The General Concepts of Pharmacokinetics and Pharmacodynamics Hartmut Derendorf, PhD University of Florida

PHARMACOKINETICS PHARMACODYNAMICS what the body does to the drug what the drug does to the body

Pharmacokinetics Pharmacodynamics PK/PD conc. vs time Conc. Time 25 0.0 0.4 Pharmacodynamics conc. vs effect 1 10 -4 -3 Conc (log) Effect PK/PD effect vs time Time Effect 1 25

the time course of drug and metabolite concentrations in the body 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 Volume of distribution Clearance Volume of distribution Half-life Protein Binding Bioavailability

Clearance quantifies ELIMINATION is the volume of body fluid cleared per time unit (L/h, mL/min) is usually constant

Clearance Eliminating Organ CL = Q·E Q Blood Flow E Extraction Ratio

Clearance Q Ci Co Eliminating Organ 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

Clearance Total body clearance is the sum of the individual organ clearances CL = CLren + CLhep + CLother

Volume of Distribution Vd = X / Cp - quantifies DISTRIBUTION - 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 C1 V 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 plasma protein binding blood cell binding, diffusion into blood cells, binding to intracellular biological material tissue cell binding, diffusion into tissue cells, binding to extracellular biological material

Microdialysis Interstitium Capillary Cell Perfusate Dialysate

Microdialysis

Bioavailability - quantifies ABSORPTION f is the fraction of the administered dose that reaches the systemic circulation

Bioavailability Rate and Extent of Absorption

Compartment Models Parameters: Rate constants, intercepts Linear and nonlinear regression Complete concentration-time-profiles Steady-state and non-steady-state

Intravenous bolus D k X E One compartment model Dose Drug in the body Drug eliminated

Plasma concentration (single dose) Intravenous bolus Plasma concentration (single dose) D Dose C0 Initial Concentration Vd Volume of Distribution

Intravenous bolus Normal Plot Semilogarithmic Plot

Plasma concentration (multiple dose, steady state) Intravenous bolus Plasma concentration (multiple dose, steady state) Peak Trough

Intravenous bolus Multiple Dose

First-order absorption One compartment model D f k k A a X E Dose Drug at absorption site Drug in the body Drug eliminated

Oral administration Plasma concentration (single dose)

Oral administration

Oral administration Average concentration (multiple dose, steady state)

Oral administration Multiple Dose

Zero-order absorption One compartment model D f R k A X E Dose Drug at absorption site Drug in the body Drug eliminated

Constant rate infusion Plasma concentration (during infusion)

Constant rate infusion

Constant rate infusion Plasma concentration (steady state)

Two-compartment model k Xc 10 E k k 12 21 Xp Dose Xc Drug in the central compartment Xp Drug in the peripheral compartment Drug eliminated

Two-compartment model Plasma concentration (single i.v. bolus dose) -phase: distribution phase -phase: elimination phase

Two-compartment model

Two-compartment model Volume of distribution Xc Xc Xc Xp Xp Xp initially steady state elimination phase

Two-compartment model

Short-term infusion

Three-compartment model Xp d k k 31 13 D k Xc 10 E k k 12 21 Xp s Xc Drug in the central compartment Xps Drug in the shallow peripheral compartment Xpd Drug in the deep peripheral compartment Dose Drug eliminated

Significance of Pharmacokinetic Parameters for Dosing Maintenance Dose Loading Dose Fluctuation Dosing Interval

Drug Delivery Pharmacokinetics Pharmacodynamics Biopharmaceutics PK-PD-Modeling ?