1. THERAPEUTIC WINDOW Lecture #19

3. Therapeutic Effectiveness ineffective effective minor ADR major ADR Therapeutic Effectiveness = Effective Therapy – Harmful Effects

4. ADR Ineffective

5. Ways to Analyze Effective Therapy with Minimum ADR % Incidence versus Systemic Exposure Weighted Probability versus Systemic Exposure

6. % Incidence

9. Therapeutic Concentration Range 3-12 mg/L % Incidence

10. Weighted Probability -0.4 -0.2 +0.4 How are the probabilities weighted?

11. Weighted Probability 4-14 mg/L

12. Therapeutic Windows Broad Narrow

15. Quantitative Measurements Therapeutic Index (TI) Certain Safety Factor or Safety Ratio Protective Index Optimal Biological Dose (OBD)

16. Therapeutic Index (TI) Sometimes called Therapeutic Ratio (TR) Related to Therapeutic Window Sensitivity of Individual Patient Low Therapeutic Index – Sensitive to Changes in Dose High Therapeutic Index – Insensitive to Changes in Dose

17. Therapeutic Index (TI) Animals Humans

18. Therapeutic Index (TI) DrugTI Remifentanyl33,000 THC (Marijuana)400-1,800 Diazepam100 Caffeine100 Morphine70 Aspirin50 Cocaine15 Ethanol4-10 Digoxin2 Warfarin Low (Requires Therapeutic Drug Monitoring)

19. Certain Safety Factor or Safety Ratio Drugs – Desirable and Undesirable Effects – Psychoactive Drugs  Non-Therapeutic (Recreational)

20. Certain Safety Factor or Safety Ratio

21. DrugCertain Safety Factor or Safety Ratio Marijuana>1000 Psilocybin1000 LSD1000 Nitrous Oxide150 Ephedra140 Caffeine100 Cocaine15 Morphine15 Ethanol10 Heroin (IV)6

22. Protective Index Similar to Animal TI, but lower number More accurate benefit-to-risk ratio Less objectively defined Phenobarbital = 3

23. Optimal Biological Dose (OBD) Vague – Desired Effect ~ Acceptable Toxicity

24. Additional Considerations Multiple Active Species Single Dose Therapy Duration (Chronic) versus Intensity of Exposure (Acute) Time Delays Synergism – Drugs with Ethanol/Grapefruit Juice

25. TI, etc. LD 1 (Normalized, human) = 100 mg/kg LD 50 (Normalized, mouse IV)=100 mg/kg TD 50 (Normalized, mouse IV)=87 mg/kg ED 50 (Normalized)=0.35 mg/kg ED 99 (Normalized)=1.00 mg/kg TD 50 (Normalized, human) =125 mg/kg Average Human Weight = 70 kg Average Mouse Weight = 0.03 kg Ro15-4513