Personalized healthcare
Variations in genetic and environmental factors can cause differences in drug response
The right drug, dose, timing for the right patient
Biomarkers as “GPS”
- Give indications about health, disease, and drug response
- Provide a molecular impression of a biological system
Drug development pipeline
1. Target discovery What is the drug target? (e.g. receptors)
2. Lead discovery Which compound modulates the target?
3. Lead optimization Optimizing efficacy of the molecule/drug
4. Exploratory Development Making the drug safe and available
5. Phase I-II-III Performing patient studies (prove of concept)
6. Introducing drug to market
You need the right Target, Tissue, Safety, Patients, and Commercial Potential
Crucial aspects of the drug Does the compound….
- Exposure …get to site of action?
- Mechanism …cause its intended effects?
- Efficacy …have beneficial effect on disease/clinical pathophysiology?
- Safety …have a safe therapeutic window?
- Responders How do sources of variability in target population affect
response?
Pharmacology
How a chemical interacts with an organism. The dose defines whether a substance is a poison
Pharmacotherapy
- Rational Mechanism based (What mechanisms does it affect?
How does it enter the target?)
- Evidence-based It doesn’t matter how it works, as long as it is effective
Pharmacological phases in pharmacotherapy
- Exposition phase Behaviour of the substance in the environment
- Toxicokinetic phase How the human responds to the drug (A-D-M-E)
- Toxicodynamic phase How, after processing/distribution, the drug interacts with
receptors/other (macro)molecules (proteins, DNA) at the
site of operation
Classification of pharmacological effects
- Agonist Turns on a receptor continuously, leading to an active
signalling transduction pathway
- Antagonist Inhibits the receptor, causing no effect when binding.
Natural substrates of the receptor are also blocked.
Drugs can interact with various types of receptors
- Ligand-gated ion channel Stimulating/blocking the channel in millisecond time frame
- G-protein coupled receptor Still very fast, but includes activation of second messengers
- Kinase-linked receptor Can be located on both plasma membrane as intracellular
Affect protein phosphorylation triggering gene transcription
- Nuclear receptor Inhibit/stimulate gene transcription
,Drug binds to Effect
- Receptor Agonist/antagonist
- Ion channel Blocker/modulator
- Enzyme Inhibitor/false substrate/pro-drug
- Transporter Normal transport, inhibitor, or false substrate
All four lead to an inhibition of the endogenous substrate
Structures of a drug
- Covalent Form strong bond between chemical structure of the drug
and AA residues
- Ionic Between negatively charged residues of AA with positively
charged part of drug or vice versa
- Hydrogen bond
- Hydrophobic interactions Stacking of aromatic rings
- Van der Waals not observed much
Characterization of inhibition of transport
- Increasing the intensity makes saturation of occupancy visible. By this, you see how much of
the receptor is occupied by a drug
- Get an S-curve by using the log-scale
- Infliction point of the curve is the Ka
o Ka = concentration at which half of the receptors are occupied (EC50)
- Can also “measure” occupation by observing changes in phenotype
o E.g. By increasing morphine dose, more and more mice rise their tails
o EC50 is the dose at which 50% of the max. response is reached. So when 50% of the
mice have lifted their tails.
- Shows how potent a drug is in obtaining a certain effect. Indicating the dose for therapeutic/
adverse effects.
Antagonists
- Can be divided into two classes
o Partial antagonists
Inhibits the response/signal
o Ful
o l antagonists
Completely inhibits the effect
- Can be competitive or non-competitive
o Competitive
Competes with the natural substrate. You need marching and increasing
concentration of the antagonist
o Non-competitive
Is not related to the dose. You can already inhibit the receptor at low concentrations
Inverse receptor agonism
- Inhibit signalling by the receptor. But you need a protein/receptor with constitutive activity
which is quite exceptional as not a lot of proteins are always on.
, Dose effects
Pharmacokinetics What does the patient do with the drug?
Plasma concentration of a drug is the parameter
Important for determining the loading dose and dosing interval of drugs
Important for adjusting the dosing and dosing interval to patient-specific
conditions
ADME Absorption
First pass effect
The ability of a drug to be taken up and its metabolism in the liver
determines how much of the unchanged drug end up in the systemic
circulation. Can determine which route is most effective for drug
application (biological availability)
F=AUCoral/AUCiv
F= biological availability
AUC= Area Under the Curve; Comparing the Area Under th Curve of
oral exposure to the one from intravenous exposure shows which
administration route is most optimal for a certain drug
Distribution
Determines how much of the drug will be dissolved into plasma instead
of ending up in fat tissue. Binding of the drug to proteins (often albumin)
also affects the Volume of distribution. This decreases the plasma
concentration as the drug is not available for instant release at target
Vd=F*D/C0
Vd= volume of distribution; depends on
F = Oral biovailability
D= Dose
C0= initial concentration
Metabolism
Drug can be metabolized in the liver, either preventing it from being
present in active state or it can be metabolized resulting in it
pharmacologically active substance.
Elimination
Elimination of the drug is an exponential process
T1/2= (ln(2)* Vd)/CL
T1/2= the half-life time; Has a natural log. Effect depending on the Volume of
distribution (Vd) and the clearance (CL).
Most drugs follow first-order kinetics. By decreasing concentrations, you get
decreased elimination speed (So decreased clearance)
Zero-order kinetics always work at the same metabolic clearance rate
because of the breakdown in the liver which remains constant.
Steady state
When drugs are dosed repeatedly, the concentration of a drug depends on the dosing
interval. Plasma concentration occurs when the drug is given, and decreases. You would not
like the concentration to go back to zero between dozing intervals. You want a steady state.
Css=(F*D)/(Δt*CL)
Solid state concentration (Css) is dependant on the biovailability (F), the dose (D),
The dosing interval (Δt) and the clearance (CL). For most drugs, a solid state is
reached at the Δt which equals 4-5 times the dose
Variations in genetic and environmental factors can cause differences in drug response
The right drug, dose, timing for the right patient
Biomarkers as “GPS”
- Give indications about health, disease, and drug response
- Provide a molecular impression of a biological system
Drug development pipeline
1. Target discovery What is the drug target? (e.g. receptors)
2. Lead discovery Which compound modulates the target?
3. Lead optimization Optimizing efficacy of the molecule/drug
4. Exploratory Development Making the drug safe and available
5. Phase I-II-III Performing patient studies (prove of concept)
6. Introducing drug to market
You need the right Target, Tissue, Safety, Patients, and Commercial Potential
Crucial aspects of the drug Does the compound….
- Exposure …get to site of action?
- Mechanism …cause its intended effects?
- Efficacy …have beneficial effect on disease/clinical pathophysiology?
- Safety …have a safe therapeutic window?
- Responders How do sources of variability in target population affect
response?
Pharmacology
How a chemical interacts with an organism. The dose defines whether a substance is a poison
Pharmacotherapy
- Rational Mechanism based (What mechanisms does it affect?
How does it enter the target?)
- Evidence-based It doesn’t matter how it works, as long as it is effective
Pharmacological phases in pharmacotherapy
- Exposition phase Behaviour of the substance in the environment
- Toxicokinetic phase How the human responds to the drug (A-D-M-E)
- Toxicodynamic phase How, after processing/distribution, the drug interacts with
receptors/other (macro)molecules (proteins, DNA) at the
site of operation
Classification of pharmacological effects
- Agonist Turns on a receptor continuously, leading to an active
signalling transduction pathway
- Antagonist Inhibits the receptor, causing no effect when binding.
Natural substrates of the receptor are also blocked.
Drugs can interact with various types of receptors
- Ligand-gated ion channel Stimulating/blocking the channel in millisecond time frame
- G-protein coupled receptor Still very fast, but includes activation of second messengers
- Kinase-linked receptor Can be located on both plasma membrane as intracellular
Affect protein phosphorylation triggering gene transcription
- Nuclear receptor Inhibit/stimulate gene transcription
,Drug binds to Effect
- Receptor Agonist/antagonist
- Ion channel Blocker/modulator
- Enzyme Inhibitor/false substrate/pro-drug
- Transporter Normal transport, inhibitor, or false substrate
All four lead to an inhibition of the endogenous substrate
Structures of a drug
- Covalent Form strong bond between chemical structure of the drug
and AA residues
- Ionic Between negatively charged residues of AA with positively
charged part of drug or vice versa
- Hydrogen bond
- Hydrophobic interactions Stacking of aromatic rings
- Van der Waals not observed much
Characterization of inhibition of transport
- Increasing the intensity makes saturation of occupancy visible. By this, you see how much of
the receptor is occupied by a drug
- Get an S-curve by using the log-scale
- Infliction point of the curve is the Ka
o Ka = concentration at which half of the receptors are occupied (EC50)
- Can also “measure” occupation by observing changes in phenotype
o E.g. By increasing morphine dose, more and more mice rise their tails
o EC50 is the dose at which 50% of the max. response is reached. So when 50% of the
mice have lifted their tails.
- Shows how potent a drug is in obtaining a certain effect. Indicating the dose for therapeutic/
adverse effects.
Antagonists
- Can be divided into two classes
o Partial antagonists
Inhibits the response/signal
o Ful
o l antagonists
Completely inhibits the effect
- Can be competitive or non-competitive
o Competitive
Competes with the natural substrate. You need marching and increasing
concentration of the antagonist
o Non-competitive
Is not related to the dose. You can already inhibit the receptor at low concentrations
Inverse receptor agonism
- Inhibit signalling by the receptor. But you need a protein/receptor with constitutive activity
which is quite exceptional as not a lot of proteins are always on.
, Dose effects
Pharmacokinetics What does the patient do with the drug?
Plasma concentration of a drug is the parameter
Important for determining the loading dose and dosing interval of drugs
Important for adjusting the dosing and dosing interval to patient-specific
conditions
ADME Absorption
First pass effect
The ability of a drug to be taken up and its metabolism in the liver
determines how much of the unchanged drug end up in the systemic
circulation. Can determine which route is most effective for drug
application (biological availability)
F=AUCoral/AUCiv
F= biological availability
AUC= Area Under the Curve; Comparing the Area Under th Curve of
oral exposure to the one from intravenous exposure shows which
administration route is most optimal for a certain drug
Distribution
Determines how much of the drug will be dissolved into plasma instead
of ending up in fat tissue. Binding of the drug to proteins (often albumin)
also affects the Volume of distribution. This decreases the plasma
concentration as the drug is not available for instant release at target
Vd=F*D/C0
Vd= volume of distribution; depends on
F = Oral biovailability
D= Dose
C0= initial concentration
Metabolism
Drug can be metabolized in the liver, either preventing it from being
present in active state or it can be metabolized resulting in it
pharmacologically active substance.
Elimination
Elimination of the drug is an exponential process
T1/2= (ln(2)* Vd)/CL
T1/2= the half-life time; Has a natural log. Effect depending on the Volume of
distribution (Vd) and the clearance (CL).
Most drugs follow first-order kinetics. By decreasing concentrations, you get
decreased elimination speed (So decreased clearance)
Zero-order kinetics always work at the same metabolic clearance rate
because of the breakdown in the liver which remains constant.
Steady state
When drugs are dosed repeatedly, the concentration of a drug depends on the dosing
interval. Plasma concentration occurs when the drug is given, and decreases. You would not
like the concentration to go back to zero between dozing intervals. You want a steady state.
Css=(F*D)/(Δt*CL)
Solid state concentration (Css) is dependant on the biovailability (F), the dose (D),
The dosing interval (Δt) and the clearance (CL). For most drugs, a solid state is
reached at the Δt which equals 4-5 times the dose
