Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5262_Библиотеки_им_академика_М_И_Перельмана.pdf
3 General Terms and Concepts in Medicinal Chemistry58
For dietary supplements, herbs, and other nutrients whose route of administration
is almost always oral, bioavailability usually simply represents the amount or
fraction of the ingested dose that is absorbed.
3.26 Pharmacology
Pharmacology is the scientific study of drugs and medications, encompassing their
origins, chemical composition, PK, PD, therapeutic applications, and toxicological
effects. It focuses on understanding the interactions between living organisms and
chemicals that influence normal or abnormal biochemical processes. A substance is
classified as a drug if it possesses medicinal properties. This field explores various
aspects, including drug composition and properties, functions, sources, synthesis,
drug design, molecular and cellular mechanisms, organ and system-level effects, signal
transduction and cellular communication, molecular diagnostics, chemical interac-
tions, chemical biology, therapeutic and medical uses, and antipathogenic capabil-
ities. Pharmacology is broadly divided into two primary areas: PD, which examines
the effects of drugs on the body, and PK, which studies how the body processes drugs.
3.27 Formulation
In pharmacy, formulation is the process of combining different chemical sub-
stances, including active pharmaceutical ingredients (API), to produce the final
medicinal product. The term formulation is often used in a way that includes dosage
forms.
Formulation research involves the development of drug formulations that are
stable and acceptable to patients. For oral medications, this usually involves incor-
porating the drug into tablets or capsules. It is important to distinguish that tablets
contain a variety of other potentially inert substances in addition to the drug itself,
and studies must be conducted to ensure that the encapsulated drug is compatible
with these other substances and will not cause harm, either direct or indirect.
Preformulation involves the characterization of the physical, chemical, and
mechanical properties of the drug in order to select which other ingredients
(excipients) should be used in the formulation. When working with protein pre-
formulation, an important aspect is to understand the solution behavior of a given
protein under various stress conditions (e.g., freeze/thaw, temperature, shear stress,
etc.) to identify degradation mechanisms and thus mitigate their effects.
Formulation studies then take into account factors such as particle size, poly-
morphism, pH, and solubility, as all of these can affect bioavailability and therefore
the activity of the drug. The drug must be mixed with the inactive ingredients in
a way that ensures a consistent amount of drug is present in each dosage unit, for
example, per tablet. The dose should have uniform appearance, acceptable taste,
tablet hardness, and capsule disintegration.
Formulation studies are often still ongoing when clinical trials commence. As a
result, basic formulations are typically developed for phase I clinical trials. These
3.29 Drug Stability 59
initial formulations usually involve manually filled capsules containing a small
quantity of the drug mixed with a diluent. Since these formulations are intended for
short-term use and will be tested within a few days, there is no requirement to dem-
onstrate their long-term stability. However, it is crucial to consider the “drug load,”
which refers to the ratio of the active drug to the total content of the dose. Low drug
loading can lead to issues with homogeneity, while high drug loading, particularly
in compounds with low bulk density, may result in flow problems or necessitate the
use of larger capsules.
By the time a drug advances to phase III clinical trials, its formulation should
closely resemble the final version intended for market use. At this critical stage,
understanding the drug’s stability is essential, and appropriate conditions must
be established to ensure the formulation remains stable. If the drug demonstrates
instability, the clinical trial results could be compromised, as it would be impossible
to determine the actual dose administered to participants.
3.28 Active Pharmaceutical Ingredient
The API is the primary component in a medication responsible for producing its
intended therapeutic effect. Some drugs may contain multiple APIs, each contrib-
uting to the desired outcome through different mechanisms of action in the body.
On the other hand, inactive ingredients, commonly referred to as excipients
in the pharmaceutical industry, play a supportive role. The main excipient used
as a carrier or medium to deliver the active ingredient is often termed a vehicle.
Examples of common vehicles include petrolatum and mineral oil. It’s important to
note that while these ingredients are labeled as “inactive,” this does not imply that
they are inert or without any function; they often serve critical roles in the formula-
tion and effectiveness of the drug.
3.29 Drug Stability
Drug stability refers to the extent to which a drug substance or product retains the
same properties and characteristics as when it was manufactured, within specified
limits and throughout its storage and use. Stability studies are performed to test if there
are any effects of temperature, humidity, oxidation, or photolysis (ultraviolet or visible
light), and the formulation is analyzed to see if any degradation products are formed.
Stability types are generally divided into chemical, physical, microbiolog-
ical, therapeutic, and toxicological stabilities. Drug stability can be divided into
pre-market stability and commercial (marketed product) stability. Pre-market
stability supports clinical trials, in which a drug product is stored under differ-
ent conditions for assessment of safety and effectiveness, typically throughout
clinical trials and during application. Commercial stability is an ongoing assurance
for post-approval batches and is used to monitor the long-term stability of a drug
product. Drug stability assessment typically involves testing the drug substance or
drug product using stability-indicating methods to determine the retest period (for
pre-market stability) and shelf life (for commercial stability).
3 General Terms and Concepts in Medicinal Chemistry60
3.30 Prodrugs
A prodrug is defined as a chemical that undergoes transformation before exerting
a pharmacological effect. In other words, when you take a prodrug, it changes in
your body before it starts to take effect. Prodrugs are often designed to increase bio-
availability when the drug itself is poorly absorbed from the gastrointestinal tract.
Prodrugs can be used to improve the selectivity of a drug for interacting with cells
or processes other than its intended target. This can reduce the unwanted or unin-
tended effects of the drug, which is especially important in treatments such as che-
motherapy, which can have serious unintended and unwanted side effects.
There are two main types of prodrugs. These categories are based on how the
prodrug is converted in the body. Type I prodrugs are converted into the active form
within the cell. Type II prodrugs are turned into their active forms extracellularly,
such as in blood or other fluids.
Different types of prodrugs can also impact drug interactions. Certain interactions
may prevent a prodrug from becoming active.
Aspirin, acetylsalicylic acid, is a synthetic prodrug of salicylic acid [56].
Clopidogrel (Plavix) is a medication that can prevent heart attacks and strokes. It’s
a prodrug that’s absorbed in the intestine and activated in the liver. Acid-reducing
medications like omeprazole (Prilosec) can make clopidogrel less effective by
preventing it from becoming active. Clopidogrel is activated in two steps: first is the
oxidation catalyzed by the enzymes CYP2C19, CYP1A2, and CYP2B6, then hydro-
lyzed by CYP2C19, CYP2C9, CYP2B6, and CYP3A [57].
O
OH
O
O
Aspirin
prodrug
Hydrolysis
O
OH
OH
Salicylic acid
active ingredient
Cl
N
S
OO
Clopidogrel
prodrug
Cl
N
S
OO
OH
Cl
N
S
OO
O
H
Cl
N
SH
OO
H
OH
O
Active ingredient
R?
Oxidation
Tautomerization
Hydrolysis
3.31 Deuterium-containing Drug 61
Around 10% of all drugs marketed globally are classified as prodrugs. Some
recently approved examples of prodrugs include benzhydrocodone (a prodrug
of hydrocodone, approved in 2018) [58], serdexmethylphenidate (a prodrug of
dexmethylphenidate, approved in 2021) [59], and omidenepag isopropyl (a prodrug
of omidenepag, approved in 2022) [60].
3.31 Deuterium-containing Drug
Deuterated drugs are small-molecule pharmaceuticals where one or more
hydrogen atoms in the drug molecule are replaced by deuterium, a heavier stable
isotope of hydrogen. This substitution can lead to kinetic isotope effects, which may
significantly slow the drug’s metabolic rate, resulting in an extended half-life.
The concept of deuterated drug candidates originated in the 1970s, building on
early research involving deuterated metabolites. Despite this early start, it wasn’t
until 2017 that the first deuterated drug, Austedo® (deuterated tetrabenazine),
gained FDA approval [61]. Chemically, deuterated tetrabenazine is an isotopic
O
O
O
O
H
N
Benzhydrocodone
(prodrug)
O
O
O
H
N
Hydrocodone
(active ingredient)
Hydrolysis
Serdexmethylphenidate
(prodrug)
N
H
O O
O
O N
+
O
HN
Hydrolysis
Dexmethylphenidate
(active ingredient)
NH
H
O O
N
N
N
N
N
H
O
O
SO
O
N
Omidenepag isopropyl
(prodrug)
Hydrolysis
N
N
N
N
N
H
O
HO
SO
O
N
Omidenepag
(active ingredient)
HO
O
OH
CI
–
3 General Terms and Concepts in Medicinal Chemistry62
isomer of tetrabenazine, with six hydrogen atoms replaced by deuterium atoms.
This deuterium incorporation reduces the drug’s metabolic breakdown, allowing
for less frequent dosing [62].
Deucravacitinib is a deuterated drug launched by Bristol-Myers Squibb for the
treatment of moderate to severe plaque psoriasis. It received FDA approval in
September 2022 [63].
3.32 Antibody Drug Conjugates
Antibody drug conjugates (ADCs) are an innovative family of drugs assembled
by covalently linking a cytotoxic drug (payload) to a monoclonal antibody (mAb)
and then delivering it to tumor tissue expressing its specific antigen, which theoret-
ically has the advantage of improving the therapeutic ratio [64, 65, 66, 67, 68, 69].
As of March 2024, 13 ADCs have been approved by the FDA and are on the market.
Unlike chemotherapy, ADCs are designed to target and kill tumor cells while spar-
ing healthy cells. ADCs are examples of bioconjugates and immunoconjugates.
ADCs combine the targeting properties of monoclonal antibodies with the anti-
cancer capabilities of cytotoxic drugs and are designed to differentiate between
healthy and diseased tissue.
3.33 Good Laboratory Practice
The principles of GLP define a framework of rules and standards for a quality
management system that governs organizational processes and conditions related
to the planning, execution, monitoring, documentation, reporting, and archiving
N
O
O
D
D
D
D
D
D
O
H
N
O
O
D
D
D
D
D
D
O
H
Deutetrabenazine
R
S
R S
N
N
N
O
HN
N
N
N
H
O
N
H
OD
D
D
Deucravacitinib
3.34 Good Manufacturing Practice 63
of nonclinical research on health and environmental safety. These principles are
applicable to the nonclinical safety testing of substances used in a wide range of
products, ensuring the reliability, consistency, and integrity of safety data that is
submitted to regulatory authorities globally.
The GLP principles established by the Organization for Economic Cooperation
and Development (OECD) apply to the testing of chemicals or chemical products in
nonclinical environments, including laboratory settings or controlled environmental
conditions like greenhouses and field experiments. These principles do not apply to
research involving human subjects. Additionally, depending on the regulations of
individual OECD member countries, the OECD GLP principles may also be applied
to nonclinical safety testing of other regulated products, such as medical devices.
Studies conducted under GLP in OECD member countries encompass a wide
range of research areas, including:
• Physical-chemical testing;
• Toxicity studies;
• Mutagenicity studies;
• Environmental toxicity studies on both aquatic and terrestrial organisms;
• Investigations into behavior in water, soil, and air, as well as bioaccumulation;
• Residue studies to determine pesticide levels in food or animal feedstuffs;
• Research on the effects on mesocosms and natural ecosystems;
• Analytical and clinical chemistry testing.
3.34 Good Manufacturing Practice
Good Manufacturing Practices (GMP, also known as “cGMP” or “Current Good
Manufacturing Practices”) is an aspect of quality assurance that ensures that
pharmaceutical products are consistently produced and controlled to quality stan-
dards suitable for their intended use and in accordance with product specifications.
GMP defines quality measures for production and quality control and defines
general measures to ensure that the processes required for production and testing
are clearly defined, verified, reviewed, and documented, and that personnel, sites,
and materials are suitable for the production of medicinal and biologicals including
vaccine products. GMP also has a legal component that covers distribution respon-
sibilities, contract manufacturing and testing, and response to product defects and
complaints. Specific GMP requirements relevant to product categories such as
sterile pharmaceutical products or biomedical products are provided in a series of
annexes to the general GMP requirements.
All guidelines are based on a set of fundamental principles:
• Clean and Hygienic Area: Manufacturing facilities must maintain a clean
and hygienic manufacturing area.
• Controlled Environmental Conditions: Manufacturing facilities must
maintain controlled environmental conditions in order to prevent cross-
contamination from adulterants and allergens that may render the product
unsafe for human consumption or use.
3 General Terms and Concepts in Medicinal Chemistry64
• Clearly Defined and Controlled Processes: Manufacturing processes must
be clearly defined and controlled. All critical processes are validated to ensure
consistency and compliance with specifications.
• Evaluate and Validate Changes: Manufacturing processes must be con-
trolled, and any changes to the process must be evaluated. Changes that affect
the quality of the drug are validated as necessary.
• Clarity and Precision in Documentation: Instructions and procedures
should be written in clear, unambiguous language, adhering to good documen-
tation practices.
• Training and Compliance: Operators must receive proper training to execute
and accurately document procedures.
• Accurate Record-Keeping: Records, whether manual or electronic, must
be maintained during production to confirm that all defined procedures and
instructions were followed. These records should verify that the quantity and
quality of the food or drug met the expected standards. Any deviations must be
thoroughly investigated and documented.
• Traceability and Retention: Manufacturing and distribution records must
be retained in a comprehensible and accessible format to ensure the complete
history of each batch can be traced.
• Risks Minimize: The distribution of products must ensure that risks to their
quality are minimized at all times.
• Robust Recalling System: A robust system must be established to facilitate
the recall of any batch from sale or supply if necessary.
• Procedures for Complaints: Complaints regarding marketed products must
be thoroughly reviewed, the root causes of quality issues must be investigated,
and appropriate corrective actions must be implemented to address defective
products and prevent future occurrences.
Regulatory agencies have recently shifted their focus toward more essential
quality metrics for manufacturers, moving beyond mere adherence to basic GMP
regulations. The U.S. FDA has observed that manufacturers who adopt quality met-
rics programs gain deeper insights into employee behaviors that influence product
quality.
3.35 Chemistry, Manufacturing, and Controls
Chemistry, manufacturing, and controls (CMC) is one of the most impor-
tant activities in pharmaceutical development. It occurs at all stages of the drug
development cycle and ensures quality and consistency during the production of
pharmaceutical products.
CMC is a critical component that cannot be ignored. It ensures that medicines
have consistent formulations so that the medicines used in clinical trials are the
same as those on the market. Because CMC applies to all stages of drug development
and focuses on establishing consistency in drug product stability, release, and man-
ufacturing, it must comply with FDA guidance. Without a CMC, the product would
be considered unsafe and would not be approved.
3.38 Clinical Trials 65
3.36 Contract Research Organization
In the life sciences sector, a contract research organization (CRO) is a company
that offers specialized research services to the pharmaceutical, biotechnology, and
medical device industries on a contractual basis. CROs deliver a wide range of ser-
vices, including biopharmaceutical development, bioassay development, commer-
cialization, clinical development, clinical trial management, pharmacovigilance,
outcomes research, and real-world evidence generation.
CROs are structured to help companies reduce costs, particularly those devel-
oping new drugs and therapies in niche markets. Their primary objective is to
facilitate smoother drug market entry and optimize the development process, elim-
inating the necessity for large pharmaceutical companies to handle all aspects of
drug development internally. Beyond serving corporate clients, CROs also collabo-
rate with government agencies, foundations, research institutions, and universities
to support their research initiatives.
3.37 Investigational New Drug Application
An Investigational New Drug (IND) Application is an application to the U.S.
FDA for authorization to use an investigational drug or biological product in human
clinical trials. Any new drug or biologic that does not have an approved NDA or
Biologics/Product License Application must obtain IND authorization prior to
interstate transportation and administration.
The U.S. FDA’s IND program is the means by which a pharmaceutical company
obtains permission to start human clinical trials and to ship an experimental drug
across state lines (usually to clinical investigators) before a marketing applica-
tion for the drug has been approved. Regulations are primarily found at 21 CFR
312. Similar procedures are followed in the European Union, China, Japan, and
Canada.
3.38 Clinical Trials
A clinical trial is a type of research that tests new medical products and evaluates
their impact on human health outcomes. People volunteer to participate in clinical
trials to test medical interventions, including drugs, cell and other biological prod-
ucts, surgery, radiation therapy, devices, behavioral treatments, and preventive care.
Clinical trials are carefully designed, reviewed, and completed, and require
approval before they can begin. People of all ages can participate in clinical trials,
including children.
Biomedical clinical trials are divided into four phases:
• Phase I studies typically test a new drug for the first time in a small group of
people (usually 20–100 healthy volunteers or people with the disease/condition)
to assess safe dosage ranges and determine side effects. Phase I studies usually
take several months. About 70% of drugs advance to the next phase.
3 General Terms and Concepts in Medicinal Chemistry66
• Phase II-a trials are primarily focused on evaluating dosing requirements,
specifically determining the appropriate amount of the drug to be adminis-
tered. In contrast, Phase II-b trials aim to assess the drug’s efficacy, typically
involving 100–300 participants with the targeted disease or condition, to eval-
uate how effectively the drug works when used as prescribed. These trials also
help establish therapeutic dose ranges and monitor for potential side effects.
Phase II studies generally span from a few months up to 2 years. Approximately
33% of the drugs that enter this phase advance to the next stage of clinical
development.
• Phase III trials involve large groups of participants, typically ranging from 1000
to 3000 individuals, who have the targeted disease or condition. These trials
aim to confirm the drug’s efficacy, assess its effectiveness, monitor potential
side effects, compare it to existing standard treatments, and gather compre-
hensive safety data to ensure its safe use. Participants in Phase III trials may
be recruited from various regions or countries, and this phase is often the final
step before a new treatment receives regulatory approval. The duration of
Phase III studies generally spans 1–4 years. Approximately 25–30% of drugs
successfully advance to the next phase. The probability of FDA approval after
submitting a NDA or Biologics License Application is 83.2% (based on a sample
size of 659). Success rates for lead indication development pathways are consis-
tently higher than those for all indication development pathways across every
phase of clinical trials.
• Phase IV studies are conducted after national approval and require further
testing in a broad population over a longer period of time. Therefore, they
persist throughout the life cycle of active medical use of the drug.
3.39 New Drug Application
For decades, regulation and control of new drugs in the United States has been
based on NDA. Since 1938, every new drug must be approved by an NDA before it
can be commercialized in the United States. An NDA is a vehicle through which a
drug sponsor formally proposes FDA approval of a new drug for sale and marketing
in the United States. Data collected during animal studies and human clinical trials
of an IND become part of the NDA.
The goal of an NDA is to provide sufficient information to allow FDA reviewers to
make the following key decisions:
• Whether patent information for the drug is provided.
• Whether the drug is safe and effective for its intended use, and whether the
drug’s benefits outweigh its risks.
• Whether the recommended labeling (package insert) for the drug is appro-
priate and what should be included in it.
• Whether the methods used to produce the drug and the controls used to main-
tain the quality of the drug are adequate to maintain the identity, strength,
quality, and purity of the drug.
• Whether the drug is susceptible to abuse.
References 67
The documents required in an NDA should tell the entire story of the drug,
including what happened during clinical trials, what the drug’s ingredients are, the
results of animal studies, how the drug behaves in the body and what it does, how it
is manufactured, processed, and packaged.
References
1 “Drug”. Drug Definition & Meaning. The American Heritage Science Dictionary.
Houghton Mifflin Company.
2 “Drug Definition”. Stedman’s Medical Dictionary.
3 Atanasov, A. G.; Waltenberger, B.; Pferschy-Wenzig, E. M.; Linder, T.; Wawrosch,
C.; Uhrin, P.; Temml, V.; Wang, L.; Schwaiger, S.; Heiss, E. H.; Rollinger, J. M.;
Schuster, D.; Breuss, J. M.; Bochkov, V.; Mihovilovic, M. D.; Kopp, B.; Bauer, R.;
Dirsch, V. M.; Stuppner, H. Biotechnol. Adv., 2015, 33, 1582.
4 Helleboid, S.; Haug, C.; Lamottke, K.; Zhou, Y.; Wei, J.; Daix, S.; Cambula, L.;
Rigou, G.; Hum, D. W.; Walczak, R. J. Biomol. Screening, 2014, 19, 399.
5 Herrmann, A.; Roesner, M.; Werner, T.; Hauck, S. M.; Koch, A.; Bauer, A.;
Schneider, M.; Brack-Werneret, R. Sci. Rep., 2020, 10, 1326.
6 Anson, D.; Ma, J.; He, J. Q., Genetic Engineering & Biotechnology News. Tech Note,
2009, 29 (9), 34.
7 Rennane, S.; Baker, L.; Mulcahy, A. INQUIRY: The J. Health Care Organ., Prov.,
and Fin., 2022, 58, 1.
8 Davis, A.; Ward, S. E. eds. “The Handbook of Medicinal Chemistry”. 2015, Royal
Society of Chemistry.
9 Barret, R. “Medicinal Chemistry: Fundamentals”. 2018, London: Elsevier.
10 Hanif, M.; Yang, X.; Tinoco, A. D.; Plażuk, D. Front. Chem., 2020, 8, 453.
11 Anthony, E. J.; Bolitho, E. M.; Bridgewater, H. E.; Carter, O. W.; Donnelly, J. M.;
Imberti, C.; Lant, E. C.; Lermyte, F.; Needham, R. J.; Palau, M.; Sadler, P. J.; Shi, H.;
Wang, F.-X.; Zhang, W.-Y.; Zhang, Z. Chem. Sci., 2020, 11, 12888.
12 Roughley, S. D.; Jordan, A. M. J. Med. Chem., 2011, 54, 3451.
13 Zheng, L.; Wang, W.; Sun, Q. Springer Nature, Signal Transduction and Targeted
Therapy, 2024, 9, 46.
14 Copeland, R. A.; Harpel, M. R.; Tummino, P. J., Expert Opin. Ther. Targets, 2007,
11, 967.
15 Copeland, R. A., “Evolution of enzyme inhibitors in drug discovery, A guide for
medicinal chemists and pharmacologists”, Wiley, 2013.
16 Williams, O.; Jacks, A. M.; Davis, J.; Martinez, S., “Case 10: Merck(A): Mevacor”.
In Allan Afuah (ed.). “Innovation Management - Strategies, Implementation, and
Profits”, 1998, Oxford University Press.
17 Ayala-Aguilera, C. C.; Valero, T.; Lorente-Macías, A.; Baillache, D. J.; Croke, S.;
Unciti-Broceta, A. J. Med. Chem., 2022, 65, 1047.
18 “FDA Authorizes First Oral Antiviral for Treatment of COVID-19” (Press release).
U.S. Food and Drug Administration. 22 December 2021.
19 Williams, M.; Rita, R. “Receptors as drug targets”. Current Protocols in
Pharmacology, 2006, 1.1.1-1.1.18, Wiley & Sons, Inc.