1. بسم الله الرّحمن الرّحيم

2. Dr Sima Sadrai TUMS 2015 2

3. Pharmacometrics is (Simple difinitions ) Quantitative “Learning” Approaches that Influence Drug Approval Rutherford said "Science is either stamp collecting or physics". Pharmacometrics provides a bridge between the stamp collecting (observations) and the physics (understanding) of medical science. 3

4. Pharmacometrics Definition Pharmacometrics is the science of interpreting and describing pharmacology, physiology, disease, and patients’ characteristics in a quantitative fashion by integrating and applying mathematical and statistical models to characterize, understand, gain insights into the determinants of efficacy and safety outcomes, predict a drug’s and biomarker-outcome, optimize drug development plans and enable critical decision making 4

5. FDA Definition Perhaps one of the best definitions from the US Food and Drug Administration (FDA) : “Pharmacometrics is an emerging science defined as the science that quantifies drug, disease and trial information to aid efficient drug development and/or regulatory decisions.” 5

6. 6 Disease progression, Dropout, Compliance modeling PK and PK/PD modeling (Conc- Response) Protocol design and Statistical Analysis plan Reporting and Decision analysis Patient selection (Predictors of efficacy & safety and covariates modeling) Simulation scenarios (Alternative trial designs) Pharmacometrics Project

7. Systems Pharmacology  We use the term "systems pharmacology" to define research that aims at understanding  how drugs work :  1. on specific pathways,  2. on different cell types  3. and in different tissues/organs/diseases  what the variability in patient response is  why many treatments fail. 7

8. 8

9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651594/

10. 10 Jamei, Drug Metab. Pharmacokinet, 2009

11. Why Pharmacometrics?  The gain in efficiency (cost to decision) associated with the implementation of a pharmacometrics strategy is measured: 1. by the saving in time necessary to conduct a study, 2. by the ratio between information gathered and the cost of the trial, 3. by the early detection of signal of efficacy or lack of efficacy triggering the decision 4. to terminate the product development and 5. to redirect resources more productively, 6. and finally by the overall time requested for filing new drug applications. 11

12. 12

13. What Is Model-Based Drug Development? A pharmacometric frame work of continuous modeling and simulation during the drug development process and decision making  Modeling: explains observed clinical data and the associated covariates of variability  Simulation: predicts future clinical behaviors and guides strategies to reduce variability 13

14. 14

15. 15

16. To date, only few ADCs (Antibody Drug Conjugates) have received market approval. However, after a request from the U.S. (FDA), Pfizer/Wyeth, the developer and marketer of the first ADC to receive marketing approval in 2001 for the treatment of patients with acute myelogenous leukemia (Gemtuzumab ozogamicin, trade name: Mylotarg®), withdrew the drug from the market in June 2010.acute myelogenous leukemiaGemtuzumab ozogamicin 16

17. WHY Mylotarg (gemtuzumab ozogamicin): Market Withdrawal Audience: Oncology, Hematology [Posted 06/21/2010] ISSUE: FDA notified healthcare professionals that results from a recent clinical trial raised new concerns about the product’s safety, and the drug failed to demonstrate clinical benefit to patients enrolled in trials. BACKGROUND: Mylotarg (gemtuzumab ozogamicin), indicated for treatment of acute myeloid leukemia (AML), a bone marrow cancer, was approved in May 2000 under the FDA’s accelerated approval program. A confirmatory, post approval clinical trial was begun by Wyeth (now Pfizer) in 2004. The trial was designed to determine whether adding Mylotarg to standard chemotherapy demonstrated an improvement in clinical benefit (survival time) to AML patients. The trial was stopped early when no improvement in clinical benefit was observed, and after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone. RECOMMENDATION: Mylotarg will not be commercially available to new patients. Patients who are currently receiving the drug may complete their therapy following consultation with their health care professional. Health care professionals should inform all patients receiving Mylotarg of the product’s potential safety risks. Any future use of Mylotarg in the United States will require submission of an investigational new drug application to the FDA. [06/21/2010 - News Release - FDA]News Release 17

18. MYLOTARG5 mg20$3048.85 18 DrugStrengthQuantityPricePharmacy Info MYLOTARG5 mg20 ml$3048.85In Stock

19. 19

20. 20

21. 21

22. 22

23. 23

24. 24 Summary of Warfarin Pharmacokinetic, Pharmacodynamics, and Pharmacogenetics Pathways Limdi, Pharmacotherapy, 2008

25. 25 Validated Algorithms Available for Clinicians and Patients

26. 26 Fear-based Mental Model ↑ Failure ↓ Company Value Merger Lose Job Company Unsafe or ineffective drugs approved People hurt Lose confidence in FDA FDA Poor Decisions Insufficient Knowledge & Decision Process

27. 27 Hope-based Mental Model Safe or Effective drugs approved ↑ Health for All Gain confidence in FDA FDA Wise Decisions Sufficient Knowledge & Decision Process Leverage Point ↑ Success ↑ Health ↑ Company Value Company Promotion

28. 28

29. Any question? 29 Any Question?