PHARMACEUTICAL MEDICINE
1.INTRODUCTION
1.1 DEFINITION:
= medical scientific discipline: discovery, development, evaluation, registration,
monitoring + medical aspects of the marketing of medicines for benefit of patients
+ health of community
Broad domain = scientists, chemists, veternerian, pharamcists, medical doctors,..
Need of laws and guidelines
1.2 DIFFERENT WAVES:
First wave = 1900: Small molecule
Screen large number of compounds
Relatively selective, but depending on the dose higher dose = off target effects
Symptomatic
For ex. Statins
Second wave = 1980: Biologicals
Designed by target: first identified then mAb development less of target
effects
Disease modifying
For ex. PCSK9 inhibitors
Third wave = 2000: genetic medicine
Treats/modulates underlying cause: potentially transformational
Included siRNA, gene therapy, mRNA based medicine
o Goal = endogenous expression or suppression of a protein
(translation/transcription)
Often rare diseases, genetic cause
1.3 DRUG LIFE CYCLE:
1st period = early period: where molecule is discovered + developed investment
Drug discovery: target selection, validation + search for and selection of a NME
Drug development :
o Preclinical- non clinical: in lab, on animals,…
o Clinical: phase 1 (safety) + phase 2 (efficacy) + phase 3 (confirming
safety+efficacy)
2d period = middle period :
Where drugs can be commercialised, sold
Return on the investment, incomes, should be larger then the investment itself
1
,3d period = late phase: pattent stops (market exclusively), decline in incomes, stop
commercialising
THE DRUG DEVELOPMENT PROCESS:
Non clinical to clinical research
Submitting for approval for clinical research
Show that it is safe + beneficial to test in
human
In Europe : CTA = clinical trial
application
o Request in CTIS = platform made
available by the EMA, where
application is submitted
In US : IND = investigational new drugs
Exploratory/early <-> confirmatory/late development
Exploratory = non clinical + phase 1 and 2 clinical research
o Still looking for its potential and value , test safety, if it works
Confirmatory = phase 3
o We are convinced that it has a future: now large trials, confirming what we
have seen in early development = that it is safe + doing what needed to
do
Clinical studies to post approval
Clinical studies done : then enough info to bring drug on market
Submission of new drug application
o Europe : MA(A) = marketing authorisation application
o US : NDA = new drug application
o CTD = common technical document : for risk-benefit balancing
Gives approval that drug can be commercialized
Guidelines: GMP-GLP-GCP = to work properly in agreement with requested min quality
standards
2. DRUG DESIGN + DISCOVERY
2.1 INTRODUCTION
1. Thousand of compounds screened
2. Preclinical pharmacology
3. Preclinical safety
4. Clinical pharamcology + safety
5. Until the product after 11-15years
2
,FIRST THINGS FIRST (MANAGEMENT)
Strategically: is it desirable to do?
Unmet medical need (present vs future): there is no good treatment of therapy
Market analysis: opportunities + risk assessment: Is it the investment worthy?
Scientifically/technically: We have a desired field decided, now can it be done?
Models (cells-animals)?
(Validated) targets? Validated = proven that is plays a role in the disease and
influences the target and can give therapeutic effect (bigger chance on success)
Compounds? Do we have already hits/leads or do we need to start from scratch?
Patents? Do we have the freedom to operate?
First in class = first one on market in that field with certain mode of action
Fast follower =next drug that wants to add value to the same field, same mode of
action
Best in class = therapeutic advance (ex. Efficacy, safety,…)
Me too drug = just another drug in same class with same mode of action added to
market segment and compete with drug already there
Operational: can we do it?
Do we have the staff and expertise?
Do we have the facilities (ex. High biosafety lab) and costs (for the investments)?
Companies stay close to the expertise : need of balance with taking risks and
making sure you can innovate
CLINICAL SITUATION – NON CLINICAL PROXY
Clinical situation = disease = complex + detailed
Models = non clinical proxy = tries to be as similar as possible, but not exactly the
same, some mechanisms are identical some are not
OBJECTIVE DRUG DISCOVERY + DESIGN
= to identify pharmacologically active molecules for which there are clear
indications that
They will reach the pharmacological target in the body in sufficient amount
In such a way that they can exert their desired effect without toxicity
Drug discovery pipeline:
1. High throughput screen : 1000s compounds : hit triage, IC50 determination
3
, 2. Hit to lead: 100s compounds : selectivity assay, in vitro efficacy assay, chemistry
assay
3. Lead optimization: dozens of compounds: in vivo efficacy assay, chemistry
assay
4. Candidate seeking: 1-3compounds: second species, PK/PD modelling, saltform +
crystal form selection
5. Preclinical development: GLP toxicology studies, genetix toxicology, safety
pharmacology, in vivo toxicology in 2 species
6. Clinical : 3phases
Flexible = depending on disease + application you make different decisions about
model, target, assay, … (high throughput screen – hit to lead – lead optimization)
Regulated = when you have reached ultimate
compound, we need to follow the steps required by policies (preclinical – clinical )
Medical chemistry plays a role in the hit to lead – lead optimization – candidate seeking
2.2 BIOLOGY: TARGET BASED OR PHENOTYPIC DISCOVERY
REVIEW 1 : HOW WERE NEW MEDICINES DISCOVERED?
In vitro antiproliferation assay (cells)
Tumor cell lines: intrinsic character = proliferate uncontrollable
Each line put in 96well plate : without compounds after 1 day, much more cells of
same cell type
Now looking for something that inhibits the proliferation
o Some lines on well plate are controls with vehicle in which compound would
be resolved
o Screens: different compounds in different lines of the cells
o After screens we can test different concentrations of that 1 compound
Visualisation: at a dye MTT in each well, when cells are alive they have enzyms
that will reduce MTT to a purple formazan NO PURPLE = NO PROLIFERATION
= COMPOUND WORKS
In vivo antitumoral assay (animal)
Animal model = in vivo : immunodeficient mice (because we want to inject
human tumoral cells, otherwise the immune system would attack these human
cells)
o Control mice = only vehicle is added : we see a growth of the tumor
o Treated mice = tumor volume is significantly smaller then control mice
o Testing body weight if the compound is well tolerated: weight is same : so
well tolerated
But to start with preclicial we need more data than this, it’s a good model but only
1, for preclinical we need more data + safety assessment
Protein tyrosine kinases:
4
1.INTRODUCTION
1.1 DEFINITION:
= medical scientific discipline: discovery, development, evaluation, registration,
monitoring + medical aspects of the marketing of medicines for benefit of patients
+ health of community
Broad domain = scientists, chemists, veternerian, pharamcists, medical doctors,..
Need of laws and guidelines
1.2 DIFFERENT WAVES:
First wave = 1900: Small molecule
Screen large number of compounds
Relatively selective, but depending on the dose higher dose = off target effects
Symptomatic
For ex. Statins
Second wave = 1980: Biologicals
Designed by target: first identified then mAb development less of target
effects
Disease modifying
For ex. PCSK9 inhibitors
Third wave = 2000: genetic medicine
Treats/modulates underlying cause: potentially transformational
Included siRNA, gene therapy, mRNA based medicine
o Goal = endogenous expression or suppression of a protein
(translation/transcription)
Often rare diseases, genetic cause
1.3 DRUG LIFE CYCLE:
1st period = early period: where molecule is discovered + developed investment
Drug discovery: target selection, validation + search for and selection of a NME
Drug development :
o Preclinical- non clinical: in lab, on animals,…
o Clinical: phase 1 (safety) + phase 2 (efficacy) + phase 3 (confirming
safety+efficacy)
2d period = middle period :
Where drugs can be commercialised, sold
Return on the investment, incomes, should be larger then the investment itself
1
,3d period = late phase: pattent stops (market exclusively), decline in incomes, stop
commercialising
THE DRUG DEVELOPMENT PROCESS:
Non clinical to clinical research
Submitting for approval for clinical research
Show that it is safe + beneficial to test in
human
In Europe : CTA = clinical trial
application
o Request in CTIS = platform made
available by the EMA, where
application is submitted
In US : IND = investigational new drugs
Exploratory/early <-> confirmatory/late development
Exploratory = non clinical + phase 1 and 2 clinical research
o Still looking for its potential and value , test safety, if it works
Confirmatory = phase 3
o We are convinced that it has a future: now large trials, confirming what we
have seen in early development = that it is safe + doing what needed to
do
Clinical studies to post approval
Clinical studies done : then enough info to bring drug on market
Submission of new drug application
o Europe : MA(A) = marketing authorisation application
o US : NDA = new drug application
o CTD = common technical document : for risk-benefit balancing
Gives approval that drug can be commercialized
Guidelines: GMP-GLP-GCP = to work properly in agreement with requested min quality
standards
2. DRUG DESIGN + DISCOVERY
2.1 INTRODUCTION
1. Thousand of compounds screened
2. Preclinical pharmacology
3. Preclinical safety
4. Clinical pharamcology + safety
5. Until the product after 11-15years
2
,FIRST THINGS FIRST (MANAGEMENT)
Strategically: is it desirable to do?
Unmet medical need (present vs future): there is no good treatment of therapy
Market analysis: opportunities + risk assessment: Is it the investment worthy?
Scientifically/technically: We have a desired field decided, now can it be done?
Models (cells-animals)?
(Validated) targets? Validated = proven that is plays a role in the disease and
influences the target and can give therapeutic effect (bigger chance on success)
Compounds? Do we have already hits/leads or do we need to start from scratch?
Patents? Do we have the freedom to operate?
First in class = first one on market in that field with certain mode of action
Fast follower =next drug that wants to add value to the same field, same mode of
action
Best in class = therapeutic advance (ex. Efficacy, safety,…)
Me too drug = just another drug in same class with same mode of action added to
market segment and compete with drug already there
Operational: can we do it?
Do we have the staff and expertise?
Do we have the facilities (ex. High biosafety lab) and costs (for the investments)?
Companies stay close to the expertise : need of balance with taking risks and
making sure you can innovate
CLINICAL SITUATION – NON CLINICAL PROXY
Clinical situation = disease = complex + detailed
Models = non clinical proxy = tries to be as similar as possible, but not exactly the
same, some mechanisms are identical some are not
OBJECTIVE DRUG DISCOVERY + DESIGN
= to identify pharmacologically active molecules for which there are clear
indications that
They will reach the pharmacological target in the body in sufficient amount
In such a way that they can exert their desired effect without toxicity
Drug discovery pipeline:
1. High throughput screen : 1000s compounds : hit triage, IC50 determination
3
, 2. Hit to lead: 100s compounds : selectivity assay, in vitro efficacy assay, chemistry
assay
3. Lead optimization: dozens of compounds: in vivo efficacy assay, chemistry
assay
4. Candidate seeking: 1-3compounds: second species, PK/PD modelling, saltform +
crystal form selection
5. Preclinical development: GLP toxicology studies, genetix toxicology, safety
pharmacology, in vivo toxicology in 2 species
6. Clinical : 3phases
Flexible = depending on disease + application you make different decisions about
model, target, assay, … (high throughput screen – hit to lead – lead optimization)
Regulated = when you have reached ultimate
compound, we need to follow the steps required by policies (preclinical – clinical )
Medical chemistry plays a role in the hit to lead – lead optimization – candidate seeking
2.2 BIOLOGY: TARGET BASED OR PHENOTYPIC DISCOVERY
REVIEW 1 : HOW WERE NEW MEDICINES DISCOVERED?
In vitro antiproliferation assay (cells)
Tumor cell lines: intrinsic character = proliferate uncontrollable
Each line put in 96well plate : without compounds after 1 day, much more cells of
same cell type
Now looking for something that inhibits the proliferation
o Some lines on well plate are controls with vehicle in which compound would
be resolved
o Screens: different compounds in different lines of the cells
o After screens we can test different concentrations of that 1 compound
Visualisation: at a dye MTT in each well, when cells are alive they have enzyms
that will reduce MTT to a purple formazan NO PURPLE = NO PROLIFERATION
= COMPOUND WORKS
In vivo antitumoral assay (animal)
Animal model = in vivo : immunodeficient mice (because we want to inject
human tumoral cells, otherwise the immune system would attack these human
cells)
o Control mice = only vehicle is added : we see a growth of the tumor
o Treated mice = tumor volume is significantly smaller then control mice
o Testing body weight if the compound is well tolerated: weight is same : so
well tolerated
But to start with preclicial we need more data than this, it’s a good model but only
1, for preclinical we need more data + safety assessment
Protein tyrosine kinases:
4
