamotrigine: an1-epilep1c
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Common ion eect

Equilibrium in saturated solu1on of sparingly soluble salt in
contact with undissolved solid:
AB (solid) A+ + B- (ions)
Ks = [A+][B-] (solubility product of AB)
Addi1on of A+ or B- (common ion) equa1on to leN
Solid AB precipitates
Common ion eect may reduce solubility of slightly soluble
salts

In vivo complex situa1on

Dicult to predict
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Complex forma,on
Complex forma1on of another substance with the API
Increase or decrease of solubility

Tetracycline with milk products, antacids

Intramolecular complex
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Solubilising agents
Emulsiers, surface ac1ve compounds

Forma1on of aggregates or micelles in solu1on at a certain

concentra1on
In aqueous solu1on: centre is organic, apolar
Apolar API may adhere to micelles

Solubilisa1on as dosage form

Microemulsion
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Dissolu,on
Process where a molecule, ion or atom of a solid enters a
liquid phase in which solid is immersed
Phase 1: interfacial reac1on, libera1on of solute molecule from solid
into liquid form, phase change
Phase 2: solute molecule migrates through boundary (diusion) layers
surrounding the crystal, solid molecule is incorporated in solvent
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Ficks Law
Ficks Law of Diusion
dC/dt = kC

Rate of change (in ,me) in concentra,on of dissolved

material is directly propor1onal to the concentra1on
dierence between the two sides of the boundary layer
Driving force: concentra1on dierence
Sink and non-sink condi1ons
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Noyes-Whitney equa,on
dm/dt = D . A (Cs-C) / = k . A (Cs-C)
dm/dt = dissolu,on rate API
D = diusion coecient
solid bulk
A = surface area
Cs = satura1on solubility
C = concentra1on in solu1on
= diusion layer thickness
k = dissolu1on rate constant

boundary or
diusion layer
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Inuence on dissolu,on rate (1)

Surface area (A) of undissolved solid
Dissolu1on rate increases with increasing A
Size of solid par1cles
Surface area increases with decreasing par1cle size
Dispersibility of powdered solid in dissolu1on medium
Wemability
Porosity of solid par1cles
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Inuence on dissolu,on rate (2)

Satura1on solubility of solid in dissolu1on medium (Cs)
Dissolu1on rate increases propor1onally with increasing dierence
between Cs and C
High Cs accelarates dissolu1on rate

Temperature
Nature of dissolu1on medium
Molecular structure of solute
Crystalline form of solid
Presence of other compounds
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Inuence on dissolu,on rate (3)

Concentra1on of solute at 1me t (C)
Dissolu1on rate increases propor1onally with increasing dierence
between Cs and C
Volume of dissolu1on medium
Increased volume decreases C
Removal dissolved solute from dissolu1on medium
Sink versus non-sink condi1ons
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Inuence on dissolu,on rate (4)

Dissolu1on rate constant (k)

Diusion coecient (D) of solute in dissolu1on medium

Viscosity of medium
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Inuence on dissolu,on rate (5)

Thickness of diusion layer (boundary layer) ()
Dissolu1on rate decreases propor1onally with increasing diusion layer
thickness
Degree of agita1on of dissolu1on medium
Increased agita1on decreases diusion layer thickness
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API with low aqueous solubility

An API must exhibit at least limited aqueous solubility
Dissolu1on rate is limi1ng step in absorp1on process
Alterna1ve formula1on strategies needed
Par1cle size reduc1on, deriva1ves, complexa1on, solid solu1on,
nanotechnology

Dissolu1on rate can be adversely aected by formula1on

addi1ves
Magnesium stearate as tablet lubricant
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Clinical relevance (examples)

Digoxin
Micronised par1cles in solid oral dosage forms
To avoid too low dissolu1on rate and poor bioavailability

Piroxicam
Cyclodextrin complex
Enhanced dissolu1on rate faster absorp1on

Chloramphenicol
Bioavailability of amorphous API higher than of crystalline
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Absorp,on
ANer dissolu1on of drug in aqueous environment
Absorbing membrane acts as lipophilic barrier
Passage of drug relates to lipohilicity
Par11on coecient between oil (octanol) and water
Concentra1on gradient is driving force
- Blood stream creates sink condi1ons

dC/dt = kC
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Dissolu,on and absorp,on

Fast dissolu,on (or drug given in dissolved form)
Rate of absorp1on depends on ability to pass absorbing membranes
Membrane permea1on depends on size, water and lipid solubility
(par11on coecient), ionic charge of molecule
- May be rate limi1ng

Slow dissolu,on (physicochemical proper1es, formula1on)

Dissolu1on may be rate limi1ng in absorp1on and inuence
bioavailability
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Determinants of absorp,on
Size and charge of drug molecule
Lipophilicity of drug
Volume available for drug dissolu1on
Administra1on condi1ons (food)
Surface and permeability of absorbing membrane
Presence of metabolising enzymes at absorp1on site
Presence of carriers (in case of ac1ve transport)

Poor absorption may be due to incomplete dissolution,

poor permeation, metabolism before and/or during absorption
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Membrane passage
Membrane of absorbing mucosa permeable to unionised API
High lipophilicity
Most small molecule API are weak acids or weak bases
pH depending ionisa1on

Poten1al problems regarding bioavailability:

Compounds with low par11on coecient
Compounds highly ionised over en1re
physiological pH range
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pH par,,on theory
Weak acids, weak bases usually absorbed in unionised form
Higher par11on coecient
Driving force: concentra1on gradient of unionised form
Unionised frac1on determined by pKa of API and pH of
surrounding environment
pH gastrointes1nal tract is 1-8

Henderson-Hasselbalch equa1on
Weak acid: pH = pKa + log [A-]/[HA]
Weak base: pH = pKa + log [B]/[BH+]
 | 52

Ionisa,on impairs absorp,on

Fully ionised (high pKa), no carrier: too hydrophilic to be
absorbed from gastrointes1nal tract
Quaternary ammonium compounds
- Vancuronium, butylscopolamine

Mul1ple H-bond acceptors and mul1ple H-bond donors with

varying pKa values in molecule
No unionised form at pH range in gastrointes1nal tract
Eprosartan (angiotensin II inhibitor)
Oral bioavailability 13-15%
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Transport across membranes

Transcellular (across the cells)
Passive diusion
Carrier-mediated
Endocytosis

Paracellular
Between the cells, via inters11al space
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Transcellular membrane transport (1)

Passive diusion
- Most important route of membrane passage of drugs
- Driving force: concentra1on gradient (Ficks Law of Diusion)
- Con1nuous blood ow maintains gradient
- Oil to water par11on (lipophilicity)

dC/dt = kC
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Predic,on of membrane permea,on

Par11on coecient
Polar surface area
Molecular weight
Preferably < 300 Da
Number of H-bond donors and H-bond acceptors
3 donors, 3 acceptors
Number of rotable bond atoms
3
Number of non-hydrogen atoms
(Lipinskis rule)
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Lipophilicity of a compound (1)

Octanol-water par,,on coecient
Log P value
- Range -0.4 to >5
- Preferably < 3
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Lipophilicity of a compound (2)

Polar surface area
Sum of surface of polar atoms in molecule
O and N atoms
> 140 2: too hydrophilic, unsuitable for oral administra1on

paracetamol
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Transcellular membrane transport (2)

Carrier-mediated
Ac1ve transport, energy dependent
- Opposed to concentra1on gradient
Involvement of transporter enzymes
Satura1on possible
Facilitated diusion
Protein channels, ion channels
Faster than passive diusion
No energy
Satura1on possible
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Enzyme kine,cs
Michaelis-Menten equa1on
Rate of transforma1on of substrate by enzyme

V = Vmax.[S] / (Km + [S])

V = enzyma1c reac1on rate
Vmax = maximum transforma1on rate Transformation
rate (v)
Vmax
(at complete enzyme satura1on)
[S] = substrate concentra1on
Km = substrate concentra1on at Vmax Vmax

Km
Concentration [S]
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Transcellular membrane transport (3)

Transport proteins
P-glycoproteins
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Interac,ons
Inhibi1on of transport enzymes (compe11on)
Induc1on of transport enzymes

Signicant eect on drug absorp1on

Ecacy, safety

Drug-drug interac1ons
Food-drug interac1ons
Herb-drug interac1ons
 | 62

Transcellular membrane transport (4)

Endocytosis
Plasma membrane of cell invaginates
Invagina1ons become pinched o
Small intracellular membrane bound vesicles enclosing material
Transport into (through) cell

Pinocytosis
Receptor-mediated endocytosis
Phagocytosis
Transcytosis
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Paracellular membrane transport

Through inters11al spaces between cells
Typical for absorp1on via mucosal membranes
Intes1ne, mouth, nose, lung
Inters11al space: 0.4 nm duodenum, up to 4 nm alveolar membranes
Generally limited to small hydrophilic molecules
Nitroglycerin
Lung: smaller proteins (MW up to 20 kDa)
 | 64

Absorp,on rate
Important aspect of bioavailability
For maximum blood concentra1on (Cmax)
Time at which maximum concentra1on occurs (tmax)

Acute situa1on: high

Epilep1c insult, sleep induc1on, pain
Slow (sustained) release
Prolonged therapeu1c eect
 | 65

Biological factors inuencing absorp,on

Residence ,me in stomach
May increase dissolu1on of poorly water soluble API (and thus its
bioavailability)
pH in stomach or intes,ne
May inuence dissolu1on rate of acidic or basic API with pH dependent
solubility
Bile acids
May increase dissolu1on rate and absorp1on of poorly water soluble
API (cyclosporine, phenytoin, levothyroxine, tacrolimus)
May reduce absorp1on of hydrophylic API (atenolol)
 | 66

Predic,on in vivo behaviour

In vitro tests
Dissolu1on rate
Par11on coecient
pKa
Establish in vitro in vivo rela1onship
Dicult
Predic1on of intes1nal absorp1on
Solubility
Permeability
Dose number
Biopharmaceu1cal classica1on system

 | 67

Dose number (DN)

Dimensionless parameter
Links solubility (Cs) of API to the dose (D) and the volume
available for dissolu1on (V) during the absorp1on process

DN = D / (Cs.V)
< 0.1: solubility does not aect absorp1on process
> 10: solubility nega1vely inuences absorp1on (rate)
0.1 10: solubility may aect absorp1on (rate) and bioavailability
 | 68

Example: dexamethasone
Water solubility 89 g/mL
Oral: volume in stomach 500 mL (taken with glass water)
Rheuma1c disease: 4 mg
DN = 0.09
No major dissolu1on problem expected
Pyodermia gangrosum: 300 mg
DN = 6.7
Dissolu1on behaviour needs to be inves1gated
 | 69

BCS
Biopharmaceu1cal Classica1on System
Solubility of API
Permeability of absorbing membranes for API
Class I: high solubility, high permeability
Class II: low solubility, high permeability
Class III: hight solubility, low permeability
Class IV: low solubility, low permeability

Used to characterise and predict poten1al problems related

to bioavailability of an API
 | 70

Solubility, permeability
Solubility of oral drug
A drug has a high solubility when the highest dose dissolves in 250 mL
of aqueous buer with a pH between 2 and 7.5
What about a rectally given drug: 250 mL s1ll relevant?

Permeability
In vitro analysis (Caco2 cells transport, Ussing chambers) show that the
drug easily passes the membrane
A drug has a high permeability when the extent of absorpCon aDer
administraCon (bioavailability) is >90%
 | 71

Poorly soluble drugs: what to do?

Par1cle size reduc1on
Surfactants
Buers in formula1on
Deriva1ve
Amorphous drug
Dierent crystalline form
Complexa1on (e.g. cyclodextrins)
 | 72

Cyclodextrins
 | 73

Reasons for low permeability

The molecule is too big
The molecule is too hydrophilic
The molecule is charged
Enzymes or condi1ons in intes1nal lumen, intes1nal wall or
liver break down the drug
There are eux transporters

How to improve permeability?

 | 74

Improve solubility, permeability

 | 75

Drug stability in physiological environment

Degrada1on under acidic condi1ons (gastric juice)
Omeprazole, erythromycin, pacrea1c enzymes
Enteric coated dosage forms
- Coa1ng of polymers that dissolves in small intes1ne
- Coated tablet, coated pellets in capsule, coated pellets compressed to tablet
- No breaking or crushing

Enzyma1c degrada1on
In stomach or intes1ne: reduc1on of amount of drug available for
absorp1on
Intes1nal wall and liver enzymes: reduced bioavailability
 | 76

First-pass eect
Drug metabolism by enzymes in intes1nal lumen or in cells
intes1nal wall
Drug metabolism during rst passage of liver
Reduc1on of bioavailability
Extent depends on dose and absorp1on rate in rela1on to
enzyma1c capacity (satura1on)
Concomitant use of food or medicines
Absorp1on rate, induc1on or inhibi1on of enzymes
Take medicine before, during, aNer meal
Prevented by other route of administra1on
Injec1on (im, sc), sublingual, nasal, pulmonary
 | 77

Bioavailability
Frac,on (F) of administered API that enters systemic
circula,on in unchanged form
Calculated from area under the curve (AUC)
Blood (plasma) concentra1on of unchanged API versus 1me prole,
corrected for dose (D)
- Intravenous administra1on (100% bioavailability)
- Oral administra1on
- For = [(AUCor.Dor)/(AUCiv.Div)] * 100%
 | 78

Food / drug eects on absorp,on (1)

pH-dependent dissolu,on
Medicines inuencing gastric pH
- H2-antagonists, proton pump inhibitors, antacids
Food and drinks inuencing gastric pH
- Milk increases the pH in the stomach
- Cola decreases the pH in the stomach
- Inuence on solubility of acids and bases
Bemer dissolu1on of drug in acidic uids (cola versus milk)
- Ketoconazole, itraconazole
 | 79

Food / drug eects on absorp,on (2)

Insoluble complex forma,on with Ca2+ or Al3+
Tetracycline precipitates with antacids, dairy products
Chela,on or binding with Fe3+
Doxycycline, penicillamine, methyldopa, ciprooxacin
Fats (food) may increase bioavailability of lipophilic drugs
Albendazole, griseofulvin
Grapefruit avonoids inhibit CYP 3A4 in intes,nal wall
Naringenin increases bioavailability of drugs (midazolam, terfenadine,
nifedipine)
 | 80

ADME
A
Distribu,on
M
E

Distribu,on of the drug substance over the body

To central and peripheral compartments
 | 81

Distribu,on
Distribu1on of drug over body 1ssues via blood stream
Protein binding in blood
Compe11on for binding places: interac1ons possible
Free drug concentra1on determines transport to 1ssues
Drug concentra1ons may be higher in certain 1ssues
Clearance of free drug may be higher
Be careful with drugs having a narrow therapeu1c window
Division over blood versus 1ssues based on anity
 | 82

Compartments
 | 83

Volume of distribu,on
Distribu1on of drug over the body
Fluids, 1ssues and organs may have dierent drug concentra1ons
Volume of distribu1on: Vd
The apparent volume in which the drug is dissolved (L/kg)
 | 84

Small versus large Vd

 | 85

Ecacy measurement
Determined by intrinsic receptor ac1vity and receptor
occupa1on of a drug
But: dicult to measure
Use drug blood concentra1ons
Analysed in whole blood, plasma or serum
Assump1on: drug blood concentra1on relates to drug
concentra1on at site of ac1on

Drug blood (plasma) concentra,on can be a measure for

therapeu,c eect and toxicity
 | 86

Plasma-,me curves
Drug plasma concentra1on measurements
 | 87

Therapeu,c window
Blood concentra1on range within which desired therapeu1c
eect occurs without serious side eects

MEC: minimal eec1ve concentra1on (lower limit)

MTC: maximal tolerable concentra1on (upper limit)
 | 88

ADME
A
D
Metabolism
E

Biotransforma,on of the drug substance by enzymes

Ac1ve or inac1ve metabolites
 | 89

Phase 1 and phase 2 metabolism

 | 90

Drug metabolism example

 | 91

Cytochrome P450 iso-enzymes

Group of monoxygenases (liver, intes1nal wall)
Oxida,ve metabolising steps
ONen preceding glucuronida1on
Followed by urinary or biliary excre1on
Inhibi1on (increasing bioavailability) or induc1on (decreasing
bioavailability)
Drug-drug interac1ons
Food-drug interac1ons
Herb-drug interac1ons
Gene1c polymorphisms
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CYP 3A4
Cytochrome P450 subtype 3A4
Inhibi,on or induc,on may be
clinically relevant
Inhibi1on: ciclosporin, verapamil,
midazolam, paclitaxel, simvas1n,
cime1dine, erythromycin,
ketokonazole, grapefruit juice
Induc1on: steroids, rifampicin,
phenobarbital, St Johns wort
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P-glycoproteins (P-gp)
Membrane bound transporters ac1ve removal (energy
dependent) of drug substance from the cell
Blood-brain barrier, intes1nal wall, liver, kidney
Reduc1on of bioavailability of substrate drug
- Digoxin, metronidazole, saquinavir, calcium antagonists
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Herb-drug interac,ons (1)

Concomitant use of herbal medicinal products and
conven1onal drugs
May be clinically relevant
Many literature reports based on in preclinical laboratory work
Complexity and variable composi1on of herbal medicinal
products complicate predictability
Awareness of possible interac1ons may avoid problems
Knowledge of mechanisms of ac1on and pharmacology
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Herb-drug interac,ons (2)

Determinants of risk
Dosage of herbal medicine
Dura1on of herbal treatment
Age / health condi1on of user
- Comedica1on
- Polypharmacy increases risk
Which herbal medicine
Which conven1onal drug
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Herb-drug interac,ons (3)

Drugs with narrow therapeu1c window
Oral an1coagulants, cardiac glycosides, oral contracep1ves,
an1depressants, an1hypertensives
St Johns wort, ginkgo, ginseng, garlic, laxa1ves
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Herb-drug interac,ons (4)

Pharmacokine,c (ADME)
Induc1on or inhibi1on of drug metabolising enzymes
Cytochrome P450 iso-enzymes, glucuronosyltransferases (UGTs),
P-glycoproteins (P-gp)
Reduced or enhanced drug plasma levels
Saponins, gastric pH uctua1ons / altera1ons, intes1nal mo1lity

Pharmacodynamic
Receptor interac1ons
Similar or (partly) antagonis1c ac1on
Cellular response
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Herb-drug interac,ons - examples

Decrease ac1vity of an1depressants, oral an1concep1ves and
oral an1cogulants by hypericum
Enhanced bleeding risk due to warfarin combined with
ginkgo, garlic
Mania caused by an1depressants plus ginseng
Enhancement of cor1costeroid eects by licorice
Decreased absorp1on of various drugs by antraquinone
containing laxa1ves and bulk formers

Case-based Pharmacovigilance
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ADME
A
D
M
Excre,on

Excre,on of drug and/or metabolites from the body

Via urine, feces, exhaled breath
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Excre,on
Most drugs are eliminated aNer biotransforma1on
Some drugs are excreted as such (without biotransforma1on)
Excre1on into
Urine (glomerular ltra1on)
Feces (via liver and bile, biliary excre1on)
Exhaled breath

Renal clearance
Hepa1c clearance
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Clearance
Metabolism and excre1on eliminate the drug from the body
Clearance: Cl
The blood or plasma volume of which all drug is cleared per
unit of 1me (mL/min)

Cp = D0/Vd e-ket ke = Cl/Vd

Cp = drug plasma concentra1on
D0 = dose
ke = elimina1on rate constant
Vd = volume of distribu1on
t = 1me
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Pharmacokine,cs of a drug
ANer absorp1on transport to site of ac1on eect
During and aNer transport, during and aNer exer1ng its
ac1on: distribu1on, metabolism, elimina1on
Time course (therapeu1c eects, adverse eects) determined
by
Rate of absorp1on
Volume of distribu1on
Rate of elimina1on
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Pharmacokine,c parameters
Absorp1on
Cmax
Tmax
Half-life t
Elimina1on
Volume of distribu1on (Vd)
Area under the curve (AUC)
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Order of kine,cs
First order process
Rate determined by concentra1on
Drug passage between compartments, elimina1on
Drug decomposi1on
Bacterial growth, sterilisa1on

Zero order process

Rate independent of concentra1on
Dissolu1on
Drug release from dosage form
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Non-linear pharmacokine,cs
Blood concentra1on increases more than propor1onal with
increasing dose
Satura1on of presystemic elimina1on at increasing substrate
concentra1ons
May cause toxic blood levels
Nitrates, nifedipine, fentanyl, theophylline, paclitaxel, lithium
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Objec,ve of any drug treatment

To yield blood levels within therapeu1c window
To maintain these levels for the period during which a
therapeu1c eect is desired
Cmax should not exceed MTC
Administra1on frequency should remain reasonable
Not > 2-3 1mes daily

Dosage form and formula1on play a key role

Control of the pharmacokine1c prole
 | 107

Eect of dierent formula,ons

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Blood concentra,on versus eect

Within therapeu1c window
Low blood concentra1on low ecacy
Increasing blood concentra1on increased ecacy
Change in bioavailability change in ecacy
Maximum therapeu1c eect below MTC: safety
Steep curve = fast eect
Narrow therapeu1c window

Response to drug
Response to drug

Therapeutic effect

Therapeutic effect

Adverse effect
Adverse effect

1 10 100 1 10 100

Concentration of drug in blood Concentration of drug in blood

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Individual varia,ons
Varia1on in drug absorp1on varia1on in drug sensi1vity
Increased / decreased bioavailability due to interac1on
Drug metabolism, food, herbal drugs
Response to drug

Response to drug
Patient B
Therapeutic effect

Patient A

Adverse effect

Concentration of Concentration of
1 10 100 drug in blood 1 10 100 drug in blood
Drug concentration Drug concentration Drug concentration Drug concentration
before interaction after interaction after interaction before interaction

Therapeu1c eect the same Pa1ent B: eect aNer interac1on reduced

Adverse eects occur aNer interac1on Pa1ent A: no eect of interac1on
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Bioequivalence
Product X and Y contain same ac1ve substance
Bioavailabili1es (rate, extent) within certain limits
Same dose
Same route
Similar in safety and ecacy
Studies on physicochemical and pharmacokine1c proper1es
Reference to BSC
Class I: biowaiver
More complex: studies to be carried out
- PK: Cmax, AUC
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Subs,tu,on of A by generic B
Bioequivalence
Narrow therapeu1c window
Small varia1ons in product (performance) may give signicant
uctua1ons in safety and eect
- Tacrolimus, digoxine, levothyroxine, phenytoin

Allergy, intolerance for specic excipient

Specic administra1on devices, performance characteris1cs
Dry powder inhalers, auto-injectors
Appearance of product
Confusion (pa1ent)
Biologicals (biopharmaceu1cals): biosimilars
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Advanced drug delivery systems

Current novel developments in this eld propelled by
Increased applica1on of biologicals, nanomedicines, etc.
- Biopharmaceu1cally dierent
- Intrinsic toxicicity when distributed over en1re body (site-specic delivery)
The drive to improve ease and comfort of drug administra1on
- Subs1tute for parenteral administra1on

Common denominator: change pharmacokine1c behaviour of API

they contain (ADME)
Advanced drug delivery systems should be considered as new
medicines
Many concepts, few reach the market
Physical, chemical, biological and mechanical
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Final remarks (1)

Each route of administra1on makes specic demands on the
drug administra1on form and its formula1on

Biopharmacy and pharmacotherapy can only be op1mal if

the formula1on and the produc1on process are suited for the
chosen route of administra1on and for the drug substance

Locally administered drugs may exert a systemic eect

A proper formula1on will reduce this
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Final remarks (2)

A pharmaceu1cal dosage must comply to
Chosen route of administra1on
Physicochemical proper1es of the drug substance
Start and dura1on of the therapeu1c eect
Pharmacokine1c and pharmacodynamic proper1es of the drug

Advanced drug delivery forms change pharmacokine1c

proper1es of the API