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The General Concepts of Pharmacokinetics and Pharmacodynamics Hartmut Derendorf, PhD University of Florida. PHARMACOKINETICS what the body does to the drug PHARMACODYNAMICS what the drug does to the body. Pharmacokinetics conc. vs time. Pharmacodynamics conc. vs effect. 0.4. 1. Conc.
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The General Concepts of Pharmacokinetics and Pharmacodynamics Hartmut Derendorf, PhD University of Florida
PHARMACOKINETICS what the body does to the drug PHARMACODYNAMICS what the drug does to the body
Pharmacokinetics conc. vs time Pharmacodynamics conc. vs effect 0.4 1 Conc. Effect 0.0 0 25 Time 0 Conc (log) 10 -4 10 -3 PK/PD effect vs time 1 Effect 0 0 25 Time
Pharmacokinetics the time course of drug and metabolite concentrations in the body
Pharmacokinetics helps to optimize drug therapy: dose dosage regimen dosage form
What happens to a drug after its administration ? ("Fate of drug") Liberation Absorption Distribution Metabolism Excretion
Pharmacokinetic Parameters Clearance Volume of distribution Half-life Protein Binding Bioavailability
Clearance • quantifiesELIMINATION • is the volume of body fluid cleared per time unit (L/h, mL/min) • is usually constant
CL = Q·E Q Blood Flow E Extraction Ratio Clearance Eliminating Organ
Q Ci Co Eliminating Organ Clearance Parameters: Blood Flow, intrinsic clearance, protein binding Good prediction of changes in clearance Steady state
High-extraction drugs Low-extraction drugs
Clearance • Clearance can be calculated from • Excretion rate / Concentration e.g. (mg/h) / (mg/L) = L/h • Dose / Area under the curve (AUC) e.g. mg / (mg·h/L) = L/h
Total body clearance is the sum of the individual organ clearances CL = CLren + CLhep + CLother Clearance
Volume of Distribution Vd = X / Cp - quantifiesDISTRIBUTION - relates drug concentration (Cp) to amount of drug in the body (X) - gives information on the amount of drug distributed into the tissues
Apparent Volume of Distribution X X V V C1 C2 C1 > C2 V < Vd C1 = X / V V = X / C1 C2 = X / Vd Vd = X / C2
Volume of Distribution Dicloxacillin 0.1 L/kg Gentamicin (ECF)0.25 L/kg Antipyrine (TBW)0.60 L/kg Ciprofloxacin 1.8 L/kg Azithromycin 31 L/kg
Half-Life Half-life is the time it takes for the concentration to fall to half of its previous value Half-life is a secondary pharmacokinetic parameter and depends on clearance and volume of distribution
Half-Life k elimination rate constant CL clearance Vd volume of distribution
Protein Binding • reversibe vs. irreversible • linear vs. nonlinear • rapid equilibrium The free (unbound)concentration of the drug at the receptor site should be used in PK/PD correlations to make prediction for pharmacological activity
vascular space extravascular space binding to extracellular biological material plasma protein binding blood cell binding, diffusion into blood cells, binding to intracellular biological material tissue cell binding, diffusion into tissue cells, binding to intracellular biological material
Perfusate Dialysate Interstitium Capillary Cell Microdialysis
Bioavailability - quantifies ABSORPTION f is the fraction of the administered dose that reaches the systemic circulation
Compartment Models Parameters: Rate constants, intercepts Linear and nonlinear regression Complete concentration-time-profiles Steady-state and non-steady-state
Intravenous bolus One compartment model D k X E • Dose • Drug in the body • Drug eliminated
Intravenous bolus Plasma concentration (single dose) D Dose C0 Initial Concentration Vd Volume of Distribution
Intravenous bolus Semilogarithmic Plot Normal Plot
Intravenous bolus Plasma concentration (multiple dose, steady state) Trough Peak
Intravenous bolus Multiple Dose
Dose Drug at absorption site Drug in the body Drug eliminated First-order absorption One compartment model D f k k a A X E
Oral administration Plasma concentration (single dose)
Oral administration Average concentration (multiple dose, steady state)
Oral administration Multiple Dose
Dose Drug at absorption site Drug in the body Drug eliminated Zero-order absorption One compartment model D f R k 0 A X E
Constant rate infusion Plasma concentration (during infusion)
Constant rate infusion Plasma concentration (steady state)
Dose Xc Drug in the central compartment Xp Drug in the peripheral compartment Drug eliminated Two-compartment model D k 10 Xc E k k 12 21 Xp
Two-compartment model Plasma concentration (single i.v. bolus dose) -phase: distribution phase -phase: elimination phase
Two-compartment model Volume of distribution Xc Xc Xc Xp Xp Xp initially steady state elimination phase
Xc Drug in the central compartment Xps Drug in the shallow peripheral compartment Xpd Drug in the deep peripheral compartment Three-compartment model Xp d k k 31 13 D k Xc E 10 k k 12 21 Xp s • Dose • Drug eliminated
Significance of Pharmacokinetic Parameters for Dosing Maintenance Dose Loading Dose Fluctuation Dosing Interval
Drug Delivery Pharmacokinetics Pharmacodynamics ? Biopharmaceutics ? PK-PD-Modeling