Transcript elimination

Practicals: pharmacokinetics
• Quiz
• Clin. examples and solutions
• Demonstrations in computer programme
Quiz – questions
• 1/ What is a biological half-life of drug ?
• 2/ What is a biological availability (bioavailability)
• 3/ What is a distribution volume?
• 4/ What is TDM? (Non mandatory question)
Quiz – answers, explanations
1/ What is a biological half-life of drug ?
After one half-life the concentration of drug will have fallen to
half the initial concentration; after two half-lives it will have
fallen to one quarter the initial concentration and so on.
2/ What is a biological availability (bioavailability)
Biol. Availability is the fraction of the administered dose of a
drug that reaches the systemic circulation.
(Oral bioavailability can be calculated by comparing the
plasma concentration achieved by giving an i.v. dose with
the plasma concentration over time following administration
of the same dose of a drug given orally. Rate of drug
absorption and first-pass metabolism are main influences on
bioavailability.)
Quiz – answers, explanations
3/ What is a distribution volume?
The volume in which a drug would need to be
uniformly distributed to produce the same
concentration throughout the body as found in plasma.
Arbitrary value useful as a guide when comparing the
relative concentration of the drug in plasma with the
rest of the body and should not be thought of as an
actual physical volume of fluid. Low Vd indicates drug
is mainly distributed in plasma, larger indicates drug
has been distributed to additional compartments.
4/ What is TDM?
Therapeutic drug monitoring (digoxin, gentamicin,
valproate, lithium etc.)
Clinical example:
• A 53 yrs old man has swollen ankles, shortness of breath,
fatigue upon mild exercise.
• He is observed:
- severe pitting edema of lower extremities, distended neck
veins with prominent pulsation
- Sinus tachycardia 105 beats/min. at rest, normal blood
pressure
• Man is diagnosed as being in congestive heart failure
• renal function is relatively normal (clearance of creatinine
115 mL/min)
Clin. Example - continued
• If treatment is begun with digoxin (inotropic
drug) per os with a maintenance dose
0,25mg once daily how long it will take to
achieve a steady state and an adequate
response?
• The biological (elimination) half-life of digoxin
is approx. 36 hours.
a/ approx. 2 hours
b/ approx. 1 day
c/ approx. 2 days
d/ approx. 1 week
Clin. Example - solution
• Summary of dosing regimen with digoxin without
use of loading dose
•
•
•
•
Initial dose 0,25mg
Maintenance dose 0,25mg
Dosing interval: 24 hrs. (once daily)
Biol. half life approx. 36 hrs.
Calculation: steady state concentration wil
be in plasma after time of 4-5 biol. half-lives
4 x 36/ 24 = 6 days
Correct answer in test is:
d/ approx. 1 week
Clin. Example : simulation using programme
PK-SIMS
Digoxine plasma levels without a loading dose
(in the programme PK-SIMS)
Dosing of digoxine with loading dose,
normal renal function (progr. PK-SIMS)
Digoxine plasma levels with a loading dose
normal renal function
digoxine plasma levels with a loading dose in if
renal failure is present (progr. PK-SIM)
Digoxine plasma levels at a reduced loading and
maintenance dose and prolonged dosing interval,
severe renal failure is present
Accumulation: dose, dose interval
and fluctuation of plasma level
Plasma concentrations of drugs
with irregular dosing
Where can be PK data found?
• In SPC = summary of product characteristics
section 5.2 „Pharmacokinetic properties“
5. Pharmacologic properties
5.1 Pharmacodynamic prop.
5.2 Pharmacokinetic prop.
• SPC is available on the EMA (european
medicines agency) web www.ema.europa.eu
or web pages of marketing authorisation holder
Recommended literature
• Rang, Dale, Ritter:
Pharmacology 7ed., 2012
• Mark A. Simmons:
Pharmacology - an illustrated review, 2012
Lecture on pharmacokinetics
M. Kršiak Department of Pharmacology, Third Faculty of Medicine,
Charles University in Prague
1. Fate of drugs in the body
1.1 absorption
1.2 distribution - volume of distribution
1.3 elimination - clearance
2. The half-life and its uses
3. The uses of the half-life
4. Plasma concentration-effect relationship
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION
ABSORBED
DISTRIBUTION
„HIDDEN“
ELIMINATED
ACTING
ELIMINATION
1.1 ABSORPTION
Depends on:
• lipid solubility
• ionization (depends on pH)
non-ionized (non-polar), local changes in the pH
• routes of administration
- per os
- presystemic elimination
FIRST-PASS EFFECT
- pharmaceutical technology
BIOAVAILABILITY, bioequivalence
- parenteral
FIRST-PASS EFFECT:
loss of a drug by a metabolism mostly in the liver that
occurs en route from the gut lumen to the systemic
circulation
e.g. in nitroglycerin, morphine
Clinical consequence of the first-pass effect:
• limited effect after oral administration
• great interindividual differences in dosage
BIOAVAILABILITY:
the proportion of drug that reaches the systemic circulation
It is usually calculated from the AUC
(Area Under the Curve)
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION
ABSORBED
DISTRIBUTION
„HIDDEN“
ELIMINATED
ACTING
ELIMINATION
1.2 DISTRIBUTION
Depends on:
- membrane penetration
- protein binding
-plasma proteins
-tissue proteins
ONLY A FREE DRUG ACTS!
The bound drug is inactive.
Free and bound drug are in equilibrium.
Displacement: drug-drug interactions
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION
ABSORBED
DISTRIBUTION
„HIDDEN“
ELIMINATED
ELIMINATION
ACTING
1.3 ELIMINATION:
METABOLIC (biotransformation)
mostly in the liver
ENZYME INDUCTION/ INHIBITION
oxidase enzymes - cytochrom P450
(CYP2D6 etc)
GENETIC POLYMORPHISM
EXCRETION
kidneys metabolites or unchanged
(almost completely unchanged e.g. digoxin, gentamycin)
GIT... enterohepatic circulation
e.g. tetracyclines
FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
ADMINISTERED
ABSORPTION depends on
- membrane penetration which depends on
ABSORBED
-lipid solubility
DISTRIBUTION depends
on:
- ionization (depends on pH)
„HIDDEN“
- routes of administration
FIRST-PASS EFFECT BIOAVAILABILITY
- membrane penetration
- protein binding
ELIMINATED
ONLY A FREE DRUG ACTS!
ELIMINATION
ACTING
- metabolic
- excretion
VOLUME OF DISTRIBUTION
Depends on:
protein binding
-plasma proteins
-tissue proteins
ONLY A FREE DRUG ACTS!
The bound drug is inactive.
Free and bound drug are in equilibrium.
Displacement: drug-drug interactions
VOLUME OF DISTRIBUTION
Vd = Amount of drug in body / Concentration of drug in plasma
Because the result of the calculation may be a volume greater than that of
the body, it is an APPARENT (imaginary, not actual) volume
For example, Vd of digoxin is about 645 liters for a 70 kg man (i.e. about 9
times bigger than his actual volume)
Clinical importance of volume of distribution:
• When Vd of a drug is big it takes long time to
achieve effective plasma concentration of the drug.
In such cases a loading dose may be given to boost
the amount of drug in the body to the required level.
This is followed by administration of lower
maintenance dose.
METABOLIC (biotransformation)
mostly in the liver
the drug is made more hydrophilic – this increases its
excretion in the urine
EXCRETION
mostly by the kidneys
metabolites or unchanged
GIT... enterohepatic circulation e.g. tetracyclines
CLEARANCE
Clearance (CL) is the volume of
plasma totally cleared of drug in unit
of time (ml/min/kg)
CLtot total
CLR renal
CLH hepatic
CLNR nonrenal (= Cltot - CLR)
Example – analogy
for utilization of information on volume of distribution (Vd) and clearance (CL):
Bathtube in a hotel
with two holes, no plugs,
and a plate indicating Vd= 1000 L, CL = 100 mL/min
How would you regulate supply of water (water tap) to fill the bath in order to
take a bath soon and for a longer time?
the half-life is the time taken for the
plasma concentration to fall by half
[plasmatic half-life]
t½
= 0,69 .
Volume of distribution
Clearance
In most drugs after therapeutic doses:
plasma concentration falls exponentially
Linear kinetics (First order)
The rate of elimination is
proportional to the concentration
[t 1/2 is stable]
In most drugs after therapeutic doses:
plasma concentration falls exponentially because elimination processes
are not saturated
Linear kinetics (First order)
Cmax
[some robustness to
dose increase]
Cmin
Elimination is the bigger the higher is
the level
The rate of elimination is
proportional to the concentration
Elimination processes are saturated e.g. in alcohol, after higher doses of
phenytoin, theophyllin
Non-linear (Zero-order, saturation)
kinetics
The rate of elimination is constant
[unstable t 1/2 ]
For example, in alcohol the
rate of metabolism remains
the same at about 1 g of
alcohol for 10 kg of body
weight per hour
In a few drugs at therapeutic doses or in poisoning, elimination
processes are saturated
Cmax
[low robustness to
dose increase]
Cmin
elimination is constant,
limited
Non-linear (Zero-order, saturation) kinetics
Kinetics
Linear
(First-order)
Non-linear
(saturation,
zero-order)
Half-life
Robustness Predictability
(plasmatic)
to dose
for any
increase
therapeutic
dose
stable
good
good
unstable
poor
poor
T1/2 as a guide to asses:
1/ At a single-dose: duration of drug action
2/ During multiple dosing:
•to asses whether a drug is accumulated in the
body (it is - if the drug is given at intervals shorter
than 1,4 half-lifes) and
•when a steady state is attained (in 4-5 half-lifes)
3/ After cessation of treatment: to asses the time
taken for drug to be eliminated from the body (in 4-5
half-lifes)
[t1/2 = 1 - 2 h]
Ampicillin - single dose
THE USES OF THE HALF-LIFE
T1/2 as a guide to asses:
1/ At a single-dose: duration of drug action
2/ During multiple dosing:
• to asses whether a drug is accumulated in the
body (it is accumulated if the drug is given at
intervals shorter than 1,4 half-lifes) and
• when a steady state is attained (in 4-5 halflifes)
3/ After cessation of treatment: to asses the time
taken for drug to be eliminated from the body (in 4-5
half-lifes)
„PRINCIPLE OF 4-5 HALF-LIFES“:
If a drug is administered in intervals shorter than 1.4 half-life, then a
steady state is attained after approximately 4-5 half-lifes
The time to attain the steady state is independent of dose.
Steady state
t1/2
Why SS is attained after 4-5 half-lifes?
Attainment of steady state (SS) during multiple dosing of drug at intervals of 1
half-life
Interval
Administered
Initial plasma
concentration at
the beginning of
interval
microg/ml
Remains at
the end of
interval
microg/ml
[Eliminated
during
interval
microg/ml]
1.
100 mg
100
50
50
2.
100 mg
150
75
75
3.
100 mg
175
88
88
4.
100 mg
188
94
94
5.
100 mg
194
97
97
THE USES OF THE HALF-LIFE
T1/2 as a guide to asses:
1/ At a single-dose: duration of drug action
2/ During multiple dosing:
•to asses whether a drug is accumulated in the
body (it is - if the drug is given at intervals shorter
than 1,4 half-lifes) and
•when a steady state is attained (in 4-5 half-lifes)
3/ After cessation of treatment: to asses the time
taken for drug to be eliminated from the body (in 4-5
half-lifes)
Elimination of a drug during 5 half-lifes
of initial level
% of total elimination
REPEATED ADMINISTRATION OF DRUGS
TIME TO STEADY STATE (attained after 4-5 half-lifes)
independen of dose
FLUCTUATIONS
• proportional to dose intervals
• blunted by slow absorption
STEADY-STATE LEVELS (CONCENTRATIONS)
proportional to dose
t1/2
Steady-state concentrations are proportional to dose
Linear kinetics - diazepam
toxic
plasma concentrations
daily
therapeutic
daily
daily
Time (days)
Non-linear, saturation kinetics - phenytoin
plasma concentrations
toxic
daily
daily
therapeutic
daily
Time (days)
REPEATED ADMINISTRATION OF DRUGS
TIME TO STEADY STATE (attained after 4-5 half-lifes)
independen of dose
FLUCTUATIONS
• proportional to dose intervals
• blunted by slow absorption
STEADY-STATE LEVELS (CONCENTRATIONS)
proportional to dose
t1/2
How to reduce fluctuations in drug
concentrations?
by administering drugs slowly, continually, e.g.:
infusion,
sustained–release or extended-release (SR or ER) tablets,
slow release from depots
(e.g. from patches transdermally, depot antipsychotics injected i.m.)
or
by administering a total dose (e.g. a daily dose) in parts at shorter intervals
(mostly inconvenient)
Effects of drug
• correlate with plasma concentrations
Therapeutic Drug Monitoring (TDM) (eg. gentamicin, lithium, some
antiepileptics)
• do not correlate with plasma concentrations
- „hit and run“
- tolerance or sensitisation
- active metabolites