20.201 | Fall 2013 | Graduate

Mechanisms of Drug Actions

Readings

[Golan] = Golan, David E., Armen H. Tashjian, and Ehrin J. Armstrong, eds. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Lippincott Williams & Wilkins, 2011. ISBN: 9781608312702. [Preview with Google Books]

[C&D] = Klaassen, Curtis. Casarett & Doull’s Toxicology: The Basic Science of Poisons. 8th ed. McGraw-Hill Professional, 2013. ISBN: 9780071769235.

SES # TOPICS READINGS
Overview of the Drug Discovery Process; Fundamental Principles
L1 Introduction and Fundamentals [Golan] Chapter 1
L2 Overview of Drug Development 1 [Golan] Chapter 49
L3 Overview of Drug Development 2 [Golan] Chapter 49
R1 Fundamentals [Golan] Chapters 1 and 2
L4 Biochemistry Review Exercise No readings for this session.
L5 Uptake and Distribution

[Golan] Chapters 2 and 3

[C&D] Chapter 5

L6 Dr. Keith Hoffmaster, Novartis: Drug Transporters 1

[Golan] Chapter 4

[C&D] Chapter 7

Giacomini, Kathleen M., Shiew-Mei Huang, et al. “Membrane Transporters in Drug Development.” Nature Reviews Drug Discovery 9, no. 3 (2010): 215–36.

Brouwer, Kim L. R., Dietrich Keppler, et al. “In Vitro Methods to Support Transporter Evaluation in Drug Discovery and Development.Clinical Pharmacology & Therapeutics 94, no. 1 (2013): 95–112.

L7 Dr. Keith Hoffmaster, Novartis: Drug Transporters 2

[Golan] Chapter 4

[C&D] Chapter 7

R2 Drug Metabolism 1

[Golan] Chapter 4

L8 Drug Metabolism 2

[Golan] Chapter 4

L9 Drug Toxicity 1

[Golan] Chapters 5 and 41

Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation. (PDF) U.S. Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER). July 2009.

Giacomini, Kathleen M., Shiew-Mei Huang, et al. “Membrane Transporters in Drug Development.” Nature Reviews Drug Discovery 9, no. 3 (2010): 215–36.

R3 Lecture Review Session No readings for this session.
L10 Drug Toxicity 2

[Golan] Chapters 5 and 41

L11 Pharmacokinetics

[Golan] Chapters 2 and 3

[C&D] Chapter 5

R4 Quiz Review No readings for this session.
Case Studies and Literature Discussions; Case Study Project
L12 Case Study: Omeprazole Pharmacogenetics

Chang, M., G. Tybring, et al. “Interphenotype Differences in Disposition and Effect on Gastrin Levels of Omeprazole—Suitability of Omeprazole as a Probe for CYP2C19.” British Journal of Clinical Pharmacology 39, no. 5 (1995): 511–18.

Furuta, Takahisa, Mitsushige Sugimoto, et al. “CYP2C19 Pharmacogenomics Associated with Therapy of Helicobacter Pylori Infection and Gastro-Esophageal Reflux Diseases with a pPoton Pump Inhibitor.” Pharmacogenomics 8, no. 9 (2007): 1199–210.

Lindberg, Per, Peter Nordberg, et al. “The Mechanism of Action of the Antisecretory Agent Omeprazole.” Journal of Medicinal Chemistry 29, no. 8 (1986): 1327–29.

Court, Michael H. “A Pharmacogenomics Primer.” The Journal of Clinical Pharmacology 47, no. 9 (2007): 1087–103.

[Golan] Chapter 6 and 46

R5 Overview of Drug Development 3 [Golan] Chapter 49
L13 Case Study No readings for this session.
L14 Case Study: Antibiotics

[Golan] Chapters 32, 33, and 34

Antibiotic Resistance Threats in the United States, 2013 (PDF - 4.0MB) Centers for Disease Control and Prevention.

Dwyer, Daniel J., Michael A. Kohanski, et al. “Role of Reactive Oxygen Species in Antibiotic Action and Resistance.” Current Opinion in Microbiology 12, no. 5 (2009): 482–9.

R6 Project Help Session No readings for this session.
L15 Case Study No readings for this session.
L16 Dr. Alex Wood, MIT Senior Lecturer/Novartis: Case Study: Oncology Drugs Hanahan, Douglas, and Robert A. Weinberg. “Hallmarks of Cancer: The Next Generation.” Cell 144, no. 5 (2011): 646–74.
R7 Project Help Session No readings for this session.
L17 Case Study: Statins

[Golan] Chapter 19

Press Release: “Rate of Kidney Damage in Crestor Patients Is 75 Times Higher Than in Patients Taking Other Cholesterol Drugs.” October 29, 2004.

R8 Project Help Session No readings for this session.
L18 Case Study: GWAS and Statin Toxicity

Niemi, M. “Transporter Pharmacogenetics and Statin Toxicity.” Clinical Pharmacology & Therapeutics 87, no. 1 (2010): 130–3.

Link, E., S. Parish, et al. “SLCO1B1 Variants and Statin-Induced Myopathy—A Genomewide Study.” The New England Journal of Medicine 359, no. 8 (2008): 789.

L19 Dr. Bernard Fermini, Pfizer: Case Study: Cardiotoxicity No readings for this session.
R9 Project Help Session No readings for this session.
L20 Dr. Teresa Wright, Shire Pharmaceuticals: Preclinical Drug Development [Golan] Chapter 49
R10 Project Help Session No readings for this session.
L21 Dr. Keith Hoffmaster: Case Study: PK / PD No readings for this session.
L22 Case Study: Sarilumab Phase III Clinical Result

Carroll, John. “Regeneron, Sanofi Hit a Trio of Goals in First PhIII Test of Rheumatoid Arthritis Drug.” Fierce Biotech, November 22, 2013.

Huet, Natalie (rep.) and Elizabeth Piper (ed.). “Sanofi, Regeneron Arthritis Drug Meets Goals in Phase 3 Trial.” Reuters, November 22, 2013.

Bennett, Simeon. “Sanofi Rheumatoid Arthritis Drug Cuts Pain, Damage in Study.” Bloomberg, November 22, 2013.

R11 Prof. Doug Lauffenburger: Systems Pharmacology No readings for this session.
L23 Dr. Tess Schmalbach, Schmalbach LLC: The Clinical Size of Drug Development [Golan] Chapters 50 and 51

Course Info

Learning Resource Types
Problem Sets with Solutions
Exams with Solutions
Lecture Notes
Projects with Examples
Written Assignments
Instructor Insights