Measurements EFFECT RELATIONSHIP .


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Observing Dose-Effect. LevelMolecular (e.g, protein inhibition)Cellular (in vitro tissue society, blood cells)Tissue or organ (in vitro or in vivo)OrganismEndpoint used to quantify impact may be distinctive at each levelOverall impact = entirety of different medication impacts and physiological reaction to medication impacts.
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Measurement EFFECT RELATIONSHIP The force and span of a medication\'s belongings are a component of the medication dosage and medication fixation at the impact site Frank M. Balis, M.D. January 25, 2007

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Monitoring Dose-Effect Level Molecular (e.g, protein hindrance) Cellular ( in vitro tissue culture, platelets) Tissue or organ ( in vitro or in vivo ) Organism Endpoint used to quantify impact might be distinctive at each level Overall impact = whole of different medication impacts and physiological reaction to medication impacts

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Dose-Effect Endpoints Graded • Continuous scale ( ­ dosage ® ­ impact) • Measured in a solitary biologic unit • Relates measurements to force of impact Quantal • All-or-none pharmacologic impact • Population ponders • Relates dosage to recurrence of impact

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Erythropoietin and Anemia Peak Hematocrit Increment [%] Erythropoietin Dose [units/kg] Eschbach et al. NEJM 316:73-8, 1987

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Maximal impact • [Drug] Effect = K D + [Drug] Drug-Receptor Interactions Drug-Receptor Complex Ligand-restricting area k 1 Effector space k 2 Receptor Effect (K D = k 2/k 1 )

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[Drug] K D + [Drug] Maximal impact Effect = K D + [Drug] Effect = Maximal impact if [Dose] >> K D Maximal impact • [Drug] Effect = K D + [Drug] Dose-Effect Relationship

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Graded Dose-Effect Curve Maximal impact % of Maximal Effect EC 50 [Drug]

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Log Dose-Effect Curve % of Maximal Effect EC 50 [Drug]

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Lidocaine Graded Dose-Effect Analog Pain Score Lidocaine Blood Level [µg/ml] Ferrante et al. Anesth Analg 82:91-7, 1996

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Theophylline Dose-Effect Relaxation % Control PDE Inhibition Theophylline [µM] Rabe et al. Eur Respir J 8:637-42, 1995

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Metformin Dose-Response Decrease in FPG from Placebo [mg/dl] Decrease in HbA 1c from Placebo [%] Dose [mg/d] Garber et al. Am J Med 102:491-7, 1997

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Dose-Effect Parameters P OTENCY : The affectability of an organ or tissue to the medication E FFICACY : The most extreme impact

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Maximal impact • [Drug] Effect = K D + [Drug] Comparing Dose-Effect Curves Drug A Drug B % of Maximal Effect Drug C [Drug]

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Thiopurine Cytotoxicity Thioguanine Mercaptopurine Cytotoxic Effect Thiopurine [M] Adamson et al. Leukemia Res 18:805-10, 1994

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Receptor-Mediated Effects % Maximum Effect [Drug]

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Drug Interactions Agonist + aggressive rival % of Maximal Effect Agonist + non-focused opponent [Drug]

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Graded Dose-Effect Analysis Identify the helpful measurement/fixation Define site of medication activity (receptor) Classify impact delivered by medication receptor cooperation (agonist, enemy) Compare the relative strength and adequacy of medications that create a similar impact Assess component of medication associations

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Quantal Dose-Effect Distribution ED 50 # of Subjects Threshold Dose

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Cumulative Dose-Effect Curve Cumulative % of Subjects Dose

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Cumulative Dose-Effect Study

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Therapeutic and Toxic Effects Therapeutic Toxic % Responding ED 99 TD 50 TD 1 ED 50 Dose Indices

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Doxorubicin Cardiotoxicity 1.0 0.80 0.60 Probability of CHF 0.40 0.20 0 200 400 600 800 1000 Total Doxorubicin Dose [mg/m 2 ] von Hoff et al. Ann Intern Med 91:710-7, 1979

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ED 90 = 490 mg ED 50 = 400 mg Lidocaine Quantal Dose-Effect % Achieving Complete Analgesia Total Lidocaine Dose (mg) Ferrante et al. Anesth Analg 82:91-7, 1996

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Antihypertensive Dose-Effect Johnston Pharmacol Ther 55:53-93, 1992

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Antihypertensive Drugs Desirable Dose Range Dose Range regularly utilized % with Maximal Effect Adverse Effects Log Dose

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Dose Intensity in Breast Cancer Response Rate (%) Relative Dose Intensity RDI Hryniuk & Bush J Clin Oncol 2:1281, 1984

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Doxorubicin Dose in Osteosarcoma 100 80 60 % with >90% Necrosis 40 20 0 100 200 0 5 10 15 20 Dose Intensity (mg/m 2/wk) Smith et al. JNCI 83:1460, 1993

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Effect site Concentration Pharmacokinetics Pharmacodynamics Relating Dose to Effect In Vivo Dose Effect Age Absorption Distribution Elimination Drug collaborations Tissue/organ affectability (receptor status)

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Effect Compartment (PK/PD Model)

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Concentration and Effect versus Time Non-Steady State Central Compartment Peripheral Compartment Conc./Amount Effect [% of E max ] Effect Compartment Time

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Hysteresis and Proteresis Loops Intensity of Drug Effect Intensity of Drug Effect Hysteresis Loop (Counterclockwise) Proteresis Loop (Clockwise) Equilibration delay in plasma and impact site conc. Arrangement of dynamic metabolite Receptor up-direction Tolerance Receptor tachyphylaxis Plasma Drug Concentration

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Role of Dose-Effect Studies Drug improvement Site of activity Selection of dosage and timetable Potency, adequacy and wellbeing Drug connections Patient administration Therapeutic medication observing Risk-advantage (helpful files)

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THE END

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Endpoints to Monitor Drug Effect Farnesyltransferase Inhibitors for Cancer

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Thiopurine Metabolic Activation

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TD 50 TD 1 ED 50 ED 99 = 1.3 Certain Safety Factor = TD 1 - ED 99 X 100 = 31% Standard Safety Margin = ED 99 Therapeutic Indices Therapeutic Ratio = 2.5

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Relative Dose Intensity

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Dose • F AUC = Clearance Oral Mercaptopurine MP AUC [µM•hr] MP Dose (mg/m 2 ) Balis et al. Blood 92:3569-77, 1998

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E max •[Drug] H Effect = EC 50 + [Drug] H Pharmacodynamic Models Fixed impact display Linear model Log-straight model E max show Sigmoid E max demonstrate Effect = E 0 + S•[Drug] Effect = I + S•Log([Drug])

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Sigmoid E max PD Model Effect (%) Effect (%) H = 5 H = 2 H = 1 H = 0.5 H = 0.1 EC 50 EC 50 [Drug]

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Theophylline Pharmacodynamics FEV 1 (% normal) E max = 63% EC 50 = 10 mg/L Theophylline [mg/L] Mitenko & Ogilvie NEJM 289:600-3, 1973

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Carboplatin PK/PD % Decrease Platelet Carboplatin Cl TB [ml/min] Creatinine Clearance [ml/min] Carboplatin AUC [µg•hr/ml] Van Echo et al. Semin Oncol 16:1-6, 1989

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Carboplatin Adaptive Dosing ADULTS CHILDREN

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