Che 360 Getting a Drug to Market (October 16, 2024) PDF

Getting a drug to market CHE 360 October 16, 2024  Outcomes Learn process for pre-clinical and clinical trials – Toxicity and efficacy testing – Metabolism, pharmacology and formulation challenges – Human trials Learn the process for filing a patent and...

Getting a drug to market CHE 360 October 16, 2024  Outcomes Learn process for pre-clinical and clinical trials – Toxicity and efficacy testing – Metabolism, pharmacology and formulation challenges – Human trials Learn the process for filing a patent and obtain approval for a new drug Discuss challenges for process chemists  Workflow for Discovery and Development JAMA Netw Open. 2024;7(6):e2415445  Regulatory Processes-Alphabet Soup FDA – Food and Drug Administration IND – Investigational exemption to a New Drug Application – Filed before clinical trials NDA – New Drug Application – Filed at the end of clinical trials – 400-700 volumes at 400 pages each – Very difficult after this stage to change synthesis or structure in any way NCE – New Chemical Entity – Novel drug structure  Development Phase Much more expensive than discovery phase – 1 in 10000 structures synthesized reaches market – At least $800 million in costs in development phase Many hurdles – Safety and efficacy tests Preclinical and clinical trials (toxicity, efficacy, stability, metabolism, formulation etc) – Patents and legal hurdles – Very large scale synthesis Chemical and process development JAMA Netw Open. 2024;7(6):e2415445  Costs by Disease JAMA Netw Open. 2024;7(6):e2415445 Toxicity and Dosing Dosing designed to maintain constant blood concentration of drug Therapeutic window – Steady state levels of drug in between therapeutic level and toxic level Drug half life (t1/2) – Range from minutes to days  Toxicity Testing LD50 and ED50 in animal models – Lethal dose for 50% of the animals – Effective dose for 50% of the animals Therapeutic ratio or index – LD50:ED50 – Ideally >>10 and no overlap on x axis LD1:ED99 better measurement of safety  More Toxicity Testing Teratogenic drugs – Animal models HERG Carcinogenicity (Ames)  Problems with Animal Toxicity Tests No toxicity issues in animal studies does not always correlate with no toxicities in humans Fialuridine tested in clinical trials as an antiviral agent for hepatitis B – Nontoxic to animals – Acute liver and kidney failure in 7 of 15 patients 5 deaths Liver transplants for 2 survivors  Metabolism Studies Identification of metabolites – Isotopically label drug Deuterium/hydrogen exchange – Simple but reversible in water 13 C or 14 C – New synthesis required – Incubate drug in liver microsomes or with pure CYP450s – Identify molecules with isotope HPLC/MS, HPLC-radioactivity detector, NMR  Formulation and Stability What is formulation? – Preparation of drug that is stable and effective Capsules, tablets, IV solution Drug alone or with other substances – Compatibility and inactivity – Must characterize physicochemical and mechanical properties of pure drug pH, solubility, polymorphism – Uniform appearance and dissolving capabilities when mixed with additive if capsule or tablet form Usually performed by chemical engineers during preliminary clinical trials for use in Phase III  Clinical Trials Desired effect in pre-clinical trials – Advantages over current therapies – Good PK and minimal metabolites – Reasonable half-life and minimal side effects Human testing over 5-7 years Phases I-IV  Phase I About 1 year in length 100-200 volunteers who are healthy – Potential age group selectivity Alzheimer’s, cardiac drugs will study older subjects Tests safety, ADME properties, and dosing levels – 1/10 of highest safe dose in animal studies initially then ramp it up until mild adverse effects are seen Highest tolerated dose – No medications, alcohol, caffeine or nicotine to avoid drug-drug interactions May appear in later studies Radiolabelled drug given to 4-8 volunteers and tracked throughout body – ADME and bioavailability  Phase II Two years in length – Sometimes starts before Phase I ends Therapeutic efficacy on patients Phase IIa – Small numbers of patients Phase IIb – Double-blind larger numbers – Multiple doses 20-80 patients per dose  Phase II Rescue medicines available – Placebo vs experimental ratio of rescues needed Lethal diseases – Unethical to use placebo – Compare efficacy of known drug to test drug Endpoint measured – Viral load in blood or tumor volume – Determines success or failure  Phase III Three years in length – May begin before Phase II finishes Phase IIIa – Double-blind very large scale patient trials testing efficacy Phase IIIb – Comparing to already approved drugs for that particular disease  Phase IV Drug Removal After approval, toxicities with marketed drugs monitored Tienilic acid (diuretic) damages liver in 1 out of 10000 – Criminal charges filed against drug company for withholding findings (1982) Phenylbutazone (anti-inflammatory) fatal side effect in 22 out of 1 million patients – Still used for animals particularly horses Cerivastatin (cholesterol) drug-drug interactions – Death and muscle damage  Ethical Implications Clinical trials-what populations of people would pose ethical hurdles? – Children – Pregnant women – Unconscious patients – Mentally ill patients  Patenting the Drug Companies protect their drugs with patents just like inventors patent their inventions – Gives them exclusive rights to make and sell drug for a limited amount of time Typically 20 years, 6-10 years of which may be preclinical and clinical trials Many patents cover syntheses of a series of compounds and their uses Information can not have been revealed anywhere before patenting – No presentations, posters, papers, or conversations outside of the company  Circumventing Patents: Chiral Switching Nexium® from Prilosec® – Esomeprazole vs omeprazole Lexapro® from Celexa® – Escitalopram vs citalopram  Fast Tracking Drugs reach market as soon as possible – Small numbers of phase II and III trials Lethal diseases with no known treatment – Bortezomib (Velcade®) for multiple myeloma Diseases affecting large populations – Sofosbuvir and velpatasvir (Epclusa®) for Hepatitis C virus Duchenne muscular dystrophy – Eteplirsen (Exondys 51®)  Orphan Drugs Disease affects less than 200,000 people in US – Cystic fibrosis – Duchenne muscular dystrophy – Specific kinds of cancers Venetoclax (Venclexta®) – Chronic lymphocytic leukemia (2016) Rucaparib (Rubraca®) – BRCA+ ovarian cancer (2016)  Chemical Development Synthetic modifications Get rid of toxic or problematic reagents with milder, higher yielding ones  Product Specifications QC-Quality control – MS, NMR, IR, UV, TLC Melting point Boiling point Color Particle size pH of solution Chemical and stereochemical purity Allowables – 2% EtOH, 0.05% MeOH, 1 ppm Hg, 300 ppm Na, 2 ppm Pb  Process Chemistry Original route in research for β3- adrenergic receptor agonist – 1.1% yield – Too many purifications required – Toxic reagents Ethylene dibromide – High pressure hydrogenation – Chiral resolution  Process Chemistry New, milder, higher yielding (33%) route – Asymmetric synthesis – No dialkylations – Less pressurized hydrogenation  Natural Products Some are too expensive and difficult to synthesize on multi-kg scale Also too costly to utilize natural source only – Penicillin – Morphine – Paclitaxel Requires 4 yew trees to treat 1 patient Total Synthesis of Paclitaxel 39 step synthesis published in multiple articles in J. Am. Chem. Soc. Semi-Synthesis of Paclitaxel Isolate intermediate Fewer synthetic steps yielding paclitaxel  Summary Development phase is most expensive phase Drugs have terrible odds that they will pass preclinical and clinical trials Patents are required to protect a company’s assets and hard work for a limited amount of time Process chemistry and chemical development are potential roadblocks having nothing to do with safety or efficacy of the drug Getting a drug to market is not easy!