Transcript VT PowerPoint Template5

VM 8314
Pharmacokinetic Modeling
(describing what happens)
Dr. Jeff Wilcke
VM 8314
Volume of distribution
 AKA “Apparent volume of distribution”
The volume of fluid that appears to contain the amount
of drug in the body
May not be actual physiologic space(s)
Relates amount to plasma concentration
The volume that must be processed by organs of
elimination
Dr. Jeff Wilcke
VM 8314
Volume of distribution
Equations
Experimentally:
Vz = Dose / Cp0
Intellectually:
Vz = Amount in the body / Cpt
Units
Liters or milliliters (whole animal or human beings)
Liters/kg or milliliters/kg (typical vet med)
Dr. Jeff Wilcke
VM 8314
Volume of distribution
1)
2)
3)
4)
Give IV Bolus
Take samples over time
Cp0 is Y axis interecept
You know the dose
Vz = Dose / Cp0
Dr. Jeff Wilcke
VM 8314
Volume of Distribution
Scenario
Physiologic Space
Drug distributed only to plasma
water
Blood volume = 7% of body weight
Plasma water = 55% of blood volume
Drug distributed evenly in ECF
only
Extracellular fluid volume = 25% of body
weight
Vz
0.0385 liters/kg
0.25 liters/kg
Drug distributed evenly ECF and Intracellular fluid volume = 40% of body weight
ICF only.
0.65 liters/kg
ICF concentration = 3 x’s ECF
1.45 liters/kg
Extracellular fluid volume + 3x intracellular
fluid volume
Dr. Jeff Wilcke
VM 8314
Volume of distribution
Much like row 2 or 3 of table
Much like row 4 of table
Dr. Jeff Wilcke
VM 8314
Clearance
The volume of plasma water cleared of drug
during a specified period of time
Dr. Jeff Wilcke
VM 8314
Clearance
Organ clearance is:
Efficiency X Flow (fraction of drug removed X organ
flow)
Clearance = Q x E
Total clearance is:
The sum of all organ clearances
Cl total=Cl hepatic + Cl renal + Cl pulmonary
Experimentally:
Clearance = Vz x λz
Dr. Jeff Wilcke
VM 8314
Clearance
I know it’s weird but:
At a particular concentration, extracting ½ the drug
from ALL the flow is the same thing as extracting ALL
the drug from ½ the flow
(We “clearance” not “amount removed” because it works
int with the samples we take and the math we can do).
Dr. Jeff Wilcke
VM 8314
So in one minute…
0% cleared from
0.5 ml.
200 µg/ml
(1 ml)
Passes through liver in
1 minute
100 % cleared from
0.5 ml.
100 µg/ml
(1 ml)
Clearance is 0.5 ml/min
Dr. Jeff Wilcke
VM 8314
Clearance
Units
Volume / unit time (l/hr, l/min, ml/min, etc.)
Whole animals or human beings
Volume / kilogram / unit time
Animals
Dr. Jeff Wilcke
VM 8314
Rate constant of elimination (λz)
The fraction of the volume of distribution cleared
per unit time.
The slope of the natural log plot of drug
concentration verus time profile.
Dr. Jeff Wilcke
VM 8314
Clearing the tank…
Dr. Jeff Wilcke
VM 8314
Clearing the tank
Concentration vs time points represent concentrations
determined for samples taken from the tank.
Dr. Jeff Wilcke
VM 8314
Elimination half-life
The time for elimination of one half of the total
amount in the body
Equation:
T1/2 = 0.693/λz (elimination rate constant)
Units:
Time (hours, minutes, seconds…)
Dr. Jeff Wilcke
VM 8314
Elimination half life
Utility
Tissue Residues
At 5 x T1/2 (after you stop dosing) 97% has been
eliminated.
 Make sure you use the longest half-life
 Metabolites MAY be more important than the drug
 Absorption may have the longest half-life.
Dr. Jeff Wilcke
VM 8314
Elimination half-life
Utility
Approach to “Steady state”
Drugs with long half-lifes “accumulate” during repeated
administration
A 5 x T1/2 concentrations reach 97% of steady state
Digoxin – maximum effects 8 days after therapy starts
Need for loading dose
A loading dose is an initial dose given to shorten the time
it takes to reach steady state (“load” the body to steady
state amounts and concentrations).
Dr. Jeff Wilcke
VM 8314
Steady state
Dr. Jeff Wilcke
VM 8314
Absorption rate constant (ka)
Fractional rate at which drug moves from the
place the dose was put INTO the circulatory
system.
Units
Time (hours, minutes, seconds…)
Application
Combined with elimination rate, determines time to
reach peak concentration (C max)
Dr. Jeff Wilcke
VM 8314
Fraction of dose absorbed
Other than IV, it is rare that the ENTIRE dose is
actually absorbed
Oral
Destroyed, eliminated unchanged
IM
Hydrolyzed in tissue, bound to tissues, stuck in abscess
Units
Percentage or decimal (80% = 0.8)
Dr. Jeff Wilcke
VM 8314
Fraction of dose absorbed
Bioavailability
60
50
40
µg/ml
Two oral dose
forms of the same
drug. F of the
“open triangle”
dose form is ½ the
“filled triangle” dose
form.
30
20
10
0
0
1
2
3
4
5
6
Hours
Dr. Jeff Wilcke
7
8
VM 8314
Fraction of dose aborbed
Bioavailability and Bioequivalence
Equal bioavailability (same F)
and Bioequivalent
Equal bioavailability (same F)
and not Bioequivalent
Dr. Jeff Wilcke