Summary advanced pharmacokinetics
At the end of the course, the student is able to:
1. explain the meaning, relevance and application of pharmacokinetic terms and processes;
2. analyze, interpret and evaluate pharmacokinetic information and apply this into practical advice on dose individualization;
3. predict and evaluate the consequences of various physiological and pathological changes on the pharmacokinetics and therapeutic effects
and to give advice on dose adjustment.
1. explain the meaning, relevance and application of pharmacokinetic terms and processes; “Basics” + nonlinear kinetics; drug interactions;
multi-compartment kinetics; metabolite kinetics; protein binding; relevance in drug development and clinical practice;pharmacokinetics of
biopharmaceuticals
2. analyze, interpret and evaluate pharmacokinetic information and apply this into practical advice on dose individualization; Interindividual
variability, including the effect of genetics, age, weight and gender in pharmacokinetics; therapeutic drug monitoring.
3. predict and evaluate the consequences of various physiological and pathological changes on the pharmacokinetics and therapeutic effects
and to give advice on dose adjustment. Effect of disease, including impaired renal and hepatic function on pharmacokinetics; the relationship
between pharmacokinetics and pharmacodynamics
College 1 revision
Chapter 1-7 and 9-11
Pharmacokinetics – fate of drug in the body
Pharmacodynamics – effect of drug in the body
Aim: to understand the relationship between dose and effect
For safer and more effective treatment of (individual) patient
Therapeutic window
Range of plasma drug concentration where therapeutic effect is adequate and adverse effects
acceptable in a certain number of patients
Below concentration failure of treatment, too high patient has risk to develop toxicity should be
somewhere in the middle.
ADME
Absorption→from site of administration to systemic circulation
Distribution→from systemic circulation to tissue, including target
Metabolism→biotransformation to metabolites
Excretion→from systemic circulation to outside the body (in urine, bile/feces)
The Role of Mathematics in PK
Ultimately we want to give a patient a dose
Qualitative reasoning is important and can suggest direction
Example
A patient is given 10 mg of a drug twice daily when their renal function suddenly decreases. Should their dose be increased or decreased?
(However, see later example where qualitative reasoning is difficult)
Example
A 18-year-old patient weighing 70 kg is started on a dosage regimen of theophylline. What dose should be administered and how often?
Pharmacokinetic Concepts
Volume of distribution, V
Clearance, CL
Elimination rate, k
(Elimination) half-life, t1/2
Bioavailability, F
Absorption rate, ka
Absorption half-life, t1/2,a
Area Under the Curve, AUC
Volume of Distribution
Systemic circulation is central to the ADME description – plasma drug concentration important
Distribution->systemic->tissue. When the drug is in our systemic circulation it can go through our bodies.
1
,Volume of a distribution allows relating
- drug plasma concentration (easily measurable) to
- total amount of drug in body (after absorption)
“Normally”
in pharmacokinetics we instead define an (apparent) volume of distribution, V, to be the volume that gives the
measured concentration
- (Often) not an actual volume
- Can be larger than a full human (e.g., > 10,000 l for quinacrine!)
- Units:
- fundamentally litres or similar
- in practice, sometimes litres/kilogram (i.e., divided by the weight of the patient)
Implies actual volume!! Not physical volume in fact some drugs were Vd is larger than human bodies. E.g. quinacrine.
Bc conc. in blood is low, volume distribution bigg—>SO NOT PHYSICAL VOLUME!!
Body weight *Vd→real Vd
Clearance
Clearance is about the drug leaving the body this can be in different ways e.g. by excretion via the
urine or metabolism.
The rate of elimination tells how much drugs leaves in e.g. minutes or hours.
Can do it with the whole body than you get the total clearance, but it can also be more specific for
one organ e.g. the liver.
Clearance of the liver can be more concrete with this equation. E=extraction ratio is always between 0-1.
0 No drug is cleared in this example the liver
1 All drug is cleared in this example by the liver
Can also be another organ
Elimination Rate Constant
Elimination rate constant very similar to clearance →how much drug is disappeared by unit
time. Concentration instead of amount of the drug in the body.
Concentration is drug plasma what you measure, amount of drug is where it is everywhere after
absorption.
(Elimination) Half-Life
2
,Bioavailability
If you inject a drug straight into the bloodstream->F will be completely 100% however for all other
administration methods there will be always be loss.
If you take a pill some drug will be absorbed in beginning and some for hours later.
Aa is the total amount being absorbed.
First-Pass Loss
Drug must pass through gut wall and liver before reaching systemic circulation proper
Loss due to elimination there is called first-pass loss
Can sometimes demand non-oral administration because loss is almost complete
Bioavailability after oral administration
First pass loss→ due to fact blood network behaves→between blood GI tract→it can first goes to the
liver before it goes to the rest of the body. Liver is the main organ that eliminates drugs. Part of the drug will not end up
in the circulation because it is metabolized in the liver. Keer teken tussen verschillende F’s.
Absorption rate constant
Ka kan je berekenen met de residuals.
Eerst extrapolarte door C(t)=C0*e^-kt
C0 weet je door een lijn te trekken van exponentiele deel
Verschil tussen conc en extrapolaratie->is residual->die vul je in de k formule eerste
deel van de curve→dit geef je weer in nieuwe lijn.
Area under the curve
0-24 hours will always be written
Nothing is said 0 to infinitive
With trapezoidal rule will not calculate to infinity
Infinity we can calculate by a decay curve, AUC 24 to infinity
=C24 h/k (valid when curve is decay)
3
, Drug plasma concentration time curves
Intravenous bolus dose
Intravenous bolus dose→no absorption necessary since it is injected directly in de veins.
Bolus=give all drug in one dose to reach high concentration.
C0= start concentration
Extravascular
Same as in oral administration we need absorption, no simple exponential curve as intravenous
bolus dose.
Drug concentration starts by zero and increases. Where do you get the maximum depends on
the absorption constant and elimination constant at some point later->function becomes
exponential. If you stop taking the drug you get eventually decay exponential.
Don’t learn this equation!!
Continuous infusion
Continous infusion starts by zero and goes up and at some point plateau is reached.
3,3 half lives plateau is reached.
Css is important! R0 infusion rate, Vd doesn’t enter here plateau is independent from the
Vd only on clearance and R0.
How quickly you reach plateau depends on K (K=CL/Vd), Vd has only influence on how long
it takes to reach plateau.
What is happening at the plateau? Not nothing, infused drug in and same amount is excreted via e.g. urine. The concentration of the drug
stays the same. Same in=same out (bankaccount).
R0=CL*Css (ss=steadystate)
R0=k*Ass (also in=out) use it few times also other formula.
Repeated administration
Repeated administration, if you take drug once or two times a day. (So curve
doesn’t start by zero).
Eventually you reach a plateau, not same plateau as given by patient who has
continuous infusion (horizontal plateau)
Same rule to estimate plateau
Tau=how often you take the pill once =24 h, twice 12 h.
In general take injection every 24 h we have some loss, F you also need to add
that so F*dose/tau=CL*Cssav.
→Ass,max is loading dose!!
4
At the end of the course, the student is able to:
1. explain the meaning, relevance and application of pharmacokinetic terms and processes;
2. analyze, interpret and evaluate pharmacokinetic information and apply this into practical advice on dose individualization;
3. predict and evaluate the consequences of various physiological and pathological changes on the pharmacokinetics and therapeutic effects
and to give advice on dose adjustment.
1. explain the meaning, relevance and application of pharmacokinetic terms and processes; “Basics” + nonlinear kinetics; drug interactions;
multi-compartment kinetics; metabolite kinetics; protein binding; relevance in drug development and clinical practice;pharmacokinetics of
biopharmaceuticals
2. analyze, interpret and evaluate pharmacokinetic information and apply this into practical advice on dose individualization; Interindividual
variability, including the effect of genetics, age, weight and gender in pharmacokinetics; therapeutic drug monitoring.
3. predict and evaluate the consequences of various physiological and pathological changes on the pharmacokinetics and therapeutic effects
and to give advice on dose adjustment. Effect of disease, including impaired renal and hepatic function on pharmacokinetics; the relationship
between pharmacokinetics and pharmacodynamics
College 1 revision
Chapter 1-7 and 9-11
Pharmacokinetics – fate of drug in the body
Pharmacodynamics – effect of drug in the body
Aim: to understand the relationship between dose and effect
For safer and more effective treatment of (individual) patient
Therapeutic window
Range of plasma drug concentration where therapeutic effect is adequate and adverse effects
acceptable in a certain number of patients
Below concentration failure of treatment, too high patient has risk to develop toxicity should be
somewhere in the middle.
ADME
Absorption→from site of administration to systemic circulation
Distribution→from systemic circulation to tissue, including target
Metabolism→biotransformation to metabolites
Excretion→from systemic circulation to outside the body (in urine, bile/feces)
The Role of Mathematics in PK
Ultimately we want to give a patient a dose
Qualitative reasoning is important and can suggest direction
Example
A patient is given 10 mg of a drug twice daily when their renal function suddenly decreases. Should their dose be increased or decreased?
(However, see later example where qualitative reasoning is difficult)
Example
A 18-year-old patient weighing 70 kg is started on a dosage regimen of theophylline. What dose should be administered and how often?
Pharmacokinetic Concepts
Volume of distribution, V
Clearance, CL
Elimination rate, k
(Elimination) half-life, t1/2
Bioavailability, F
Absorption rate, ka
Absorption half-life, t1/2,a
Area Under the Curve, AUC
Volume of Distribution
Systemic circulation is central to the ADME description – plasma drug concentration important
Distribution->systemic->tissue. When the drug is in our systemic circulation it can go through our bodies.
1
,Volume of a distribution allows relating
- drug plasma concentration (easily measurable) to
- total amount of drug in body (after absorption)
“Normally”
in pharmacokinetics we instead define an (apparent) volume of distribution, V, to be the volume that gives the
measured concentration
- (Often) not an actual volume
- Can be larger than a full human (e.g., > 10,000 l for quinacrine!)
- Units:
- fundamentally litres or similar
- in practice, sometimes litres/kilogram (i.e., divided by the weight of the patient)
Implies actual volume!! Not physical volume in fact some drugs were Vd is larger than human bodies. E.g. quinacrine.
Bc conc. in blood is low, volume distribution bigg—>SO NOT PHYSICAL VOLUME!!
Body weight *Vd→real Vd
Clearance
Clearance is about the drug leaving the body this can be in different ways e.g. by excretion via the
urine or metabolism.
The rate of elimination tells how much drugs leaves in e.g. minutes or hours.
Can do it with the whole body than you get the total clearance, but it can also be more specific for
one organ e.g. the liver.
Clearance of the liver can be more concrete with this equation. E=extraction ratio is always between 0-1.
0 No drug is cleared in this example the liver
1 All drug is cleared in this example by the liver
Can also be another organ
Elimination Rate Constant
Elimination rate constant very similar to clearance →how much drug is disappeared by unit
time. Concentration instead of amount of the drug in the body.
Concentration is drug plasma what you measure, amount of drug is where it is everywhere after
absorption.
(Elimination) Half-Life
2
,Bioavailability
If you inject a drug straight into the bloodstream->F will be completely 100% however for all other
administration methods there will be always be loss.
If you take a pill some drug will be absorbed in beginning and some for hours later.
Aa is the total amount being absorbed.
First-Pass Loss
Drug must pass through gut wall and liver before reaching systemic circulation proper
Loss due to elimination there is called first-pass loss
Can sometimes demand non-oral administration because loss is almost complete
Bioavailability after oral administration
First pass loss→ due to fact blood network behaves→between blood GI tract→it can first goes to the
liver before it goes to the rest of the body. Liver is the main organ that eliminates drugs. Part of the drug will not end up
in the circulation because it is metabolized in the liver. Keer teken tussen verschillende F’s.
Absorption rate constant
Ka kan je berekenen met de residuals.
Eerst extrapolarte door C(t)=C0*e^-kt
C0 weet je door een lijn te trekken van exponentiele deel
Verschil tussen conc en extrapolaratie->is residual->die vul je in de k formule eerste
deel van de curve→dit geef je weer in nieuwe lijn.
Area under the curve
0-24 hours will always be written
Nothing is said 0 to infinitive
With trapezoidal rule will not calculate to infinity
Infinity we can calculate by a decay curve, AUC 24 to infinity
=C24 h/k (valid when curve is decay)
3
, Drug plasma concentration time curves
Intravenous bolus dose
Intravenous bolus dose→no absorption necessary since it is injected directly in de veins.
Bolus=give all drug in one dose to reach high concentration.
C0= start concentration
Extravascular
Same as in oral administration we need absorption, no simple exponential curve as intravenous
bolus dose.
Drug concentration starts by zero and increases. Where do you get the maximum depends on
the absorption constant and elimination constant at some point later->function becomes
exponential. If you stop taking the drug you get eventually decay exponential.
Don’t learn this equation!!
Continuous infusion
Continous infusion starts by zero and goes up and at some point plateau is reached.
3,3 half lives plateau is reached.
Css is important! R0 infusion rate, Vd doesn’t enter here plateau is independent from the
Vd only on clearance and R0.
How quickly you reach plateau depends on K (K=CL/Vd), Vd has only influence on how long
it takes to reach plateau.
What is happening at the plateau? Not nothing, infused drug in and same amount is excreted via e.g. urine. The concentration of the drug
stays the same. Same in=same out (bankaccount).
R0=CL*Css (ss=steadystate)
R0=k*Ass (also in=out) use it few times also other formula.
Repeated administration
Repeated administration, if you take drug once or two times a day. (So curve
doesn’t start by zero).
Eventually you reach a plateau, not same plateau as given by patient who has
continuous infusion (horizontal plateau)
Same rule to estimate plateau
Tau=how often you take the pill once =24 h, twice 12 h.
In general take injection every 24 h we have some loss, F you also need to add
that so F*dose/tau=CL*Cssav.
→Ass,max is loading dose!!
4
