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, 2007Slide 2
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 impactsSlide 3
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 impactSlide 4
Erythropoietin and Anemia Peak Hematocrit Increment [%] Erythropoietin Dose [units/kg] Eschbach et al. NEJM 316:73-8, 1987Slide 5
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 )Slide 6
[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 RelationshipSlide 7
Graded Dose-Effect Curve Maximal impact % of Maximal Effect EC 50 [Drug]Slide 8
Log Dose-Effect Curve % of Maximal Effect EC 50 [Drug]Slide 9
Lidocaine Graded Dose-Effect Analog Pain Score Lidocaine Blood Level [µg/ml] Ferrante et al. Anesth Analg 82:91-7, 1996Slide 10
Theophylline Dose-Effect Relaxation % Control PDE Inhibition Theophylline [µM] Rabe et al. Eur Respir J 8:637-42, 1995Slide 11
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, 1997Slide 12
Dose-Effect Parameters P OTENCY : The affectability of an organ or tissue to the medication E FFICACY : The most extreme impactSlide 13
Maximal impact • [Drug] Effect = K D + [Drug] Comparing Dose-Effect Curves Drug A Drug B % of Maximal Effect Drug C [Drug]Slide 14
Thiopurine Cytotoxicity Thioguanine Mercaptopurine Cytotoxic Effect Thiopurine [M] Adamson et al. Leukemia Res 18:805-10, 1994Slide 15
Receptor-Mediated Effects % Maximum Effect [Drug]Slide 16
Drug Interactions Agonist + aggressive rival % of Maximal Effect Agonist + non-focused opponent [Drug]Slide 17
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 associationsSlide 18
Quantal Dose-Effect Distribution ED 50 # of Subjects Threshold DoseSlide 19
Cumulative Dose-Effect Curve Cumulative % of Subjects DoseSlide 20
Cumulative Dose-Effect StudySlide 21
Therapeutic and Toxic Effects Therapeutic Toxic % Responding ED 99 TD 50 TD 1 ED 50 Dose IndicesSlide 22
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, 1979Slide 23
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, 1996Slide 24
Antihypertensive Dose-Effect Johnston Pharmacol Ther 55:53-93, 1992Slide 25
Antihypertensive Drugs Desirable Dose Range Dose Range regularly utilized % with Maximal Effect Adverse Effects Log DoseSlide 26
Dose Intensity in Breast Cancer Response Rate (%) Relative Dose Intensity RDI Hryniuk & Bush J Clin Oncol 2:1281, 1984Slide 27
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, 1993Slide 28
Effect site Concentration Pharmacokinetics Pharmacodynamics Relating Dose to Effect In Vivo Dose Effect Age Absorption Distribution Elimination Drug collaborations Tissue/organ affectability (receptor status)Slide 29
Effect Compartment (PK/PD Model)Slide 30
Concentration and Effect versus Time Non-Steady State Central Compartment Peripheral Compartment Conc./Amount Effect [% of E max ] Effect Compartment TimeSlide 31
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 ConcentrationSlide 32
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)Slide 33
THE ENDSlide 35
Endpoints to Monitor Drug Effect Farnesyltransferase Inhibitors for CancerSlide 36
Thiopurine Metabolic ActivationSlide 37
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 = 2.5Slide 38
Relative Dose IntensitySlide 39
Dose • F AUC = Clearance Oral Mercaptopurine MP AUC [µM•hr] MP Dose (mg/m 2 ) Balis et al. Blood 92:3569-77, 1998Slide 40
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])Slide 41
Sigmoid E max PD Model Effect (%) Effect (%) H = 5 H = 2 H = 1 H = 0.5 H = 0.1 EC 50 EC 50 [Drug]Slide 42
Theophylline Pharmacodynamics FEV 1 (% normal) E max = 63% EC 50 = 10 mg/L Theophylline [mg/L] Mitenko & Ogilvie NEJM 289:600-3, 1973Slide 43
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, 1989Slide 44
Carboplatin Adaptive Dosing ADULTS CHILDREN
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