Lecture 01/02 Key concepts DMPK Flashcards
What is pharmacokinetics?
Kinetic change of a drug in the body over time
Name the four main process in PK
Absorption
Distribution
Metabolism
Elimination
Properties of the drug for a save an effective concentration
Good disolution
Good permeation
Metabolic Stability
Effect of drug-drug interactions
What H2 receptors antagonist treat?
Gastric acid production
Draw the concentration- time porfiles of a drug.
Define MTC and MEC concepts using concentration and time profiles.
MTC: Maximun tolerance concentration.
MEC: Minimun effective concentration
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?
Absoption phase is missing-Intravenously administration goes directly to circulation system.
sketch what you would
expect the PK profile of intravenously- intramuscular and oral administered.
Define Therapeutic index
provided an indication of the relative safety of a drug
Which PK parameter are derivated from conc-time porfiles?
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
Which PK parameter can be used to determinate, how often the drug is administrate?
Volume of distribution
Clearance
Half life
Which PK parameter can be used to determinate, how much of the drug is administrated?
Clearance
Absorption
Bioavailability
Main diferences of primary and secondary PK parameters?
Primary PK parameters depend directly on
the physiology of
specie and secondary pk do not but are derived from 1st PK parameters.
True or false. Clearance depend directly on physiology specie.
True
True or false. Volume of distribution is a secondary pk parameters hence depend directly on physiology specie.
False, Volume of distribution is a primary pk parameters hence depend directly on physiology specie.
True or false, Bioavailability is a secondary Pk parameter derivated from volume distribution.
False, Bioavailability is a secondary Pk parameter derivated from clearance and absoption.
True or false, Half-life and Area under the curve are secondary Pk parameters.
True
What is clearance (CL) ?
The ability of the body to eliminate a drug
What volume of distribution (V)?
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
what is bioavailability (F)?
The extent (amount) of drug reaching the systemic circulation. From 0 ( no drug absorption) to 1 ( complete drug absorption)
what is Half-life (t1/2)?
Time take for a drug concentration to fall by one-half its original values.
How is the clearance measure? Provide the units
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
Volume distribution meaning
- Relates [drug] (C) to amount of drug in the body
- Measure of the apparent volume/space in the body which contains the
compound, i.e. gives info on amount distributed into tissues
Name the factors of distribution is dependent
– Affinity of drug to blood, tissue and plasma proteins
– Blood flow to the tissue (tissue perfusion)
– Tissue size
If we have low perfusion rate and large tissue. Is this consider good or poor tissue distribution?
Poor tissue distribution
CA = concentration in arterial blood
CV = concentration in venous blood
VT = volume of tissue
CT = concentration in tissue
Q = tissue perfusion rate
Where the drug is bound if the volume distribution is high?
Drug is bound in tissues
What is bioavailability? Units and range 0-1 meaning
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)
Diferences between bioavalability and Absolute bioavailability
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.
How can you calculate absolute bioavailability ?
How can you calculate relative bioavailability ?
What is half- life? How can you calculate it?
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
Complete Key parameters and defining relationships.
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?
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.
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
When or why might people respond
differently to the same drug?
People responds diferent because people vary in:
People vary in:
– Appearance and philosophy
– Physiology and biochemistry
– Occupations and habits
– Genetics – genotype vs. phenotype
What are the effects of Higher activity of CYP1A2?
-Leads to increased clearance of drugs
metabolized by CYP1A2
– Including the atypical antipsychotics olanzapine and clozapine
– Dosage-correction required
What are the effects of Higher activity of CYP1A2?
-Leads to increased clearance of drugs
metabolized by CYP1A2
– Including the atypical antipsychotics olanzapine and clozapine
– Dosage-correction required
How is DMPK used?
DMPK analysis is used to assess safety/toxicity potentials of the drugs and for preclinical optimisation of doses in animal studies
How is DMPK used during clinical trials?
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
How many phases have clinical trials? Explain each one.
4 Phases
- 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
- Phase IV: Trials performed after marketing to gather further information on the drug’s safety or efficacy profile.
How long it takes to develop a drug? How much it cost?
10-15 y and USD2-3 bn
True or false, DMPK contribute to the reduction in drug attrition during the Drug Discovery process
True
Give some reason a patient has lack of effect
- A drug may not get to the site of action
- A drug can be rapidly (or slowly) metabolized
- Useful drugs may have no benefit, because doses are too small to establish therapy
Give reason for unwanted effects
1.Metabolites may prove toxic
2.Toxic drugs may accumulate
3. Drug may accumulate in certain tissues
Give reason for Patient adherence
Dose intervals too long or too brief
How you can calculate the Predicted Human Dose ? Give the equation and explain each compound.
Name 4 prediction methods for absorption
- 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 - Lipinski’s rule of 5
Name 4 prediction methods for distribution
- In vivo determination (from animal studies) of tissue to plasma partition coefficient Kp, then Vss
- Tissue composition-based models to determine Kp, then Vss (mathematical models and can be implemented in silico)
- Interspecie scaling to predict Kp
- QSAR using molecular descriptors
Name 4 prediction methods for Clearance (hepatic, renal or biliary)
- Interspecie scaling – allometric scaling of CL (hepatic or renal)
- In vitro – in vivo extrapolation (IVIVE) of clearance (hepatic)
- Physiologically based approach of clearance (renal or hepatic or biliary)
- In silico correlate between molecular descriptors and observed CL using statistical method like multiple linear regression, partial least squares (drug screening stage)
Explain QSAR method
– use molecular descriptors
- Mathematical relationships to correlate chemical structure to biological activity
