PHRM 3310 Test 2

Drug Development & Lifecycle; Toxicology, Pharmacology, & Special Patient Populations; Herbal Drugs; Autonomic Pharmacology

What are the MAIN sequential stages of the drug developmental process?

Discovery & Development → Preclinical Research → Clinical Development → Regulatory Review → Post-Market Surveillance

What is the fundamental purpose of discovering new drugs?

to develop safe, effective drugs that fill a therapeutic need

Who discovers drugs?

• government labs

• pharmaceutical companies

• public & private university research centers

Through what methods/approaches do scientists discover drugs?

• new drug targets: basic science, disease mechanisms

• rational drug design: molecular modeling

• structure/activity: medicinal chemistry

• screening: natural products, chemical libraries, high-throughput assays (to find drug candidates w/ highest efficacy & lowest toxicity)

What is the timeline & cost from drug discovery to U.S. market approval?

10+ years (12-14 years average) & $>100,000,000 per successful drug

What is the value of the worldwide annual pharmaceutical market?

$1.6 trillion

What are the 2 distinct pathways for drug discovery?

• (1) rational drug design

  • disease → mechanism → target → structure → lead compound → refine

• (2) screening

  • disease → model of disease → huge chemical diversity → lead compound → mechanism → refine

What are the optimization techniques?

• efficacy

• toxicity

• dosage form

• A.D.M.E.

What biological/pharmaceutical disciplines contribute to drug discovery?

• cell biology

• biochemistry

• genetics

• physiology

• pharmacology

• pharmaceutics

• medicinal chemistry

What are the KEY steps in the drug discovery workflow?

• (1) choose target (e.g., enzyme)

  • know the mechanism

• (2) choose system: simple assay (e.g., cell lines)

  • work up: In vitro, cells, animals

• (3) determine specificity: off-target effects

• (4) identify “hits”

Why is it critical to choose a good animal model?

• predict toxicity/side effects

• identify lead compounds

• optimize lead compounds

What tools & methodologies are used during the DRUG DISCOVERY (0-5+ years) stage of the U.S. Drug Development Process?

• combinatorial chemistry

• natural product isolation

• QSAR (qualitative structure activity relationship)

• pharmacology

• biology

• In vitro

• future: In vivo & ADME

What tools & methodologies are used during the PRECLINICAL (1-3+ years) stage of the U.S. Drug Development Process?

• synthesis

• pre/formulation

• development

• pharmacokinetics

• animal testing

• stability

What are the MAIN causes of drug failure during development & their percentage rates?

• pharmacokinetics (39%)

• lack of efficacy (30%)

• animal toxicity (11%)

• commercial reasons (11%)

• adverse effects in people (10%)

• miscellaneous (5%)

Why is it important to fail early in drug development?

failing early minimizes financial loss from expensive late-stage R&D + clinical trials

What role does the Food & Drug Administration (FDA) play in drug development?

• regulates BOTH development & marketing

• safety & efficacy

• pre-clinical & clinical testing requirements

What are the primary preclinical requirements BEFORE clinical (human) trials?

*stringency influenced by urgency & proposed use*

• toxicity studies in animals

• demonstration of efficacy in animals (where applicable)

• pharmacokinetic studies

• mechanism

How many years can the CLINICAL stage of the U.S. Drug Development Process take?

3-8+ years

What specific types of toxicity are tested during preclinical animal studies?

• acute: lethal dose

• subacute: proposed dose & course of treatment

• chronic: proposed dose for longer time course

What specific general safety measures are tested during preclinical animal studies?

• pharmacological profile: blood pressure, GI activity, renal function

• reproductive toxicity: teratogenesis, mutagenesis

• carcinogenesis: malignancy

What limitations exist in preclinical testing?

• time & money

  • 2-5 years before being administered to humans

  • $41,000,000 per successful drug

• animal welfare

  • heavy concerns

• humans do NOT equal animals

  • special differences

What is an IND?

it is an Investigational New Drug application

When is an IND filed?

it is filed after successful preclinical testing & BEFORE human clinical trials start (“first in man”)

What does an IND contain?

it contains…

• composition & sources of drug, manufacturing information

• animal studies

• clinical plans/protocols with physicians’ credentials

What defines Phase I clinical trials?

• focuses on SAFETY & pharmacokinetics in humans

  • usually “open”

  • uses 20-30 participants who are usually healthy (except in chemotherapy trials)

What defines Phase II clinical trials?

• focuses on EFFICACY (limited efficacy study) & side effects

  • usually single-blind

  • uses 100-300 patients WITH the disease

  • placebo controls

What defines Phase III clinical trials?

• focuses on POPULATION (BOTH expanded SAFETY & EFFICACY)

  • usually double-blind

  • uses 1,000-5,000 patients across multiple locations

  • compares drug to placebo OR existing therapy

  • toxicity screening

What are the primary limitations & biases in clinical trials?

• rare effects will NOT likely be detected

• positive controls (existing drug on the market) & negative controls (placebo)

  • patients with terminal illnesses (late-stage cancer)

• interference by medical history or subjects

  • screening (full disclosure)

  • legitimate randomization

• bias

  • placebo effect (20-40%)

  • placebo NOT used in terminal or severe illness

  • subject bias addressed w/ single-blind design

  • subject + observer bias addressed w/ double-bind design

What is an NDA?

it is a New Drug Application

When is an NDA submitted?

it is submitted to the FDA after successfully passing Phase III clinical trials to request permission to market the drug (“to market”)

What does an NDA contain?

contains all clinical & preclinical data

How long does it take for an NDA to be reviewed?

it may take several years to review

What defines Phase IV (Post-Marketing Surveillance)?

• monitors long-term safety, efficacy, & low-incidence toxicities/side effects (e.g., 1:10,000) that ONLY appear AFTER wide marketing

• checks for new indications

• not as tightly regulated

When do generic drugs appear on the market?

they appear 20 years after patent application, or up to 14 years after NDA approval if an extension was granted due to approval delays

What are PREDICTED adverse reactions?

they are toxicity related to known pharmacological mechanism or identified off-target effects

What are UNEXPECTED adverse reactions?

• they are unidentified off-target effects or allergic reactions

  • IgE-mediated: anaphylaxis, urticaria, angioedema

  • IgG/IgM-mediated: lupus, serum sickness, contact dermatits

What is the primary purpose of Phase II clinical trials?

to evaluate efficacy & side effects in a small group of patients

During which phase are large-scale, controlled clinical trials conducted to confirm effectiveness & monitor side effects of a drug?

Phase III

What document must be filed with the FDA after successful preclinical testing & before starting human clinical trials?

Investigational New Drug (IND) Application

Which of the following best describes “Phase IV” of the drug approval process?

post-marketing surveillance to monitor safety & efficacy

A drug company submits a(n) ____ to the FDA to ask for approval to market a new drug after completing Phases I-III?

New Drug Application (NDA)

Which statement best describes toxicology as a scientific discipline?

it is arguably the oldest scientific discipline, since early humans had to recognize which plants were safe to eat

Most human exposure to chemicals occurs through…

naturally occurring compounds consumed from food plants

Humans are exposed to chemicals…

BOTH inadvertently & deliberately

Toxicology is best defined as the study of…

toxic or drug-related adverse effects of drugs or chemicals on the health of living systems

Who is considered the father of modern toxicology?

Paracelsus

The statement “the dose makes the poison” means…

ANY chemical or drug can be toxic if given at a high enough dose

A toxicologist is trained to…

examine the nature of adverse effects & assess the probability of their occurrence

Toxicogenomics is used to…

identify & protect genetically susceptible individuals from harmful environmental exposures and to customize drug therapies based on individual genetic makeup

Which of the following is NOT a MAJOR category of toxic exposure?

dietary supplements

Which of the following is a route of EXPOSURE?

all

The spectrum of toxic effects includes ALL of the following EXCEPT…

acute vs. chronic potency

Animal testing for drug toxicity must be approved by which committee?

the Institute Animal Ethics Committee (IAEC)

Researchers are trying to minimize animal testing using alternative methods such as…

in vitro & in silico studies

Why are researchers seeking to minimize animal testing?

because of expensive & complex protocols and the difficulty of extrapolating data to humans

LD50 is defined as…

the dose that is LETHAL to 50% of the population

When comparing toxicants using LD50, the most potent (lethal) compound is the one with…

the LOWEST LD50 value

Exposure to a chemical for < 24 hours is classified as…

acute

Repeated exposure to a chemical for 1 month or less is classified as…

subacute

Repeated exposure to a chemical for 1-3 months is classified as…

sub-chronic

Repeated exposure to a chemical for > 3 months is classified as…

chronic

The main goal of toxicology studies during drug development is to…

provide a PRE-liminary safety level of drug candidates from SEVERAL routes of exposure

Which of the following is a question addressed during animal PRE-clinical testing?

all

In human clinical testing, safety studies in a SMALL number of patients occur in…

Phase I

Post-marketing surveillance occurs in…

Phase IV

Safety monitoring in THOUSANDS of patients occurs in…

Phase III

Which phase involves healthy volunteers vs. patients?

Phase I

Which of the following is an observation made in animal toxicity studies?

body weight, feed/water intake, appearance, & activity levels

Hepatocellular evaluation in clinical testing uses which markers?

alanine aminotransferase (ALT) & aspartate aminotransferase (AST)

Hepatobiliary evaluation uses which markers?

alkaline phosphatase & total bilirubin

Which if the following is measured as part of clinical toxicity testing?

all

In the study of 150 compounds, what was the concordance between rodent & human target organs?

43%

In the study of 150 compounds, what was the concordance between NON-rodent & human target organs?

63%

Overall, in the study of 150 compounds, what concordance was observed between animal special & humans for the SAME organ toxicity?

70%

In the study of 150 compounds, the 70% overall concordance between animals & humans was specifically for which toxicities?

cardiovascular (CV), GI, & hematological

The “3 Rs” in animal research refer to…

reduction, refinement, & replacement

Why are laboratory animals STILL needed?

NO real substitutes exist; the complexity of living organisms requires testing on animals “similar to” humans for reliable, effective results

Which of the following is a developmental population requiring special consideration?

all

Which factor affects a drug’s access to the placenta?

all

Regarding lipid solubility & placental transfer,…

NON-ionized compounds reach the placenta at HIGH concentrations

Regarding molecular size & placental transfer,…

compounds <500 Da cross easily, but compounds >1000 Da cross VERY slowly

Why is heparin a safe anticoagulant for pregnant women while heparin is NOT?

heparin is BIG & POLAR, so it does NOT cross the placenta; warfarin CAN cross

The MDR1 transporter in the placenta…

pumps many drugs BACK to the mother & its effect depends on expression level

The placenta is capable of which types of metabolic reactions?

BOTH Phase I (oxidation, reduction, hydrolysis) & Phase II (conjugation) reactions

Why does MOST fetal blood enter the liver directly?

for detoxification

Which drugs are delivered to the mother to target the fetus therapeutically?

BOTH corticosteroids (to induce lung development) & zidovudine (to minimize HIV transmission)

A teratogenic drug…

disturbs the development of the embryo or fetus & can affect oxygen or nutrient availability

Characteristics of teratogens include ALL of the following EXCEPT…

they affect ALL stages of development EQUALLY

Regarding counseling about drug use in pregnancy,…

all

What is Pregnancy Category D?

there is POSITIVE evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, BUT potential benefits MAY warrant use of the drug in pregnant women DESPITE potential risks

What is Pregnancy Category X?

studies in animals or humans have demonstrated fetal abnormalities and/or there is POSITIVE evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, & the risks involved in use of the drug in pregnant women clearly OUTWEIGH potential benefits

Which of the following affects drug absorption in INFANTS?

all

Compared to adults, INFANTS have…

HIGHER relative water volume & less fat, affecting lipophilic drug distribution

INFANTS have LOWER plasma protein binding, which results in…

HIGHER available (free) drug concentration, requiring careful dosing

NEONATES have LOWER liver metabolic enzyme levels, resulting in…

LONGER half-life

Regarding drug excretion in INFANTS,…

GFR is VERY low for the 1st week of a full-term baby & normal BY 1 year

Which drugs are cleared VERY slowly in NEONATES?

penicillin & aminoglycoside antibiotics

They KEY takeaway about dosing INFANTS & CHILDREN is that they…

canNOT be considered SMALLER versions of adults when giving them drugs

Regarding drug use during breastfeeding,…

MOST drugs are safe while breastfeeding & breastfeeding is BEST for the baby

What is the SAFEST time to take a drug relative to feeding?

3 hours PRIOR to feeding