Drug Administration Pharmacokinetic Phase (Time course of ADME processes) Absorption Distribution Pharmaceutical Phase Disintegration of the Dosage Form Drug and Drug Dissolution Active Site Metabolism Excretion Accumulation Pharmacodynamic Phase Pharmacological Effects Therapeutic EffectsToxic Effects

I.V. Bolus

Oral administration

Half-life Time for the concentration to decrease by half Clearance Volume of Distribution

SYSTEMIC EXPOSURE PARAMETERS Peak Drug Concentration (C max ) and AREA UNDER THE PLASMA CONCENTRATION TIME CURVE (AUC)

Multiple I.V. Dosing (Bolus) The AUC within a dosing interval at steady state is equal to the total AUC of a single dose.

Oral administration Multiple Dose

CONCEPT The absorption, distribution and elimination of a drug may be qualitatively similar in all individuals. However, for several reasons, the quantitative aspects may differ considerably. Each person must be considered individually and doses adjusted accordingly.

Daily Dose (mg/kg) Plasma Drug Concentration (mg/L) Variability in Pharmacokinetics

Co-variates affecting Drug Disposition Age Gender Genetic Make-Up Dietary Factors Environmental Factors Drug-Drug Interactions Disease State

PHARMACOKINETIC MODELING

Pharmacokinetic models are used to: Predict plasma, tissue and urine drug levels with any dosing regimen Calculate the optimum dosage regimen for each patient individually Estimate the possible accumulation of drugs and/or metabolites Correlate drug concentrations with pharmacologic or toxicologic activity Evaluate differences in the rate or extent of availability between formulations (bioequivalence) Describe how changes in physiology or disease affect the ADME of the drug Explain drug interactions

I. Physiologic Models Arterial blood Venous blood QHQH QMQM QSQS QRQR QKQK QLQL keke Urine kmkm IV injection

I. Physiologic Models Important factors – 1. Organ tissue size 2. Blood flow 3. Drug tissue-blood ratios Can be applied to several species (extrapolation of human data from animal data) Also known as blood flow/perfusion models

II. Compartmental Modeling

1. Catenary Models 13 2 kaka k 12 k 21 k 23 k 32

2. Mammillary Modeling Central P1 P2 P3 P4

One-Compartment Open Model D B 1 Cp 1 Vd I.V. bolus k 10 K 10 = overall elimination rate constant

I.V. Bolus

Two-compartment Open Model Cp 1 VC Dp Dt Ct Vt I.V. bolus k 12 k 21 tissue

Two-compartment model   b a C0C0

Plasma concentration (single dose) 1 -phase: distribution phase z -phase: elimination phase

Two-compartment model

Compartment Modeling - Stochastic Approach storderstochasticsim.html#sim condorderstochasticsim2.html#sim

IV BOLUS Central K12 K21 K10 TWO COMPARTMENT MODEL Blood, Liver Kidney Muscle fatty Cp = Ae - 1t + Be - zt Elimination Peripheral

Blood flow to human tissues TissuePercent Body Weight Percent Cardiac Output Blood Flow (ml/100 g tissue/min) Adrenals Kidney Liver Hepatic Portal Brain Skin Muscle (basal) Connective Tissue Fat

Extravascular dose Dp Cp Vd k 10 kaka Site of absorption e.v. dose

Oral administration

Drugs appear to distribute in the body as if it were a single compartment. The magnitude of the drug’s distribution is given by the apparent volume of distribution (V d ). Vd = Amount of drug in body ÷ Concentration in Plasma PRINCIPLE (Apparent) Volume of Distribution: Volume into which a drug appears to distribute with a concentration equal to its plasma concentration

DrugL/KgL/70 kg Sulfisoxazole Phenytoin Phenobarbital Diazepam Digoxin7490 Examples of apparent Vd’s for some drugs