Module 7 Preclinical phase: Drug Safety Evaluation In Vivo, In Vitro Flashcards
This is the phase in which it is being decided whether a drug is ready for clinical trials (the so called move from bench to bedside).
Preclinical Phase
Involves extensive studies that yield preliminary efficacy, toxicity, pharmacokinetic and safety. information.
Preclinical Phase
Wide doses of the drug are tested using:
in vitro (test tube or cell culture)
In vivo (animal experiments).
In silico profiling (using computer models of the drug-target interactions).
Promising drugs often shelved based on rat or dog toxicity.
Research into early formulations tablet capsule or injection.
Preclinical results submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug (IND)-needed before move to clinical phase (human trial).
Preclinical Studies
Prior to human clinical trials there are cell studies to look at activity and toxicity.
Then animal studies to look at toxicity and elimination- rat, dog, macaque. Different animals used for different types of studies and different type of drug.
Preclinical Studies
The preclinical _______ tests involves various biological systems and reveals the species-, organ and dose-specific toxic effects of an investigational product.
Toxicity studies
The toxicity of substances can be observed by:
(a) studying the accidental exposures to a substance
(b) in vitro studies using cells/cell lines
(c) in vivo exposure on experimental animals
is a branch of science that deals with toxins and poisons and their effects and treatment.
Toxicology
is very important for the development of new drugs and for the extension of the therapeutic potential of existing molecules.
Toxicological screening
The US Food and Drug Administration (FDA) states that it is essential to screen new molecules for pharmacological activity and toxicity potential in animals (______).
21CFR Part 314
The history of toxicity studies begins with _____ (1493-1541), who determined specific chemicals responsible for the observed toxicity of plants and animals.
(Father of toxicology)
He demonstrated the harmless and beneficial effects of toxins and proved dose-response relationships for the effects of drugs.
“All substances are poisons, there is none which is not poison. The right dose differentiates a poison and a remedy”
Paracelsus
A Spanish Physician, determined the relationship between poisons and their biological properties and demonstrated specific organ damage caused by toxins.
“Father of Modern Toxicology”
Mathieu Orfila, (1787-1853)
proposed the use of the 50% lethal dose (LD) test to determine the lethal dose of individual chemicals.
Initiates the use of animals for toxicity studies
J. W. Trevan (1920)
developed a method for testing eye and skin irritation using rabbits, and this method was widely accepted for testing the effects of chemicals and pharmaceuticals on the eye and skin.
John Draize
helps predict a drug’s toxicity to humans.
In the early 1960s, thousands of babies were born with debilitating birth defects caused by ________. After this incident, all the regulatory agencies concentrated on determining the toxicity profiles of all pharmaceutical substances available for regular patient use and made mandatory the submission of toxicity profiles of investigational new drugs (IND).
Toxicity studies…
thalidomide
The term ___ refers to a medical test, experiment or procedure that is done on (or in) a living organism, such as a laboratory animal or human.
In vivo
The term ___, in contrast to in vivo, refers to a medical study or experiment which is done in the laboratory within the confines of a test tube or laboratory dish.
In vitro
This allows researchers to learn as much as possible about a drug before exposing humans to these potential effects.
___ are important in that they allow more rapid development of new treatments-many drugs can be studied at one time (and they can be studied in a large number of samples of cells) and only those that appear to be efficacious go on to human studies.
In vitro studies
___ are needed to see how the body as a whole will respond to a particular substance.
In some cases in vitro studies of a drug will be promising, but subsequent in vivo studies fail to show any efficacy (or, on the other hand, find a drug to be unsafe) when used within the multiple metabolic processes that are continually taking place in the body.
In vivo studies
It’s important to note that often times ____ studies are first done in non-human animals such as mice.
These studies allow researchers an opportunity to see how a drug works amid other bodily processes.
in vivo
Systems
-Gastric or gastrointestinal phases
-Static and dynamic controls
Advantages
-No ethical concerns
-Controllable systems
-High repeatability
-High-throughput potential
Challenges
-Parameter selection
-Missing unknown key factors
-Lacking physiological feedback loops
-Lacking infant gut microbes
In Vitro
Common Subjects
-Mice
-Piglets
-Human infants
Advantages
-Infant-specific biological environment
-Providing delicate feedback controls
-Revealing overall health outcomes
Challenges
-Ethical concerns
-Sampling limitations
-Subject variations
-High costs
In Vivo
5 ethical guiding principles:
- Autonomy - concept of independence
- Justice - treating equals equally and unequals unequally but in proportion to their relevant differences.
- Fidelity involves the notions of loyalty, faithfulness, honoring commitments.
- Beneficence - contribute to the welfare of the client, it means to do good.
- Nonmaleficence - not causing harm to others.
