Lecture 01/02 Key concepts DMPK

Question 1

What is pharmacokinetics?

Answer 1

Kinetic change of a drug in the body over time

Question 2

Name the four main process in PK

Answer 2

Absorption
Distribution
Metabolism
Elimination

Question 3

Properties of the drug for a save an effective concentration

Answer 3

Good disolution
Good permeation
Metabolic Stability
Effect of drug-drug interactions

Question 4

What H2 receptors antagonist treat?

Answer 4

Gastric acid production

Question 5

Draw the concentration- time porfiles of a drug.

Answer 5

Question 6

Define MTC and MEC concepts using concentration and time profiles.

Answer 6

MTC: Maximun tolerance concentration.
MEC: Minimun effective concentration

Question 7

sketch what you would
expect the PK profile of an
intravenously administered drug to
be like.
What phase of the profile is missing
and why?

Answer 7

Absoption phase is missing-Intravenously administration goes directly to circulation system.

Question 8

sketch what you would
expect the PK profile of intravenously- intramuscular and oral administered.

Answer 8

Question 9

Define Therapeutic index

Answer 9

provided an indication of the relative safety of a drug

Question 10

Which PK parameter are derivated from conc-time porfiles?

Answer 10

Cmax = Peak concentration
tmax = Peak time
AUC = area under the curve exposure over time
t½ = half-life
mrt = mean resident time
Clearance
Volume of distribution
Bioavailability

Question 11

Which PK parameter can be used to determinate, how often the drug is administrate?

Answer 11

Volume of distribution
Clearance
Half life

Question 12

Which PK parameter can be used to determinate, how much of the drug is administrated?

Answer 12

Clearance
Absorption
Bioavailability

Question 13

Main diferences of primary and secondary PK parameters?

Answer 13

Primary PK parameters depend directly on
the physiology of
specie and secondary pk do not but are derived from 1st PK parameters.

Question 14

True or false. Clearance depend directly on physiology specie.

Answer 14

True

Question 15

True or false. Volume of distribution is a secondary pk parameters hence depend directly on physiology specie.

Answer 15

False, Volume of distribution is a primary pk parameters hence depend directly on physiology specie.

Question 16

True or false, Bioavailability is a secondary Pk parameter derivated from volume distribution.

Answer 16

False, Bioavailability is a secondary Pk parameter derivated from clearance and absoption.

Question 17

True or false, Half-life and Area under the curve are secondary Pk parameters.

Answer 17

True

Question 18

What is clearance (CL) ?

Answer 18

The ability of the body to eliminate a drug

Question 19

What volume of distribution (V)?

Answer 19

The hypothetical volume of body fluid that would be required to dissolve the total
amount of drug at the same concentration as that found in the blood

Question 20

what is bioavailability (F)?

Answer 20

The extent (amount) of drug reaching the systemic circulation. From 0 ( no drug absorption) to 1 ( complete drug absorption)

Question 21

what is Half-life (t1/2)?

Answer 21

Time take for a drug concentration to fall by one-half its original values.

Question 22

How is the clearance measure? Provide the units

Answer 22

The total body clearance is the sum of individual organ clearance
CLt= CL(renal)+CL(Hepatic)+CL(others)
CL=Q.E where
Q= Tissue perfusion rate
E= Extraction ratio
E= (ci-co)/ci
ci= concentration drug in
co= Concentration drug out
Units: volume/time -L/min

Question 23

Volume distribution meaning

Answer 23

1. Relates [drug] (C) to amount of drug in the body
2. Measure of the apparent volume/space in the body which contains the
   compound, i.e. gives info on amount distributed into tissues

Question 24

Name the factors of distribution is dependent

Answer 24

– Affinity of drug to blood, tissue and plasma proteins
– Blood flow to the tissue (tissue perfusion)
– Tissue size

Question 25

If we have low perfusion rate and large tissue. Is this consider good or poor tissue distribution?

Answer 25

Poor tissue distribution

Question 26

Answer 26

CA = concentration in arterial blood CV = concentration in venous blood VT = volume of tissue CT = concentration in tissue Q = tissue perfusion rate

Question 27

Where the drug is bound if the volume distribution is high?

Answer 27

Drug is bound in tissues

Question 28

What is bioavailability? Units and range 0-1 meaning

Answer 28

The fraction of a compound that reaches the systemic circulation following extravascular (eg p.o.) administration Ranges from 0 (no drug absorption) to 1 (complete drug absorption)

Question 29

Diferences between bioavalability and Absolute bioavailability

Answer 29

Absolute bioavailability is the the proportion of intact drug reaching the systemic circulation following extravascular administration compared with an intravenous dose and biovalability just extravascular administration.

Question 30

How can you calculate absolute bioavailability ?

Answer 30

Question 31

How can you calculate relative bioavailability ?

Answer 31

Question 32

What is half- life? How can you calculate it?

Answer 32

The time it takes for a compound to decrease to half of its initial concentration in the fluid or tissue in which it is measured in plasma

Question 33

Complete Key parameters and defining relationships.

Answer 33

Question 34

A drug has an elimination rate constant of 0.16h-1 . How long does it take 50% of the drug to be eliminated from the body?

Answer 34

Question 35

Drug X has an AUC of 212mg/L.h after administration a 200mg oral dose. The same drug has a an AUC of 326mg/L.h when a 150mg dose is given via IV bolus. What is its absolute bioavailability.

Answer 35

Question 36

The hepatic extraction ratio of a drug is 0.36, what is its hepatic clearance in L/h if the blood flow to the liver is 30 ml/min/kg in 50 kg individual

Answer 36

Question 37

When or why might people respond differently to the same drug?

Answer 37

People responds diferent because people vary in: People vary in: – Appearance and philosophy – Physiology and biochemistry – Occupations and habits – Genetics – genotype vs. phenotype

Question 38

What are the effects of Higher activity of CYP1A2?

Answer 38

-Leads to increased clearance of drugs metabolized by CYP1A2 – Including the atypical antipsychotics olanzapine and clozapine – Dosage-correction required

Question 39

What are the effects of Higher activity of CYP1A2?

Answer 39

-Leads to increased clearance of drugs metabolized by CYP1A2 – Including the atypical antipsychotics olanzapine and clozapine – Dosage-correction required

Question 40

How is DMPK used?

Answer 40

DMPK analysis is used to assess safety/toxicity potentials of the drugs and for preclinical optimisation of doses in animal studies

Question 41

How is DMPK used during clinical trials?

Answer 41

During clinical trials, DMPK is used for dose adjustment for first-in-human studies and used to propose final dosing schedule for FDA submission and marketing

Question 42

How many phases have clinical trials? Explain each one.

Answer 42

4 Phases 1. Phase I: Healthy Volunteers - evaluate safety of new compound, determine a safe dosage range, and identify side effects 2.Phase II: Pilot study in patient population to evaluate efficacy (and safety) 3.Phase III: Large studies in target patient groups to evaluate efficacy (and safety), and provide info for product insert 4. Phase IV: Trials performed after marketing to gather further information on the drug's safety or efficacy profile.

Question 43

How long it takes to develop a drug? How much it cost?

Answer 43

10-15 y and USD2-3 bn

Question 44

True or false, DMPK contribute to the reduction in drug attrition during the Drug Discovery process

Answer 44

True

Question 45

Give some reason a patient has lack of effect

Answer 45

1. A drug may not get to the site of action 2. A drug can be rapidly (or slowly) metabolized 3. Useful drugs may have no benefit, because doses are too small to establish therapy

Question 46

Give reason for unwanted effects

Answer 46

1.Metabolites may prove toxic 2.Toxic drugs may accumulate 3. Drug may accumulate in certain tissues

Question 47

Give reason for Patient adherence

Answer 47

Dose intervals too long or too brief

Question 48

How you can calculate the Predicted Human Dose ? Give the equation and explain each compound.

Answer 48

Question 49

Name 4 prediction methods for absorption

Answer 49

1. In vitro methods, e.g CaCo-2, PAMPA (determines Papp, then F) 2.In vivo e.g. animal species. Less accurate estimate of humans absorption 3.In silico (computational) models QSAR PBPK models 4. Lipinski’s rule of 5

Question 50

Name 4 prediction methods for distribution

Answer 50

1. In vivo determination (from animal studies) of tissue to plasma partition coefficient Kp, then Vss 2. Tissue composition-based models to determine Kp, then Vss (mathematical models and can be implemented in silico) 3. Interspecie scaling to predict Kp 4. QSAR using molecular descriptors

Question 51

Name 4 prediction methods for Clearance (hepatic, renal or biliary)

Answer 51

1. Interspecie scaling – allometric scaling of CL (hepatic or renal) 2. In vitro – in vivo extrapolation (IVIVE) of clearance (hepatic) 3. Physiologically based approach of clearance (renal or hepatic or biliary) 4. In silico correlate between molecular descriptors and observed CL using statistical method like multiple linear regression, partial least squares (drug screening stage)

Question 52

Explain QSAR method

Answer 52

– use molecular descriptors - Mathematical relationships to correlate chemical structure to biological activity