Pharmacokinetics Samenvatting
- ADME (Absorption, Distribution, Metabolism and Excretion)
- Therapeutic window/effectiveness
- Various administration routes
- IV dosing
- Extravascular dosing
- Constant rare input (infusion)
- Multiple dosing
- 1- and 2- compartment kinetics
- Plasma concentration-time profiles
Pharmacokinetics aim —> Right drug, right patient, right dose and right time
Pharmacokinetic/Pharmacology
essential knowledge of pharmacists that complements that of physicians to optimize the treatment
of patients
physicians know more about the patient and the pharmacists know more about the drug.
SOWISO —> extra points!
December 8, 2020 14:00-17:00 !!
January 18, 2021 —> Exam
Basic considerations
Chapter 1: Therapeutic Relevance
Chapter 2: Fundamental Concepts and Terminology
Preclinical phase animal studies are performed of the drug development.
Stomach is not an excretion organ. Lung, Liver and Skin are excretion organs.
Enteral administration of drugs is via the Gastrointestinal tract. Enteral —> Via gastrointestinal
tract. Parental —> Not via gastrointestinal tract.
Platelets are components present in blood but not in plasma.
Pharmacokinetics especially deals with concentration.
Albumin is the most common plasma protein that can bind drugs.
12.5% of the dose remain in the blood after 3 half-lives.
Drugs with a narrow therapeutic window there is high chance of toxicities
Intra-arterial administration is associated with the highest plasma concentrations.
Occupation (bezigheid) is the least common source of variability in the pharmacokinetics of drugs.
The routing of a drug in case of enterohepatic circulation is plasma - liver - intestine - liver -plasma.
Enterohepatic cycle & First pass effect
24-11-20 | 27
Enterohepatic cycle and First past effect
Fig 2-10
Fig2-9
Pagina 1 van 68
, Administration routes
11/24/20 | 28
Administration routes Pharmacokinetics -> concentration-time curve
11/24/20 | 29
Quantitation of the concentration of a drug (and its metabolites)
in the body in time
• Absorption
• Distribution
• Elimination
Pharmacokinetics -> Concentration-time curve
Pharmacokinetics
Quantitation -> adequate
of the effectof a drug (and its
concentration
metabolites) in the body in time… in order to assess a
11/24/20 | 30
proper dose regimen to achieve adequate therapeutic
Quantitation of the concentration of a drug (and its metabolites)
responses
in the body in time … in order to assess a proper dose regimen
to achieve adequate therapeutic responses
Fig 2.1
Dose regimen —> Plasma concentration —>
Concentration in bio phase —> Effect
—> the development of appropriate models to
plasma concentration
dose regimen
concentration in biophase
effect describe observations and predict outcomes in
other situations
Pharmacokinetics -> adequate effect?
-> the development of appropriate models to describe 11/24/20 | 32
Compartment
observations and predict models
outcomesand equations
in other situations
therapeutic
Pharmacokinetics -> adequate effect (Therapeutic window) window
(Ch 9)
—> Concentration of drug
Fig 1-5
[plasma] [effect compartment]
Therapeutic window
Variability in Drug response —> Variabilities in patients
Gender, race, body size, renal/Hepatic function, Gastric pH, Drug-drug interactions, Environmental
factors, Type/degree/concomitant disease. Drug metabolism polymorphisms, Medication
compliance
Basic considerations
Chapter 1: Therapeutic Relevance
Chapter 2: Fundamental Concepts and Terminology
Learning objectives chapter 1 and 2:
- Define the terms: adherence, therapeutic window, bioavailability, clinical response,
compartment, absorption, disposition, distribution, elimination, excretion, enterohepatic cycling,
first pass loss, metabolism/metabolites prodrugs.
- Define and give examples of various drug administration routes including parental, enteral, local,
intravascular, extravascular and systemic.
- Explain how Pharmacokinetics and Pharmacodynamics are related to drug responses
- Explain why plasma drug concentration can serve as a useful correlate of response.
- Explain how variability (pharmacokinetics-related causes) and adherence influence drug
responses.
- Be familiar with type of pharmacokinetics studies performed in the various (pre)clinical drug
development phases
Pagina 2 van 68
, Pharmacology: Pharmacokinetics (PK) + Pharmacodynamics (PD)
Pharmacokinetics: What is the body doing to the drug
PK & DrugPharmacodynamics:
Development What is the drug doing to the body
9/4/20 | 5
Pharmacokinetics in Pharmacy practice
- Community Pharmacy
- Hospital Pharmacy
- Drug Development
Pharmacokinetics and Drug Development
Pharmacokinetics
Preclinical (several years) —> Phase 1 (months) —> Phase 2
(months to years) —> Phase 3 (years to decades) —> Phase 9/4/20 | 7
4 (ongoing) › PK: study of the fate of a drug in
Fig 1-11
the body in time
The Ultimate goal of pharmacokinetics:
Having the right drug for the right patient at the right ›time
Various
andprocesses (‘ADME’):
in the right dose.
Absorption – How will it get in?
Treat the patient with the best possibilities.
Distribution – Where will it go?
Pharmacokinetics: Study of the fate of a drug in the body in time.
Elimination – How does it leave the
- Various processes (‘ADME’): body?
Absorption - How will it get in? • Excretion & Metabolism
Distribution - Where will it g0?
Elimination - How does it leave the body? PK: ADME
- Excretion and Metabolism 9/4/
Distribution is how the drug divide itself over the body.
Disposition is the distribution and the elimination together
Elimination is the process of Metabolism and Excretion
Excretion is only the process how the drug leaves the body
! Distribution vs Disposition Fig 2
! Elimination vs Excretion
Absorption: Various administration routes and dosage forms.
Administration routes (terminology)
Intravascular = Directly into the blood (Intravenous injection/infusion or intra-arterially)
Extravascular = Need absorption
Parenteral = Drug that is not administered via the gastro-intestinal tract (Intravenous/
intra-arterial, intramuscular, sub-/intracutaneous, pulmonary, intranasal,
intra-/transdermal and inhalation)
Enteral = Drug that is administered via the gastro-intestinal tract (oral, rectal,
sublingual and buccal)
Local/Regional = Skin, mucosa, cerebrospinal fluid, pleural or peritoneal cavity
(cutaneous/nasal/vaginal/ocular)
Systemic = Via the blood stream not directly to the specific place.
ADME Distribution
04-09-20 | 15 Some drugs are only present in the blood stream and other
drugs have a more broad distribution. Distribution is related
Fig 2-4 to Effects, Adverse effects, Toxic effects (toxicokinetics) and
Accumulation (ophoping).
Enterohepatic cycle means a cycling of drugs between the
enter (gut and intestine, gut wall and gut lumen) and the liver.
The drug is not excreted but it is somehow turning back and
it can be taken up by the circulation again.
Pagina 3 van 68
, Enterohepatic cycle & First pass effect
24-11-20 | 27
Enterohepatic cycle and First past effect
Enterohepatic —> Left image
First pass effect —> Right image
First pass effect belongs to absorption of drugs and the
bioavailability of drugs.
Elimination
Enterohepatic is a recirculation of the drug. Fig2-9
Fig 2-10
9/4/20 | 16
Drugs can be excrete via different organs.Excretion & Metabolism
For example the kidneys, the parent drug and/or metabolite
liver by feces, the skin by sweating etc. - Main organs: kidneys and liver
-> Metabolites: compounds formed
Elimination
from the drug usually by enzymatic
Excretion and Metabolism (Mainly by the liver)
reactions
- Metabolites: compounds formed from drug (cytochroom
usually P450
by enzymatic
Plasma concentration-time curve ~ administration route
reactions (cytochroom P450 enzymes) enzymes)
- Inactive and active metabolites
- Implication for PharmacoKinetics -> Inactive and active metabolites! 04-09-20 | 20
->Implication for PK
Pharmacokinetics
Quantitation of the concentration of a drug and its metabolites in the
body in time
- Plasma concentration-time curve Fig 2.5
www.msdmanuals.nl
These curves can give all kind of information with regard to absorption,
skin distribution and elimination. More information in chapter 3 and 5
blood blood blood blood blood
Drug concentration in the body - in time
Sampling sites —> To test concentration
1 by intravenous2blood taking, Feces
Arm 3 4 excretion.
excretion, Urine 5
Plasma concentration-time curve - administration route
The first curve is typically for an administration route that needs absorption. First there is an
increase in concentration to a certain max (Tmax) and than there is a decrease.
The second curve is typically for an administration route when a drug is injected immediately into
the blood stream. There is high concentration at T0 and than there is a decrease
The third curve is typically for an infusion for a prolonged time or a difficult device which releases
the drug.
The curve is steadily increasing until it reaches a steady concentration.
Plasma concentration-time curves are very helpful.
Dose regimen —> Pasma concentration —> Concentration in biophase —> Effect
Quantitation of the concentration of a drug and its metabolites in the body in time …in order to
asses a proper dose regimen to achieve adequate therapeutic responses.
Pagina 4 van 68
- ADME (Absorption, Distribution, Metabolism and Excretion)
- Therapeutic window/effectiveness
- Various administration routes
- IV dosing
- Extravascular dosing
- Constant rare input (infusion)
- Multiple dosing
- 1- and 2- compartment kinetics
- Plasma concentration-time profiles
Pharmacokinetics aim —> Right drug, right patient, right dose and right time
Pharmacokinetic/Pharmacology
essential knowledge of pharmacists that complements that of physicians to optimize the treatment
of patients
physicians know more about the patient and the pharmacists know more about the drug.
SOWISO —> extra points!
December 8, 2020 14:00-17:00 !!
January 18, 2021 —> Exam
Basic considerations
Chapter 1: Therapeutic Relevance
Chapter 2: Fundamental Concepts and Terminology
Preclinical phase animal studies are performed of the drug development.
Stomach is not an excretion organ. Lung, Liver and Skin are excretion organs.
Enteral administration of drugs is via the Gastrointestinal tract. Enteral —> Via gastrointestinal
tract. Parental —> Not via gastrointestinal tract.
Platelets are components present in blood but not in plasma.
Pharmacokinetics especially deals with concentration.
Albumin is the most common plasma protein that can bind drugs.
12.5% of the dose remain in the blood after 3 half-lives.
Drugs with a narrow therapeutic window there is high chance of toxicities
Intra-arterial administration is associated with the highest plasma concentrations.
Occupation (bezigheid) is the least common source of variability in the pharmacokinetics of drugs.
The routing of a drug in case of enterohepatic circulation is plasma - liver - intestine - liver -plasma.
Enterohepatic cycle & First pass effect
24-11-20 | 27
Enterohepatic cycle and First past effect
Fig 2-10
Fig2-9
Pagina 1 van 68
, Administration routes
11/24/20 | 28
Administration routes Pharmacokinetics -> concentration-time curve
11/24/20 | 29
Quantitation of the concentration of a drug (and its metabolites)
in the body in time
• Absorption
• Distribution
• Elimination
Pharmacokinetics -> Concentration-time curve
Pharmacokinetics
Quantitation -> adequate
of the effectof a drug (and its
concentration
metabolites) in the body in time… in order to assess a
11/24/20 | 30
proper dose regimen to achieve adequate therapeutic
Quantitation of the concentration of a drug (and its metabolites)
responses
in the body in time … in order to assess a proper dose regimen
to achieve adequate therapeutic responses
Fig 2.1
Dose regimen —> Plasma concentration —>
Concentration in bio phase —> Effect
—> the development of appropriate models to
plasma concentration
dose regimen
concentration in biophase
effect describe observations and predict outcomes in
other situations
Pharmacokinetics -> adequate effect?
-> the development of appropriate models to describe 11/24/20 | 32
Compartment
observations and predict models
outcomesand equations
in other situations
therapeutic
Pharmacokinetics -> adequate effect (Therapeutic window) window
(Ch 9)
—> Concentration of drug
Fig 1-5
[plasma] [effect compartment]
Therapeutic window
Variability in Drug response —> Variabilities in patients
Gender, race, body size, renal/Hepatic function, Gastric pH, Drug-drug interactions, Environmental
factors, Type/degree/concomitant disease. Drug metabolism polymorphisms, Medication
compliance
Basic considerations
Chapter 1: Therapeutic Relevance
Chapter 2: Fundamental Concepts and Terminology
Learning objectives chapter 1 and 2:
- Define the terms: adherence, therapeutic window, bioavailability, clinical response,
compartment, absorption, disposition, distribution, elimination, excretion, enterohepatic cycling,
first pass loss, metabolism/metabolites prodrugs.
- Define and give examples of various drug administration routes including parental, enteral, local,
intravascular, extravascular and systemic.
- Explain how Pharmacokinetics and Pharmacodynamics are related to drug responses
- Explain why plasma drug concentration can serve as a useful correlate of response.
- Explain how variability (pharmacokinetics-related causes) and adherence influence drug
responses.
- Be familiar with type of pharmacokinetics studies performed in the various (pre)clinical drug
development phases
Pagina 2 van 68
, Pharmacology: Pharmacokinetics (PK) + Pharmacodynamics (PD)
Pharmacokinetics: What is the body doing to the drug
PK & DrugPharmacodynamics:
Development What is the drug doing to the body
9/4/20 | 5
Pharmacokinetics in Pharmacy practice
- Community Pharmacy
- Hospital Pharmacy
- Drug Development
Pharmacokinetics and Drug Development
Pharmacokinetics
Preclinical (several years) —> Phase 1 (months) —> Phase 2
(months to years) —> Phase 3 (years to decades) —> Phase 9/4/20 | 7
4 (ongoing) › PK: study of the fate of a drug in
Fig 1-11
the body in time
The Ultimate goal of pharmacokinetics:
Having the right drug for the right patient at the right ›time
Various
andprocesses (‘ADME’):
in the right dose.
Absorption – How will it get in?
Treat the patient with the best possibilities.
Distribution – Where will it go?
Pharmacokinetics: Study of the fate of a drug in the body in time.
Elimination – How does it leave the
- Various processes (‘ADME’): body?
Absorption - How will it get in? • Excretion & Metabolism
Distribution - Where will it g0?
Elimination - How does it leave the body? PK: ADME
- Excretion and Metabolism 9/4/
Distribution is how the drug divide itself over the body.
Disposition is the distribution and the elimination together
Elimination is the process of Metabolism and Excretion
Excretion is only the process how the drug leaves the body
! Distribution vs Disposition Fig 2
! Elimination vs Excretion
Absorption: Various administration routes and dosage forms.
Administration routes (terminology)
Intravascular = Directly into the blood (Intravenous injection/infusion or intra-arterially)
Extravascular = Need absorption
Parenteral = Drug that is not administered via the gastro-intestinal tract (Intravenous/
intra-arterial, intramuscular, sub-/intracutaneous, pulmonary, intranasal,
intra-/transdermal and inhalation)
Enteral = Drug that is administered via the gastro-intestinal tract (oral, rectal,
sublingual and buccal)
Local/Regional = Skin, mucosa, cerebrospinal fluid, pleural or peritoneal cavity
(cutaneous/nasal/vaginal/ocular)
Systemic = Via the blood stream not directly to the specific place.
ADME Distribution
04-09-20 | 15 Some drugs are only present in the blood stream and other
drugs have a more broad distribution. Distribution is related
Fig 2-4 to Effects, Adverse effects, Toxic effects (toxicokinetics) and
Accumulation (ophoping).
Enterohepatic cycle means a cycling of drugs between the
enter (gut and intestine, gut wall and gut lumen) and the liver.
The drug is not excreted but it is somehow turning back and
it can be taken up by the circulation again.
Pagina 3 van 68
, Enterohepatic cycle & First pass effect
24-11-20 | 27
Enterohepatic cycle and First past effect
Enterohepatic —> Left image
First pass effect —> Right image
First pass effect belongs to absorption of drugs and the
bioavailability of drugs.
Elimination
Enterohepatic is a recirculation of the drug. Fig2-9
Fig 2-10
9/4/20 | 16
Drugs can be excrete via different organs.Excretion & Metabolism
For example the kidneys, the parent drug and/or metabolite
liver by feces, the skin by sweating etc. - Main organs: kidneys and liver
-> Metabolites: compounds formed
Elimination
from the drug usually by enzymatic
Excretion and Metabolism (Mainly by the liver)
reactions
- Metabolites: compounds formed from drug (cytochroom
usually P450
by enzymatic
Plasma concentration-time curve ~ administration route
reactions (cytochroom P450 enzymes) enzymes)
- Inactive and active metabolites
- Implication for PharmacoKinetics -> Inactive and active metabolites! 04-09-20 | 20
->Implication for PK
Pharmacokinetics
Quantitation of the concentration of a drug and its metabolites in the
body in time
- Plasma concentration-time curve Fig 2.5
www.msdmanuals.nl
These curves can give all kind of information with regard to absorption,
skin distribution and elimination. More information in chapter 3 and 5
blood blood blood blood blood
Drug concentration in the body - in time
Sampling sites —> To test concentration
1 by intravenous2blood taking, Feces
Arm 3 4 excretion.
excretion, Urine 5
Plasma concentration-time curve - administration route
The first curve is typically for an administration route that needs absorption. First there is an
increase in concentration to a certain max (Tmax) and than there is a decrease.
The second curve is typically for an administration route when a drug is injected immediately into
the blood stream. There is high concentration at T0 and than there is a decrease
The third curve is typically for an infusion for a prolonged time or a difficult device which releases
the drug.
The curve is steadily increasing until it reaches a steady concentration.
Plasma concentration-time curves are very helpful.
Dose regimen —> Pasma concentration —> Concentration in biophase —> Effect
Quantitation of the concentration of a drug and its metabolites in the body in time …in order to
asses a proper dose regimen to achieve adequate therapeutic responses.
Pagina 4 van 68
