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…

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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