Lecture 4 - Winter 2025 BIO200 Drug Development and Regulation II PDF

BIO200 Introduction to Pharmacology Lecture 4 Drug Development and Regulation II Clinical Trials – Case study Dr. Nagham Abdalahad January 16th 2025 Readings (Katzung, Chapter 1) Chapter 1, pages10-19...

BIO200 Introduction to Pharmacology Lecture 4 Drug Development and Regulation II Clinical Trials – Case study Dr. Nagham Abdalahad January 16th 2025 Readings (Katzung, Chapter 1) Chapter 1, pages10-19 1  Clinical Trials Phase Goal of Phase # of Participants Phase I Test range of doses in healthy volunteers; determine 20-100 limits of safe clinical dosage (more toxic drugs, ex/for cancer/AIDS: patients participate) “blinded” + placebo OR open; predictable toxicities Urgent need (i.e. cancer therapy): detected accelerated process and Drug Pharmacokinetic measurements done (drug absorption, ½ can be marketed before Phases II/III are done life, metabolism) Controlled marketing Phase II Testing drug in patients with target disease; efficacy 100-200 (“proof of concept”) evaluated PHASE II: HIGHEST Single-blind design (inert placebo – neg. control; test RATE OF DRUG drug; established drug – pos. control) FAILURES (25% pass Broader range of toxicities detected to Phase III) Phase III Testing in patients; establish/confirm safety & efficacy >1000 (avg. 5000) Drug formulated as intended for market (pill, serum, etc.) (drugs pass Phase III = Certain toxic effects become visible (immunological, etc.) marketed as new agent) ~50% of drugs = pre-approved for controlled marketing Phase IV “Postmarketing surveillance” – monitoring drug safety in >100,000 public (large number of patients); detect low-incidence of rare drug effects (i.e. 1 in 10,000 chance) Phase V Translational research anyone 2  A Fail / Success Story HYPERTENSION: Chronic elevated arterial pressure (>140/90 mmHg) Results from consistently constricted blood vessels 90% of cases: no underlying medical origin (“primary hypertension”) Major risk factor for: Heart attack Stroke Arterial aneurysms Peripheral arterial disease One of the causes of chronic kidney disease Treatment goal : blood vessel dilation/smooth muscle relaxation http://www.medicalnewstoday.com/articles/150109.php 3 Recall: Process of Drug Discovery 4  A Fail/Success Story 1989, Sandwich, England Pfizer Pharmaceuticals develop compound UK-92480 to treat angina and hypertension Dr. Nicholas Terrett Dr. David Brown, pyrazolopyrimidinone (effective in treating angina pectoris) 5 http://www.xconomy.com/author/nterrett/;  Smooth Muscles Contraction Contraction Rise in intracellular calcium ions (Ca2+) action potential depolarizes plasma membrane L-type voltage-gated Ca2+ channels open, causing intracellular Ca2+ levels to rise 2+ Ca are sequestered in sarcoplasmic reticulum inside the cell when excited, Ca2+ channels on sarcoplasmic reticulum membrane open free Ca2+ are released into the cytoplasm Ca2+ bind to calmodulin, which induces conformational change Ca2+-calmodulin (CaM) complex activates the myosin light- chain kinase (MLCK) this phosphorylates myosin light chain (MLC) and triggers actin-myosin binding and smooth muscle contraction Termination of Contraction Nitric oxide nitric oxide activate a soluble guanylyl cyclase that produces cyclic guanosine monophosphate (cGMP) cGMP activates protein kinase G, which activates MLCP Myosin light chain phosphatase (MLCP) dephosphorylates and inactivates MLC allowing the myofibrils to relax https://step1.medbullets.com/msk/112020/smooth-muscle-contractions 6  Nitric Oxide Pathway – Selecting a Drug Target “Animations by Sara R. da Silva, PhD” Smooth muscle relaxation controlled by nitric oxide pathway UK-92480 (SILDENAFIL) endothelial nitric endothelial cell oxide synthetase eNOS nitric oxide NO MUSCLE CONTRACTION arginine MUSCLE RELAXATION phosphodiesterase 5 PDE5 Guanylate cGMP cyclase Smooth muscle cell GTP cGMP = sends cell signal PDE5 = breaks down cGMP soluble guanylate cyclase 7 INCREASE VASODILATION = TREAT ANGINA  Drug Discovery - Rational Design SCAFFOLD Medicinal Chemistry & Rational Design Take main part of molecule (“scaffold”) Connect different functional groups off the “scaffold” Make a large collection of molecules that vary in a few positions (“library” of compounds) Test compounds to find your lead Bring your lead to clinical trials UK-92480 Target: Nitric Oxide pathway (to induce vasodilation) http://www.xconomy.com/author/nterrett/; 8  Problems with Clinical Trials 1990: UK-92480 enters clinical trials for treatment of angina pectoris Phase I (1991): well tolerated (no toxic effects) Phase II (1992-1993): no effects on angina ▪ Research team was running Dr. David Brown, out of $$$ “Serendipity or Hard Work?” A ▪ Project was doomed to shut lecture by Dr. David Brown, down in 3 months Cambridge University, ▪ 8 years of research down November 15, 2011. the drain 9  More Info on Target Discovered It was found that… sildenafil doesn't affect the entire cardiovascular system? 1. PDE5 = constricts blood vessels 2. UK-92480 (sildenafil) = dilated blood vessels in corpus cavernosum (penile tissue) Inhibit PDE5 with sildenafil = erections occurred due to vasodilation Boolell, M.; Allen, M.J.; Ballard, S.A.; Gepi-Attee, S.; Muirhead, G.J.; Naylor, A.M.; Osterloh, I.H.; Gingell, C. Int. J. Impot. Res. 10 1996, 8(2), 47-52; http://www.viagrabox.com/category/viagra/how-viagra-works/  Re-purposing of Sildenafil Researchers thought that PDE5 was expressed in all blood vessels Later: expression levels of PDE5 found predominately in lungs blood https://www.britannica.com/science/pulmon vessels and penile tissue ary-circulation One drug, very specific effects in the body (SERENDIPITY) Market it for two diseases!! https://accesspharmacy.mhmedical.com/Content. aspx?bookId=462&sectionId=41100870#7994536 11  New Drug, New Purpose - ED Sildenafil citrate: Patented as VIAGRA in 1996 6 months after entering clinical trials: In 1998, FDA released as prescription drug (fastest turn-around time in clinical trials) →due to minimal side effects and incredible results Erectile dysfunction (ED) due to: Spinal cord injury Diabetes Prostate surgery Genetic First week on the market: 300,000 prescriptions in U.S.A. alone 12 http://www.viagrabox.com/history-of-viagra-sildenafil-citrate/  New Drug, New Purpose - PAH In 2005: Pfizer and the FDA approved using sildenafil for the treatment of Pulmonary Arterial Hypertension (PAH) Results from failure of right ventricle of heart due to heart attack Increased pressure in lung arteries Treatment: induce vasodilation Birth of Revatio Same drug as Viagra (sildenafil citrate) Smaller doses, different formulation Prescribed to treat PAH “Serendipity or Hard Work?” A lecture by Dr. David Brown, Cambridge University, November 15, 2011. 13  Success of Viagra “Serendipity or Hard Work?” A lecture by Dr. David Brown, Cambridge University, November 15, 2011. Jan. 1997 April, 1998 More than $25 billion in Viagra sales worldwide More than $0.5 billion in Revatio sales since 2005 Blockbuster success story for Pharma and small molecule drugs 14  After Screening: Clinical Trials Phase Goal of Phase # of Participants Phase I Test range of doses in healthy volunteers; determine 20-100 limits of safe clinical dosage (more toxic drugs, ex/for cancer/AIDS: patients participate) “blinded” + placebo OR open; predictable toxicities detected Pharmacokinetic measurements done (drug absorption, ½ life, metabolism) Phase II Testing drug in patients with target disease; efficacy 100-200 (“proof of concept”) evaluated Single-blind design (inert placebo – neg. control; test drug; established drug – pos. control) Broader range of toxicities detected Phase III Testing in patients; establish/confirm safety & efficacy >1000 (avg. 5000) Drug formulated as intended for market (pill, serum, etc.) (drugs pass Phase III = Certain toxic effects become visible (immunological, etc.) marketed as new agent) ~50% of drugs = pre-approved for controlled marketing Phase IV “Post marketing surveillance” – monitoring drug safety in >100,000 public (large number of patients); detect low-incidence of rare drug effects (i.e. 1 in 10,000 chance) Phase V Translational research anyone 15  New Drug Application- NDA Application starts after Phase III and just before marketing! The company will have the patent lifetime of 20 years to market the drug as trademark After the expiration of patent, other companies can produce the drug under generic name without paying license fee to the original company Still sold as Viagra, but generics are now available 16  Viagra: Present-day https://www.accessrx.com/research/viagra-patent-expires/ 17  Clinical Trials –Phase IV Post-market Surveillance If drug made today: would likely not be over- the-counter Improper use/dosing = leading cause of acute liver failure in Canada Max daily allowance = 4 grams (~8 pills) Change labels with better dosing info Reduce maximum allowed dose Warning labels of liver toxicity 18 https://www.thestar.com/news/canada/2016/09/15/health-canada-announces-stricter-acetaminophen-labelling.html  Drug Development: Other Considerations Adverse Drug Reactions Harmful, unintended response Can occur in anyone (overdose, drug interactions, etc.) Specific to certain patients: intolerance; allergy; failure of drug action MUST be reported to FDA Predicting and avoiding adverse drug reactions = focus of Pharmacogenetic & Personalized medicine 19 http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm292276.htm; https://www.health.harvard.edu/media/content/images/Grapefruit%26Pillsdreamstime_m_4253586.jpg  Drug Development: Other Considerations Ex: Grapefruit Juice & Prescription Drug Interactions 2012 – FDA released report on negative effects of taking some drugs with grapefruit juice 20 https://en.wikipedia.org/wiki/Grapefruit%E2%80%93drug_interactions  Drug Development: Other Considerations Rare Diseases & Orphan Drugs Classification of rare disease: a. Any disease/condition that occurs infrequently in population (i.e. affects less than 200,000 people in USA) b. Because infrequent occurrence: no expectation to recover drug development expenses from sales profits Drugs for rare diseases = “orphan” (also refers to drugs abandoned from other trials) Difficult to research, develop, and sell drugs for rare diseases o Small population affected o Both academia and industry = little $$ to fund research in pathophysiology and mechanisms of disease Orphan Drug Amendment (FDA), 1983: Incentives for drug development for rare diseases >300 orphan drugs, 82 rare diseases treated since 1983 21  Summary: From Bench to Bedside (Katzung, Chap. 1) 22