Transcript C&C PPT Format (14안)

『창의적 예측경영』『 효율적 내실경영 』
Chapter 17
Toxicity
2014. 03. 14
Lee, sang-hwi
Overview
 Toxicity remains a significant cause of attrition during development.

Many toxic outcomes are possible, including carcinogenicity(발암독성),
teratogenicity(기형발생물질), reproductive toxicity(생식기독성), cytotoxicity(세포독
성), and phospholipidosis.

Toxic mechanisms include reactive metabolites, gene induction, mutagenicity(돌
연변이), oxidative stress, and autoimmune response.

The safety window is the concentration range between efficacious response and
toxic response.
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Significant cause of attrition
 Maximize the safety window (therapeutic index) between efficacy and toxicity
 A major cause of drug candidate attrition during preclinical and clinical
development
Ex)
Kola-Landis study documented 20% to 30% attrition due to toxicity and clinical safety
KMR study reported 44% toxicity attrition.
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Significant cause of attrition
 Many drugs have been withdrawn from the market due to human toxicity observed
during clinical study.
 All companies perform Food and Drug Administration (FDA)-prescribed in vivo toxicity
studies prior to clinical studies.
 Most Componies also have addressed key safety issues, such as CYP450 inhibition and
hERG blocking, with in vitro screens during drug discovery.
 ADME/Toxicity properties
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Toxicity Fundamental
 IND (investigational new drug) : 의약품임상시험계획승인제도
 Standard Animal Toxicity Studies
- Chronic study : regular dosing over extended time periods (반복투여)
 독성이 나타나지 않는 최대용량 (무독성량 NOAEL, No Observed Adverse Event
Level)으로 투여,
- Acute study : single dose (단회투여)
- MTD : Maximum tolerated dose
used as a marker during first in human phase I studies
 Safety window (Therapeutic index)
- LD50 / ED50  높을수록 안전한 약물임!!!
- A large safety window improves the chances of the drug being safe in the
clinic
 Toxicity may be observed during phase I human studies that was not observed in
animals during preclinical safety studies.
의약품 개발과 허가 과정
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Toxicity Terms & Mechanisms

Therapeutic target (Target based 독성)
 Unintended effects of modulating the therapeutic target can be toxic.
 These are referred to as target- or mechanism-based toxicity.

Off-target (Other enzyme 등에도 영향을 미쳐 나오는 독성)
 The compound also can affect other enzymes, receptors, or ion channels in the
body.
 The effects of target or off-target modulation can be observed as
pharmacological (functional effect), pathological (lethal effect), or carcinogenic
(producing cancer)

Reactive metabolic intermediates
Reactive metabolites produce undesirable effects by covalent reaction with
endogenous macromolecules, which can lead to cell death, carcinogenicity, or
immunotoxicity
Toxicity Terms
 Acute toxicity is the toxic response from a single dose.
 Chronic toxicity is the toxic response from long term dosing.
 Cytotoxicity is the production of cell death, such as in liver cells (hepatotoxicity).
 Carcinogenicity is the production of cancer. There is often a long latency period from
compound exposure to tumor appearance. (잠복기간이 길수도 있다)
 Genotoxicity (유전독성) is a mutagenic change of the DNA sequence or chromosome
damage. It often leads to cancer.
 Chromosomal aberration assay (CA)
 Ames assay : liver S9(+), liver S9(-)
 Idiosyncratic reactions(특이체질반응) are immune-mediated effects having delayed
onset and are caused by reactive metabolites.
Proposed mechanisms involve cell damage and individual patient conditions, such as
enzyme irregularities or polymorphism(같은 종의 생물이지만, 모습이나 고유한 특징이 다
양한 성질).
 Immunotoxicity is an immune reaction (e.g., lymphoproliferation:임파구 증식
,autoimmunity) triggered by the compound (e.g., penicillin) or reaction of a metabolite
with endogenous macromolecules to form an antigen.
 Organ toxicity deteriorates the function of the organ
(e.g., heart, liver, kidney, blood cells, brain).
 Phospholipidosis is the accumulation of polar phospholipids in lysosomes as lamellated
(층판) bodies in response to cationic amphiphilic drugs.
 Reproductive toxicology(생식독성) is a change in reproductive systems, normal
function, or sexual behavior.
 Safety pharmacology studies the effects of a compound on normal physiological
functions. Abnormal function is often caused by inhibition of enzymes or antagonism or
agonism of receptors or ion channels.
 Teratogenicity(최기형) is embryo toxicity or abnormal development.
(The effect of thalidomide on human embryo development is well known.)
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예)
Thalidomide
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Toxicity Mechanisms
 Therapeutic Target Effects
 Undesirable effects in the target tissue or elsewhere in the body.
 These effects are observed in animal dosing studies or reports from human
clinical use.
 Off-Target Effects
 The lead compound or series might inhibit an unintended enzyme or receptor in
the body.
 This disrupts the normal function and can cause toxicity or side effects.
 If these are not severe and can be tolerated by the patient, they may be
manageable in clinical use of the drug.
ex) drug–drug interaction (DDI)
 DDI can cause a buildup of the second compound to a concentration that
causes toxic effects.
 Off-target effects usually are screened in drug discovery by sending the
compound to an outside laboratory (e.g., Novascreen, MDS PanLabs).
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 Reactive Metabolites
 A major cause of drug toxicity is metabolic bioactivation.
 An unfortunate consequence of metabolism is that a reactive metabolite or
intermediate can cause toxicity.
 The reactive intermediate or metabolite might be an electrophile, which
covalently binds to endogenous nucleophiles (e.g., proteins, DNA).
 The resulting adduct does not function normally.
 It can cause DNA mutation, which can lead to cancer.
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(아래 Substructre는 조심해서 design 할것!!)
Nitrogen mustard
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NuNu
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 Gene Induction
A compound can induce the expression of a gene and its protein product.
ex) Rifampicin : CYP3A4 inducer (the higher 3A4 levels result in faster metabolism
of 3A4 substrate)
 Oxidative Stress
 Some compounds undergo redox cycling (one electron reduction to the radical
followed by reoxidation) within the cell and induce an oxidative environment
through enhancing the process of oxygen reduction.
 Normally cells are maintained in a reducing environment by enzyme systems
and glutathione.
 Oxidative stress results in the increase of free radicals and peroxides.
 These can abstract a hydrogen atom from lipids, glutathione, and DNA,
resulting in cell damage and death.
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Structure Modification Strategies to improve safety
 Avoid substructures that are known to induce toxic responses.
 Early synthetic modifications should be undertaken to remove any potentially
toxic substructures from lead series.
 Potentially toxic substructures should not be added to lead series structures during
lead optimization.
 Perform reactive metabolite assays to screen for potentially toxic compounds.
 Data indicating potential toxicity from in vitro assays can be further investigated by
structure elucidation of the metabolites or trapped intermediate using spectroscopy.
 Utilize the metabolite structural modification strategies discussed to attempt to
reduce metabolic bioactivation.
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