Dose-effect

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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)

THE END