PHARMACEUTICAL MEDICINE
INTRODUCTIE
Pharmaceutical medicine = the medical scientific discipline concerned with the discovery, development,
evaluation, registration, monitoring and medical aspects of the marketing of medicines for the benefit of
the patients and the health of the community.
Clinical pharmacology and pharmaceutical medicine are different types of specialties within medicine
that doctors can choose. Pharmaceutical medicine is a rare specialty that is not available in many
countries yet.
PHARMACEUTICAL CLASSES
Within pharmaceutical classes we can speak of waves of medications:
• First wave: small molecules
o Screening of large numbers of compounds on an unique target
o Gives a lot of off-target effects/toxicity because the drugs are designed on high affinity
and not specific for a target. This will give the drug also affinity for other
receptors/binding places.
o Symptomatic treatment
o Statins are an example
• Second wave: biologicals
o Designed by target
▪ More efficient
o Fewer off-target effects
▪ Toxicity rather from binding the target or nature of the biological than off-target
binding
▪ New side effects -> Ab production against biological by our own immune system
o Disease modifying
o PCSK9-inhibitors are an example
• Third wave: genetic medicine
o Treats/modulates the underlying cause -> play into the cause of the disease
▪ Difference in price and efficiency with 1st and 2nd wave
o Examples are siRNA and gene therapy
o Often rare diseases/genetic causes
o Potentially transformational
THE DRUG LIFE CYCLE
The life cycle of a drug can be divided into 3 periods:
• Early stage
o Phase from discovery until launch of the drug onto the market
▪ Typically takes around 10/15 years
o Investing the money in the new drug -> this phase will cost money
▪ Investors/sponsors are needed
▪ Companies try to shorten this period to get a greater return on investment (ROI)
• Middle stage
o Phase of the drug being on the market with probably a patent
, ▪ Earning money – return on investment
▪ The duration of the patent will play a role in how long this phase will last
• Late stage
o The phase were the patent is probably expired and generics are being brought onto the
market -> less interest in the drug
o The drug can be totally replaced with a different drug or this phase can go very slowly and
the drug will stay in small amounts on the market
DRUG DEVELOPMENT PROCESS
This figure shows the drug development process. The exploratory/early development phase of the drug
development process ≠ early phase of the drug life cycle. During this exploratory development the
potential of a molecule is explored. At this moment it is sort of safe and effective. The confirmatory
development will confirm this safety in phase I trials and the efficacy in phase II trials. After this
conformation the company can ask for commercialisation of the drug.
, 1. Non clinical research
o Discovery
o Animal testing / in vitro testing
o Synthesis and formulation -> how can the new product be formulated? (tablet, liquid)
2. IND = investigational new drug
o First step in testing of a new pharmaceutical compound in humans
o Submission at FDA by sponsor of the medicine of the information about the medicine for
testing of safety and efficacy in clinical trials in humans -> medicine will be studied for
the first time in humans
3. Clinical studies
o Can take up to 10 years
o Phase 1: prove the safety of the molecule
o Phase 2: show the efficacy of the molecule
o Phase 3: confirmation of safety and efficacy of the molecule in big studies
4. NDA/BLA
o Ask for permission to bring medicine on the market
5. NME
o Drug that went through all the phases of development and is approved by the FDA to be
on the market
6. Post approval = surveillance after approval and being on the market
o Phase 4: recording of all side effects. Rare side effects will be put on the leaflet
(bijsluiter). Medicine can be called back.
DRUG DESIGN AND DISCOVERY
Before the design and discovery of a new drug begins some questions need to be answered by
management:
• Strategically: is it desirable to do?
o Is there a unmet medical need?
▪ What trials are happening right now related to the drug/disease?
o Market analysis
▪ Are there opportunities?
▪ Make a risk assessment
• Scientifically/technically: can it be done?
o Are there models and/or (validated) targets already available?
o Is there freedom to operate?
▪ Patents, compounds
o Will this be a
▪ First-in-class: the first medicine for a certain target
▪ Fast follower: 2dn/3rd drug that is shortly produced after the first-in-class that
does the same
• = me-too drug
▪ Best-in-class: the drug is better in efficiency/tolerance/toxicity
• Operational: can we do it?
o Is the staff, facilities, money and expertise available?
Mostly drug discovery makes use of non-clinical proxy to create the clinical situation. The optimal clinical
model would be the clone of the patient, but this is not possible. Therefore multiple, thoroughly
researched non-clinical proxy are use to get as close as possible to the clinical situation.
, Objective drug discovery and design = to identify pharmacologically active molecules for which there are
clear indications that they will reach the pharmacological target in the body in sufficient amounts such
that they can exert their desired effect without toxicity.
PHENOTYPIC DRUG DISCOVERY
An empirical, ‘’holistic’’ method based on observable characteristics (read outs) of an organism (cell,
animal).
Advantages:
• Target-agnostic, ‘’target unbiased’’ approach: knowledge of pathomechanistic details
unnecessary
• Increased chance on first-in-class medication
• Also in vivo: indirectly, also ADME tested
o If there is an effect, it is certain that the drug crossed multiple barriers to get to the target
Disadvantages:
• No knowledge of the target -> target identification needs to be done after the hit
• Often ‘’low throughput’’ (in vivo)
In vitro antiproliferation assay (cells)
Testing a compound on a cancer/tumour cell line to see if there is a change in proliferation -> unlimited
proliferation is unique characteristic of the cell line. Makes the cell lines very suitable for anti-proliferation
compounds. With purple dye being activated by mitochondrial enzymes the activity and viability of the
cells can be seen. More purple dye means more mitochondrial activity = cells are alive
In vivo antitumoral assay (animal)
Taking an animal model with the disease and giving them the compound to see the effect of the
compound on the disease.
➔ Inject compound in cancer-induced mice to see the effect of the drug in time on the cancer
• Tumour volume, body weight, tumour weight
➔ Costs will increase due to animal use
TARGET-BASED DRUG DISCOVERY
An rational, ‘’molecular’’ method based on knowledge of pathomechanism. The target and its mechanism
is already known and with this knowledge a compound can be designed specifically for this target.
Fundamental biomedical research (often academic) -> published data -> target
Advantages:
• ‘’High throughput’’ possible
• Monoclonal antibodies-approach possible
• Rational method: intellectually attractive
Disadvantages:
o There needs to be certainty about the target
o Is it relevant in larger context?
In vitro kinase assay (enzyme)
INTRODUCTIE
Pharmaceutical medicine = the medical scientific discipline concerned with the discovery, development,
evaluation, registration, monitoring and medical aspects of the marketing of medicines for the benefit of
the patients and the health of the community.
Clinical pharmacology and pharmaceutical medicine are different types of specialties within medicine
that doctors can choose. Pharmaceutical medicine is a rare specialty that is not available in many
countries yet.
PHARMACEUTICAL CLASSES
Within pharmaceutical classes we can speak of waves of medications:
• First wave: small molecules
o Screening of large numbers of compounds on an unique target
o Gives a lot of off-target effects/toxicity because the drugs are designed on high affinity
and not specific for a target. This will give the drug also affinity for other
receptors/binding places.
o Symptomatic treatment
o Statins are an example
• Second wave: biologicals
o Designed by target
▪ More efficient
o Fewer off-target effects
▪ Toxicity rather from binding the target or nature of the biological than off-target
binding
▪ New side effects -> Ab production against biological by our own immune system
o Disease modifying
o PCSK9-inhibitors are an example
• Third wave: genetic medicine
o Treats/modulates the underlying cause -> play into the cause of the disease
▪ Difference in price and efficiency with 1st and 2nd wave
o Examples are siRNA and gene therapy
o Often rare diseases/genetic causes
o Potentially transformational
THE DRUG LIFE CYCLE
The life cycle of a drug can be divided into 3 periods:
• Early stage
o Phase from discovery until launch of the drug onto the market
▪ Typically takes around 10/15 years
o Investing the money in the new drug -> this phase will cost money
▪ Investors/sponsors are needed
▪ Companies try to shorten this period to get a greater return on investment (ROI)
• Middle stage
o Phase of the drug being on the market with probably a patent
, ▪ Earning money – return on investment
▪ The duration of the patent will play a role in how long this phase will last
• Late stage
o The phase were the patent is probably expired and generics are being brought onto the
market -> less interest in the drug
o The drug can be totally replaced with a different drug or this phase can go very slowly and
the drug will stay in small amounts on the market
DRUG DEVELOPMENT PROCESS
This figure shows the drug development process. The exploratory/early development phase of the drug
development process ≠ early phase of the drug life cycle. During this exploratory development the
potential of a molecule is explored. At this moment it is sort of safe and effective. The confirmatory
development will confirm this safety in phase I trials and the efficacy in phase II trials. After this
conformation the company can ask for commercialisation of the drug.
, 1. Non clinical research
o Discovery
o Animal testing / in vitro testing
o Synthesis and formulation -> how can the new product be formulated? (tablet, liquid)
2. IND = investigational new drug
o First step in testing of a new pharmaceutical compound in humans
o Submission at FDA by sponsor of the medicine of the information about the medicine for
testing of safety and efficacy in clinical trials in humans -> medicine will be studied for
the first time in humans
3. Clinical studies
o Can take up to 10 years
o Phase 1: prove the safety of the molecule
o Phase 2: show the efficacy of the molecule
o Phase 3: confirmation of safety and efficacy of the molecule in big studies
4. NDA/BLA
o Ask for permission to bring medicine on the market
5. NME
o Drug that went through all the phases of development and is approved by the FDA to be
on the market
6. Post approval = surveillance after approval and being on the market
o Phase 4: recording of all side effects. Rare side effects will be put on the leaflet
(bijsluiter). Medicine can be called back.
DRUG DESIGN AND DISCOVERY
Before the design and discovery of a new drug begins some questions need to be answered by
management:
• Strategically: is it desirable to do?
o Is there a unmet medical need?
▪ What trials are happening right now related to the drug/disease?
o Market analysis
▪ Are there opportunities?
▪ Make a risk assessment
• Scientifically/technically: can it be done?
o Are there models and/or (validated) targets already available?
o Is there freedom to operate?
▪ Patents, compounds
o Will this be a
▪ First-in-class: the first medicine for a certain target
▪ Fast follower: 2dn/3rd drug that is shortly produced after the first-in-class that
does the same
• = me-too drug
▪ Best-in-class: the drug is better in efficiency/tolerance/toxicity
• Operational: can we do it?
o Is the staff, facilities, money and expertise available?
Mostly drug discovery makes use of non-clinical proxy to create the clinical situation. The optimal clinical
model would be the clone of the patient, but this is not possible. Therefore multiple, thoroughly
researched non-clinical proxy are use to get as close as possible to the clinical situation.
, Objective drug discovery and design = to identify pharmacologically active molecules for which there are
clear indications that they will reach the pharmacological target in the body in sufficient amounts such
that they can exert their desired effect without toxicity.
PHENOTYPIC DRUG DISCOVERY
An empirical, ‘’holistic’’ method based on observable characteristics (read outs) of an organism (cell,
animal).
Advantages:
• Target-agnostic, ‘’target unbiased’’ approach: knowledge of pathomechanistic details
unnecessary
• Increased chance on first-in-class medication
• Also in vivo: indirectly, also ADME tested
o If there is an effect, it is certain that the drug crossed multiple barriers to get to the target
Disadvantages:
• No knowledge of the target -> target identification needs to be done after the hit
• Often ‘’low throughput’’ (in vivo)
In vitro antiproliferation assay (cells)
Testing a compound on a cancer/tumour cell line to see if there is a change in proliferation -> unlimited
proliferation is unique characteristic of the cell line. Makes the cell lines very suitable for anti-proliferation
compounds. With purple dye being activated by mitochondrial enzymes the activity and viability of the
cells can be seen. More purple dye means more mitochondrial activity = cells are alive
In vivo antitumoral assay (animal)
Taking an animal model with the disease and giving them the compound to see the effect of the
compound on the disease.
➔ Inject compound in cancer-induced mice to see the effect of the drug in time on the cancer
• Tumour volume, body weight, tumour weight
➔ Costs will increase due to animal use
TARGET-BASED DRUG DISCOVERY
An rational, ‘’molecular’’ method based on knowledge of pathomechanism. The target and its mechanism
is already known and with this knowledge a compound can be designed specifically for this target.
Fundamental biomedical research (often academic) -> published data -> target
Advantages:
• ‘’High throughput’’ possible
• Monoclonal antibodies-approach possible
• Rational method: intellectually attractive
Disadvantages:
o There needs to be certainty about the target
o Is it relevant in larger context?
In vitro kinase assay (enzyme)
