Lecture 5: 9/10
Pharmacokine,cs in drug discovery
Introduc)on
- One of the major reasons of drug a2ri4on
o You will stop for development
- If the compound fails you want to know it fast
o Fail fast, fail cheap
- 50%
o Second one is the lack of efficacy
o On the third place you have toxicology
o Adverse effects in man
o 10% are due adverse effects in the clinical phase
o 5% of the drug failure is because of commercial considera4ons
R&D posi)oning
- PK
o Once you come to your lead finding -> in vitro work
o Once we start with the animal studies you will assess exposure of the animals ->
hopefully these exposures correlate with what you predicted in vitro
- Detailed R&D posi4oning
o Assay to assess certain metabolites
o Assess the absorp4on, distribu4on and excre4ng
o Assess the PK in the clinical situa4on
§ You want to know if you reach the clinical relevant concentra4on
o …
Pharmacokine)cs: some basics
- PK: What is your body doing with the drug?
o Rela4onship between what you take in and the drug concentra4on in the blood/certain
4ssues/milk
§ BreasWeeding: children are exposed to the drug -> for lipophilic compounds it can
be that children are exposed to a higher concentra4on than the mother
o Oral drug -> taken up by the enterocytes -> uptake -> liver -> metabolism -> perifer
blood circula4on -> determining bioavailability
- PD: What is the drug doing with your body?
o Rela4onships between the drug concentra4on-4me profile and therapeu4c and adverse
effects
o What is the drug response? What is the therapeu4cal effect?
Distribu(on
- For some of the compounds depending the target you want that the compound stays in the
circula4on.
o Compound against Altzheimer -> compound should enter the brain
- The VD = volume of distribu4on
o Low VD -> compound will stay in the vessels
o High VD -> will easily disturbed to the issues
, o It is a virtual parameter, it is not real, mathema4cally parameter to determine the other
PK parameters
- Can be influenced with the blood flow
o More perfused vs less perfused
§ More perfused is exposed to more compound
- Protein binding is very important
o Albumin is present in the plasma
o In theory it is only the free drug that has a impact
§ Free drug concentra4on is important -> that’s the one that can interact with the
target
o Compound highly bind to albumin -> not permanent (off and on) => you should be
carefully when you determine your free drug concentra4on
- Ioniza4on will also influence the distribu4on
Elimina(on
- Can be also metabolism of the drug, so also the liver
o Hepa4c clearance, kidney clearance
- Some compound are eliminated by the faeces
- First order process
o Amount of drug eliminated is correlated with serum drug concentra4on
§ Paracetamol -> reach some 4me to reach the steady state concentra4on (to get to
the plasma concentra4on which are stable).
- Kel = elimina4on constant
- The clearance: what will eliminated from the liver/kidney or total
o Kel and Vd will determine this
- Elimina4on half life
o In order to know how much of the drug you need to take in and the frequency
§ Short -> take the drug reglementary
§ Example: 30 min -> drug concentra4on is half of what you have taken in => you
want this as long as possible
§ 4 half lifes => drug will be eliminated for 94%
Steady state
- As successive doses are administered, drug begins to accumulate in the body. With first-order
elimina4on, at a certain point in therapy, the amount of drug administered during a dosing
interval exactly replaces the amount of drug excreted (rate in = rate out).
- When this equilibrium occurs, the peak and trough drug concentra4ons are the same for
each addi4onal dose given
- 4 to 5 half lives to get to the steady state
Pharmacokine,cs in drug discovery
Introduc)on
- One of the major reasons of drug a2ri4on
o You will stop for development
- If the compound fails you want to know it fast
o Fail fast, fail cheap
- 50%
o Second one is the lack of efficacy
o On the third place you have toxicology
o Adverse effects in man
o 10% are due adverse effects in the clinical phase
o 5% of the drug failure is because of commercial considera4ons
R&D posi)oning
- PK
o Once you come to your lead finding -> in vitro work
o Once we start with the animal studies you will assess exposure of the animals ->
hopefully these exposures correlate with what you predicted in vitro
- Detailed R&D posi4oning
o Assay to assess certain metabolites
o Assess the absorp4on, distribu4on and excre4ng
o Assess the PK in the clinical situa4on
§ You want to know if you reach the clinical relevant concentra4on
o …
Pharmacokine)cs: some basics
- PK: What is your body doing with the drug?
o Rela4onship between what you take in and the drug concentra4on in the blood/certain
4ssues/milk
§ BreasWeeding: children are exposed to the drug -> for lipophilic compounds it can
be that children are exposed to a higher concentra4on than the mother
o Oral drug -> taken up by the enterocytes -> uptake -> liver -> metabolism -> perifer
blood circula4on -> determining bioavailability
- PD: What is the drug doing with your body?
o Rela4onships between the drug concentra4on-4me profile and therapeu4c and adverse
effects
o What is the drug response? What is the therapeu4cal effect?
Distribu(on
- For some of the compounds depending the target you want that the compound stays in the
circula4on.
o Compound against Altzheimer -> compound should enter the brain
- The VD = volume of distribu4on
o Low VD -> compound will stay in the vessels
o High VD -> will easily disturbed to the issues
, o It is a virtual parameter, it is not real, mathema4cally parameter to determine the other
PK parameters
- Can be influenced with the blood flow
o More perfused vs less perfused
§ More perfused is exposed to more compound
- Protein binding is very important
o Albumin is present in the plasma
o In theory it is only the free drug that has a impact
§ Free drug concentra4on is important -> that’s the one that can interact with the
target
o Compound highly bind to albumin -> not permanent (off and on) => you should be
carefully when you determine your free drug concentra4on
- Ioniza4on will also influence the distribu4on
Elimina(on
- Can be also metabolism of the drug, so also the liver
o Hepa4c clearance, kidney clearance
- Some compound are eliminated by the faeces
- First order process
o Amount of drug eliminated is correlated with serum drug concentra4on
§ Paracetamol -> reach some 4me to reach the steady state concentra4on (to get to
the plasma concentra4on which are stable).
- Kel = elimina4on constant
- The clearance: what will eliminated from the liver/kidney or total
o Kel and Vd will determine this
- Elimina4on half life
o In order to know how much of the drug you need to take in and the frequency
§ Short -> take the drug reglementary
§ Example: 30 min -> drug concentra4on is half of what you have taken in => you
want this as long as possible
§ 4 half lifes => drug will be eliminated for 94%
Steady state
- As successive doses are administered, drug begins to accumulate in the body. With first-order
elimina4on, at a certain point in therapy, the amount of drug administered during a dosing
interval exactly replaces the amount of drug excreted (rate in = rate out).
- When this equilibrium occurs, the peak and trough drug concentra4ons are the same for
each addi4onal dose given
- 4 to 5 half lives to get to the steady state
