Pharmacology (7 parts) 1. General Principles 2. Peripheral Nervous Pharmacology 3. Central Nervous Pharmacology 4. Cardiovascular Pharmacology 5. Splanchnic Pharmacology 6. Endocrine Pharmacology 7. Chemotherapeutic Pharmacology
DOSE-EFFECT RELATIONSHIP The intensity and duration of a drug’s effects are a function of the drug dose and drug concentration at the effect site
Endpoints to Monitor Drug Effect Farnesyltransferase Inhibitors for Cancer LEVEL
ENDPOINT
Molecular
Farnesyltransferase inhibition
Cellular
Proliferation rate, apoptosis
Tumor
Response (change in tumor size)
Organism
Survival, quality of life
Dose-Effect Endpoints Graded
• Continuous scale (↑dose → ↑effect) • Measured in a single biologic unit • Relates dose to intensity of effect
Quantal
• All-or-none pharmacologic effect • Population studies • Relates dose to frequency of effect
Erythropoietin and Anemia 25 20
Peak 15 Hematocrit Increment 10 [%] 5 0
0
100
200
300
400
Erythropoietin Dose [units/kg] Eschbach et al. NEJM 316:73-8, 1987
500
Drug-Receptor Interactions Drug
Ligand-binding domain
Drug-Receptor Complex k1
Effector domain
Receptor
k2
Effect Maximal effect • [Drug] Effect = KD + [Drug] (KD = k2/k1)
Dose-Effect Relationship Maximal effect • [Drug] Effect = KD + [Drug] [Drug] Effect = Maximal effect KD + [Drug] Effect = Maximal effect
if [Dose] >> KD
Graded Dose-Effect Curve Maximal effect
100 80
% of Maximal Effect
60 40 20 0
0
200 EC50
400
[Drug]
600
800
Log Dose-Effect Curve 100 80
% of Maximal Effect
60 40 20 EC50
0
1
10
100
[Drug]
1000
Lidocaine Graded Dose-Effect 0 1 2 3 Analog Pain Score 4 5 6 7 0
1
2
3
Lidocaine Blood Level [µg/ml] Ferrante et al. Anesth Analg 82:91-7, 1996
Theophylline Dose-Effect 100 Relaxation
80 60
% Control
PDE Inhibition
40 20 0
1
10
100
Theophylline [µM] Rabe et al. Eur Respir J 8:637-42, 1995
1000
Metformin Dose-Response 3 2.5
80
2 60 1.5 40 1 20
0.5
0
0 500
1000
1500
2000
Dose [mg/d] Garber et al. Am J Med 102:491-7, 1997
2500
Decrease in HbA1c from Placebo [%]
Decrease in FPG from Placebo [mg/dl]
100
Dose-Effect Parameters
POTENCY: The sensitivity of an organ or tissue to the drug EFFICACY: The maximum effect
Comparing Dose-Effect Curves 100 Drug A Drug B
80 60 % of Maximal Effect
Drug C
40 20 0
Effect = 1
10
100
[Drug]
Maximal effect • [Drug] KD + [Drug] 1000
Thiopurine Cytotoxicity 100%
Thioguanine S
80% H H22N N
Cytotoxic Effect
N N
N N
Mercaptopurine
N N H H
N N
60%
S N N
N N N N
40% 20% 0% -9 10
-8
10
-7
10
Thiopurine [M] Adamson et al. Leukemia Res 18:805-10, 1994
-6
10
-5
10
N N H H
Thiopurine Metabolic Activation MP
SH N
SH
N
6
N
N
N
H 22N
N
6
N
N
H
H
PRPP
PRPP
SH
SH N
N
N
N PO 44CH 22
HO
OH
TIMP
SH N
N
HO
N
N
PO 44CH 22
O
TG
HO
N
N
H2 N
OH
TXMP
N
N
PO 44CH 22
O
SH
HO
N
N H 22N
(PO 4 )3 CH 22
O
OH
TGMP
N
N O
R (d)TGTP
HO
Receptor-Mediated Effects 100
Agonist
80 60
% Maximum 40 Effect
Partial agonist
20 Antagonist
0
1
10
100
[Drug]
1000
Drug Interactions 100
Agonist Agonist + competitive antagonist
80
% of 60 Maximal Effect 40
Agonist + non-competitive antagonist
20 0
1
10
100
[Drug]
1000
Graded Dose-Effect Analysis Identify the therapeutic dose/concentration Define site of drug action (receptor) Classify effect produced by drug-receptor interaction (agonist, antagonist) Compare the relative potency and efficacy of drugs that produce the same effect Assess mechanism of drug interactions
Quantal Dose-Effect Distribution 50 ED50
40
# of Subjects
30 20 10 0
1
3
5
7
9
11
Threshold Dose
13
15
Cumulative Dose-Effect Curve 100 80
Cumulative % of Subjects
60 40 20 0
1
3
5
7 9 Dose
11
13
15
Cumulative Dose-Effect Study DOSE LEVEL
NO. OF SUBJECTS
NO.
RESPONDING
% RESPONSE
1 2 3 4 5 6 7 8
10 10 10 10 10 10 10 10
0 1 3 5 7 8 9 10
0 10 30 50 70 80 90 100
Therapeutic and Toxic Effects 100 80
% Responding
Therapeutic Toxic
60 40 20
ED99 ED50
0
TD50
TD1
70 80 90100
200
Dose
300 Indices
Therapeutic Indices Therapeutic Ratio =
Certain Safety Factor =
Standard Safety Margin =
TD50 ED50 TD1 ED99
= 2.5
= 1.3
TD1 - ED99 ED99
X 100 = 31%
Doxorubicin Cardiotoxicity 1.0 0.80
Probability of CHF
0.60 0.40 0.20 0
0
200
400
600
800
Total Doxorubicin Dose [mg/m2] von Hoff et al. Ann Intern Med 91:710-7, 1979
1000
Lidocaine Quantal Dose-Effect 100 ED90 = 490 mg
80
% 60 Achieving Complete Analgesia 40
ED50 = 400 mg
20 0 100
1000
Total Lidocaine Dose (mg) Ferrante et al. Anesth Analg 82:91-7, 1996
Antihypertensive Dose-Effect
DOSE RANGE (MG) DRUG
EARLY STUDIES
Propranolol Atenolol Hydrochlorothiazide Captropril Methyldopa
160-5000 100-2000 50-400 75-1000 500-6000
Johnston Pharmacol Ther 55:53-93, 1992
LOWEST EFFECTIVE PRESENT DOSE DOSE (MG) 160-320 50-100 25-50 50-150 500-3000
80 25 12.5 37.5 750
Antihypertensive Drugs 100
Desirable Dose Range Dose Range most often used
80
% with Maximal Effect
60 40
Adverse Effects
20 0
Log Dose
Dose Intensity in Breast Cancer 100 80
Response Rate (%)
60 40 20 0
0
0.2
0.4
0.6
0.8
Relative Dose Intensity Hryniuk & Bush J Clin Oncol 2:1281, 1984
1 RDI
Relative Dose Intensity
Doxorubicin Dose in Osteosarcoma 100 80 60 % with >90% Necrosis
40 20 0
Smith et al. JNCI 83:1460, 1993
0
0
100
200
5 10 15 Dose Intensity (mg/m2/wk)
20
Relating Dose to Effect In Vivo
Dose
Effect site Concentration
Effect
Pharmacokinetics
Pharmacodynamics
Age Absorption Distribution Elimination Drug interactions
Tissue/organ sensitivity (receptor status)
Oral Mercaptopurine 5
AUC =
4
MP AUC [µM•hr]
3
2
1
0
0
Balis et al. Blood 92:3569-77, 1998
20
40
60
MP Dose (mg/m2)
80
100
Dose • F Clearance
Effect Compartment (PK/PD Model) Peripheral
d X p = k • C • V − k • X 1 2 c 2 1 p d t
k21
k12
d Ck k • X p 0 2 1 = − ( k + k ) • C + 1 0 1 2 d t V V c c
Central
Effect
k0
d C • C • V e k 1 e c = − k • C e 0 e d t V e
k1e
H E • C a x e E (t)= m H H E C C 5 0+ e
k10
ke0
Pharmacodynamic Models Fixed effect model Linear model
Effect = E0 + S•[Drug]
Log-linear model
Effect = I + S•Log([Drug])
Emax model Sigmoid Emax model
Effect =
Emax •[Drug]H EC5H0 + [Drug]H
Sigmoid Emax PD Model Effect (%)
Effect (%) H=5
100
100
H=2 H=1
80
80
H = 0.5
60
60
H = 0.1 40
40
20
20
0
EC50 0
20
40
60
80
100
0
EC50 1
[Drug]
10
100
Theophylline Pharmacodynamics 60 50 40
FEV1 30 (% normal) 20
Emax = 63%
10
EC50 = 10 mg/L
0
0
Mitenko & Ogilvie NEJM 289:600-3, 1973
5
10 15 20 25 Theophylline [mg/L]
30
Carboplatin PK/PD % Decrease Plt
Carboplatin ClTB [ml/min] 140
100
120
90
100 80
80 60
70
40 60 50 40
20 0 45
50
55
60
65
70
Carboplatin AUC [µg•hr/ml] Van Echo et al. Semin Oncol 16:1-6, 1989
75
0
20
40
60
80 100 120 140
Creatinine Clearance [ml/min]
Carboplatin Adaptive Dosing ADULTS
CHILDREN
Concentration and Effect vs. Time Non-Steady State
10
Central Compartment
8
Conc./ Amount
80
Peripheral Compartment
6 4
60
Effect
2
40 20
Effect Compartment
0 0
5
100
10 15 Time
20
0 25
Effect [% of EMAX ]
Hysteresis and Proteresis Loops Intensity of Drug Effect
Intensity of Drug Effect
Hysteresis Loop (Counterclockwise)
4
4
• Equilibration delay in plasma and effect site conc.
3
• Tolerance • Receptor tachyphylaxis
3
• Formation of active metabolite
2
Proteresis Loop (Clockwise)
2
• Receptor up-regulation 1
1
0
0
0
1
2
3
4
0
1
Plasma Drug Concentration
2
3
4
Role of Dose-Effect Studies Drug development • Site of action • Selection of dose and schedule • Potency, efficacy and safety • Drug interactions
Patient management • Therapeutic drug monitoring • Risk-benefit (therapeutic indices)
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