Lecture 5 Flashcards
NOAEL and LOAEL
NOAL- highest dose a which there was not an observed toxic or adverse effect, can produce some effects but are not considered adverse (statistically or biologcally significant increses in frequency or severity of adverse effects between exposed population and control)
LOAEL- lowest dose at which there was an observed toxic or adverse effect
NOEL
no oberved effect level: highest dose at which no effecs of compound are observed. Similar to NOAEL but not always the same thing
-NOEL refers to ANY effect
MRSD for FIH study
maximum recommended starting dose for first in human study
based on NOAEL from animal model preclinical testing
how to determine NOAEL? (3)
-over toxicity (clincal signs, macro and microscopic lesions)
-surrogate markers of toxicity (serum liver enzyme levels)
-exaggerate pharmacodynamic effects
HED
Human equivlent dose (of the NOAEL)
-dose in humans expected to provide same degree of effect as oberved in animals at a given dose
-based on allometric scaling from animals to humans (allometric = study of how biological processes scale with body size)
-based on body surface area and body weight (mg/kg conversion)
Correction factor Km
Km = body weight (kg) / body surface area (m^2)
HED =
dose given to animal * (Animal Km/Human km)
safety factor
lowering the human starting dose from the HED of the species NOAEL
-accomodates for differences between animal and human such as enhances sensitivty to pharmacologic activity, toxicity detection, receptor densities and affinities, unexpected toxicity, ADME
clinical trial definition
stuy conducted in human subjects to assess safety, and efficacy of new drugs, devices, diagnostics and therapeutic protocols
adverse event definition
and advser occurance in the health of clinical trial subject who is adminstered drug, may or may not be caused by a drug reaction
serious adverse drug reaction
requires hospitalization or prolonging current hospitalization, causes congenital malformation, disability ot incapacity, life threatening or results in death
tradition approach to clinical trials
extensice preclinical studies and based on collected info application for phase 1 clinical trials submitted to regulatory agency
exploratory microdose approach
minimum preclinical info collected and microdose in human subjects proposed (phase 0)
-microdose is a very low dose that cannot product harm to humans (1/100 of expected therapeutic dose)
Phase 0 trials
singe subtherpeutic dose adminnisered to small group of people, provides some data on pharmacodynamics and pharmacokinetics, no safety or efficacy data
-bases for go/no go decision
-may help speed clinical testing of new drugs
Phase 1
small (20-100) heathy people, for safety, PK, PD, ADME, and maximum safe dose
MTD
maximum tolerable dose
-start low and escalate
-about 3 people sequentially testing
-if toxicitiy obersved, test 3 more people, or if no toxicity, increse dose
-MTD is dose where 1/3 people experience unacceptable toxicity or the previous dose from that point
phase II
larger (20-300) patients with relevant condition
-assess safety and efficacy
-risk-benefit analysis (side effects vs efficacy)
-treatment and control groups
-blinding
Phase III
randomized controlled multucentre trials on large patient groups (300-3000)
-double blinded
-compare new treatement to “gold standard” on market
-comprehensive safety and efficacy data
-set dosage, frequency, and target patients for market
-submission for market approval
Phase IV
post-marketing studies, follow safety and efficacy in diff. populations. May be required for market approval
