Drug Administration Pharmacokinetic Phase (Time course of ADME processes) Absorption Distribution...

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 PhasePharmacological

Effects

Therapeutic Effects Toxic Effects

I.V. Bolust

p10

pkeCC

Oral administration

0

2

4

6

8

10

12

0 4 8 12 16 20 24

Time (hr)

Dru

g C

once

ntra

tion

(ng/

mL

)

Half-life

1010

693.0)2ln(693.02/1 kkCL

Vdt

Time for the concentration to decrease by half

Clearance

VdKAUC

DoseFCL 10

.

Volume of Distribution

Cp

Amount

oC

DoseVd

p

SYSTEMIC EXPOSURE PARAMETERSPeak Drug Concentration (Cmax)

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

CONCEPTCONCEPT

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)

Pla

sma

Dru

gC

once

ntra

tion

(mg/

L)

0 5 10 150

10

20

30

40

50

60

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

QH

QM

QS

QR

QK

QL

keUrine

km

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

1 32ka

k12

k21

k23

k32

2. Mammillary Modeling

Central

P1 P2

P3 P4

One-Compartment Open Model

DB1 Cp1 VdI.V. bolus

k10

K10 = overall elimination rate constant

I.V. Bolus

tp

10p

keCC

Vd

DpC

Two-compartment Open Model

Cp1 VC

Dp

Dt Ct Vt

I.V. bolus

k12

k21

tissue

Two-compartment model

Time (hours)

0 2 4 6 8 10

10-1

100

101

102

103

C (ng

/ml)

0 1 2 3 4 5

Time (hours)

10-1

100

101

102

103

C (ng

/ml)

b

aC0

Two-compartment modelPlasma concentration (single dose)

ttzCCCp 2

11

1-phase: distribution phase

z-phase: elimination phase

Two-compartment model

0 1 2 3 4 5 6 7 8

Time (hours)

10-1

100

101

102

103

C (ng

/ml)

Compartment Modeling - Stochastic Approach

http://vam.anest.ufl.edu/simulations/firstorderstochasticsim.html#sim

http://vam.anest.ufl.edu/simulations/secondorderstochasticsim2.html#sim

IV BOLUS

Central

K12 K21

K10

TWO COMPARTMENT MODELBlood,LiverKidney

Musclefatty

Cp = Ae-1t + Be-zt

0.1

1

10

100

0 5 10 15 20

Time(hr)

LN

Co

nc

Elimination

Peripheral

Blood flow to human tissuesTissue Percent Body

WeightPercent Cardiac

OutputBlood Flow

(ml/100 g tissue/min)

Adrenals 0.02 1 550

Kidney 0.4 24 450

Liver 2.0 25

Hepatic

Portal

5 20

20 75

Brain 2.0 15 55

Skin 7.0 5 5

Muscle (basal)

40.0 15 3

Connective Tissue

7.0 1 1

Fat 15.0 2 1

Extravascular dose

DpCpVd

k10

kaSite of absorption

e.v. dose

Oral administration

0

2

4

6

8

10

12

0 4 8 12 16 20 24

Time (hr)

Dru

g C

once

ntra

tion

(ng/

mL

)

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 (Vd).

Vd = Amount of drug in body ÷ Concentration in Plasma

PRINCIPLEPRINCIPLE

(Apparent) Volume of Distribution:Volume into which a drug appears to distribute with a concentration equal to its plasma concentration

Drug L/Kg L/70 kg

Sulfisoxazole 0.16 11.2

Phenytoin 0.63 44.1

Phenobarbital 0.55 38.5

Diazepam 2.4 168

Digoxin 7 490

Examples of apparent Vd’s for some drugs