VM 8314 Dr. Jeff Wilcke Pharmacokinetic Modeling (describing what happens)
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Transcript of VM 8314 Dr. Jeff Wilcke Pharmacokinetic Modeling (describing what happens)
VM 8314
Dr. Jeff Wilcke
Pharmacokinetic ModelingPharmacokinetic Modeling
(describing(describing what happens) what happens)
VM 8314
Dr. Jeff Wilcke
AKA “Apparent volume of distribution”The volume of fluid that appears to contain
the amount of drug in the bodyMay not be actual physiologic space(s)
Relates amount to plasma concentration
The volume that must be processed by organs of elimination
Volume of distributionVolume of distribution
VM 8314
Dr. Jeff Wilcke
Volume of distributionVolume of distributionEquations
Experimentally: Vz = Dose / Cp0
Intellectually: Vz = Amount in the body / Cpt
UnitsLiters or milliliters (whole animal or
human beings)Liters/kg or milliliters/kg (typical vet
med)
VM 8314
Dr. Jeff Wilcke
Volume of distributionVolume of distribution1) Give IV Bolus2) Take samples over time3) Cp0 is Y axis interecept4) You know the dose
Vz = Dose / Cp0
VM 8314
Dr. Jeff Wilcke
Volume of DistributionVolume of DistributionScenario Physiologic Space Vz
Drug distributed only to plasma water
Blood volume = 7% of body weightPlasma water = 55% of blood volume
0.0385 liters/kg
Drug distributed evenly in ECF only
Extracellular fluid volume = 25% of body weight
0.25 liters/kg
Drug distributed evenly ECF and ICF only.
Intracellular fluid volume = 40% of body weight
0.65 liters/kg
ICF concentration = 3 x’s ECF
Extracellular fluid volume + 3x intracellular fluid volume
1.45 liters/kg
VM 8314
Dr. Jeff Wilcke
Volume of distributionVolume of distribution
Much like row 2 or 3 of table Much like row 4 of table
VM 8314
Dr. Jeff Wilcke
ClearanceClearanceThe volume of plasma water cleared of
drug during a specified period of time
VM 8314
Dr. Jeff Wilcke
ClearanceClearanceOrgan 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
VM 8314
Dr. Jeff Wilcke
ClearanceClearanceI 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).
VM 8314
Dr. Jeff Wilcke
So in one minute…So in one minute…
200 µg/ml (1 ml)
100 µg/ml(1 ml)
0% cleared from 0.5 ml.
100 % cleared from
0.5 ml. Clearance is 0.5 ml/min
Passes through liver in
1 minute
VM 8314
Dr. Jeff Wilcke
ClearanceClearanceUnits
Volume / unit time (l/hr, l/min, ml/min, etc.)Whole animals or human beings
Volume / kilogram / unit timeAnimals
VM 8314
Dr. Jeff Wilcke
Rate constant of elimination Rate constant of elimination ((λλz)z)The fraction of the volume of
distribution cleared per unit time.The slope of the natural log plot of
drug concentration verus time profile.
VM 8314
Dr. Jeff Wilcke
Clearing the tank…Clearing the tank…
VM 8314
Dr. Jeff Wilcke
Clearing the tankClearing the tank
Concentration vs time points represent concentrations determined for samples taken from the tank.
VM 8314
Dr. Jeff Wilcke
Elimination half-lifeElimination half-lifeThe 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…)
VM 8314
Dr. Jeff Wilcke
Elimination half lifeElimination half lifeUtility
Tissue ResiduesAt 5 x T1/2 (after you stop dosing) 97%
has been eliminated.Make sure you use the longest half-lifeMetabolites MAY be more important than the drugAbsorption may have the longest half-life.
VM 8314
Dr. Jeff Wilcke
Elimination half-lifeElimination half-lifeUtility
Approach to “Steady state”Drugs with long half-lifes “accumulate” during
repeated administrationA 5 x T1/2 concentrations reach 97% of steady stateDigoxin – maximum effects 8 days after therapy
starts
Need for loading doseA 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).
VM 8314
Dr. Jeff Wilcke
Steady stateSteady state
VM 8314
Dr. Jeff Wilcke
Absorption rate constant Absorption rate constant (ka)(ka)Fractional rate at which drug
moves from the place the dose was put INTO the circulatory system.
UnitsTime (hours, minutes, seconds…)
ApplicationCombined with elimination rate,
determines time to reach peak concentration (C max)
VM 8314
Dr. Jeff Wilcke
Fraction of dose Fraction of dose absorbedabsorbedOther than IV, it is rare that the
ENTIRE dose is actually absorbedOral
Destroyed, eliminated unchanged
IMHydrolyzed in tissue, bound to tissues, stuck
in abscess
UnitsPercentage or decimal (80% = 0.8)
VM 8314
Dr. Jeff Wilcke
Fraction of dose Fraction of dose absorbedabsorbedBioavailability
Two oral dose forms of the same drug. F of the “open triangle” dose form is ½ the “filled triangle” dose form.
VM 8314
Dr. Jeff Wilcke
Fraction of dose aborbedFraction of dose aborbedBioavailability and
Bioequivalence
Equal bioavailability (same F) and Bioequivalent
Equal bioavailability (same F) and not Bioequivalent