drug administration pharmacokinetic phase (time course of adme processes) absorption distribution...
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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
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I.V. Bolust
p10
pkeCC
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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
)
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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
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SYSTEMIC EXPOSURE PARAMETERSPeak Drug Concentration (Cmax)
and AREA UNDER THE PLASMA CONCENTRATION
TIME CURVE (AUC)
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Multiple I.V. Dosing
(Bolus)
The AUC within a dosing interval at steady state is equal to the total AUC of a single dose.
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Oral administration
Multiple Dose
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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.
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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
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Co-variates affecting Drug Disposition Age Gender Genetic Make-Up Dietary Factors Environmental Factors Drug-Drug Interactions Disease State
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PHARMACOKINETIC MODELING
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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
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I. Physiologic Models
Arterial blood
Venous blood
QH
QM
QS
QR
QK
QL
keUrine
km
IV injection
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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
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II. Compartmental Modeling
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1. Catenary Models
1 32ka
k12
k21
k23
k32
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2. Mammillary Modeling
Central
P1 P2
P3 P4
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One-Compartment Open Model
DB1 Cp1 VdI.V. bolus
k10
K10 = overall elimination rate constant
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I.V. Bolus
tp
10p
keCC
Vd
DpC
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Two-compartment Open Model
Cp1 VC
Dp
Dt Ct Vt
I.V. bolus
k12
k21
tissue
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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
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Two-compartment modelPlasma concentration (single dose)
ttzCCCp 2
11
1-phase: distribution phase
z-phase: elimination phase
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Two-compartment model
0 1 2 3 4 5 6 7 8
Time (hours)
10-1
100
101
102
103
C (ng
/ml)
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Compartment Modeling - Stochastic Approach
http://vam.anest.ufl.edu/simulations/firstorderstochasticsim.html#sim
http://vam.anest.ufl.edu/simulations/secondorderstochasticsim2.html#sim
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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
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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
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Extravascular dose
DpCpVd
k10
kaSite of absorption
e.v. dose
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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
)
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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
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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