ICH Guidelines Flashcards
These studies are are often performed in a very early phase of development before a bioanalytical method has been developed and toxicokinetic monitoring of these studies is therefore not normally possible.
Single-dose toxicity studies
For negative results of this type of study, it may be appropriate to have demonstrated systemic exposure in the species used or to have characterized exposure in the indicator tissue.
Genotoxicity studies
During this type of study, the treatment regimen and species should be selected whenever possible with regard to pharmacodynamic and pharmacokinetic principles.
Repeated-dose toxicity studies
Thus, the emphasis of this guidance is on the need to estimate systemic exposure, to parent compound and/or metabolite(s) at appropriate dose levels and at various stages of this type of study, so that the findings of the study may be considered in the perspective of comparative exposure for the animal model and humans.
Oncogenicity Study
The limitation of exposure in reproductive toxicity is usually governed by what?
Maternal Toxicity
The chemical entity assayed in biological samples.
Analyte
What is the definition of Matrix?
Blood, plasma, urine, serum or other fluid or tissue selected for assay.
Toxicokinetic measurements performed in the toxicity study, either in all animals or in representative subgroups or in satellite groups.
Concomitant toxicokinetics
This is represented by pharmacokinetic parameters demonstrating the local and systemic burden on the test species with the test compound and/or its metabolites. The area under the matrix level concentration-time curve (AUC) and/or the measurement of matrix concentrations at the expected peak-concentration time Cmax, or at some other selected time C(time),are the most commonly used parameters.
Exposure
What is it called to take a small number of matrix samples (e.g. 1-3) during a dosing interval to estimate C(time) or Cmax?
Monitor
What is it called to take (e.g. 4-8) matrix samples during a dosing interval to make an estimate of Cmax and/or C(time) and area under matrix concentrationtime curve (AUC)?
Profile
What are Satellite Groups?
Groups of animals included in the design and conduct of a toxicity study, treated and housed under conditions identical to those of the main study animals, but used primarily for toxicokinetics.
What word means - to ratify or confirm the design of a toxicity study with respect to pharmacokinetic and metabolic principles?
Support
What word means - to establish the accuracy, precision, reproducibility, response function and the specificity of the analytical method with reference to the biological matrix to be examined and the analyte to be quantified?
Validate
What is Cmax?
Maximum peak concentration
What is C(time)?
Maximum concentration at a specified time after administration of a given dose.
What is tmax?
Time to reach peak or maximum concentration following administration
What is AUC(0-t)?
Area under concentration-time curve from zero to time t. It should be noted that AUC(0-infinity) is a special case of AUC(0-t).
Which of these is false?
1. Increases in exposure may arise unexpectedly as a result of nonlinear kinetics due to saturation of a clearance process.
2. Decreasing exposure may also occur during the course of a study for those compounds which have a particularly long plasma half-life.
3. Careful attention should also be paid to compounds which achieve high Cmax values over comparatively short time periods within the dosing interval.
4. Unexpectedly low exposure may occur during a study as a result of auto-induction of metabolising enzymes.
2. It should read “Increasing”
What are the purposes of the ICH Safety Guidelines
1st- Describe systemic exposure and relationship to dose level and time
2nd- Relate exposure to toxicity, support choice of species, provide information to design subsequent non-clinical studies
What term is a method to collect a very small amount of blood (typically ≤50 µL) that is generally used to measure concentrations of a drug and/or its metabolites, and subsequently calculate the appropriate TK parameters? And what species are typically used?
Microsampling
Rodents and non-rodents
What are the benefits/advantages of microsampling?
Minimizing the volume of blood collection can reduce pain and distress in animals and improve the animal welfare (refinement) of rodents and non-rodents. It can also eliminate the TK satellite group or reduce the number of animals required.
When should microsampling be avoided?
Microsampling is not warranted when the drug concentration is low and the majority or all samples are Below the Limit of Quantification (BLQ) (e.g., exposure after topical or inhaled administration).
For liquid sampling, which of the following issues should NOT be considered:
1) ensuring sample homogeneity, for example by pipetting;
2) small volume handling issues (e.g. potential freezing/drying effects during the storage and subsequent freeze/thaw process, as applicable);
3) potential decrease in the LLOQ due to the limited sample volume; 4) impact of addition of anticoagulants to small containers/capillaries, resulting in dilution of the sample;
5) potential for increased adsorption of the analyte to the collection container (i.e. increased surface area to volume ratio);
6) keeping the appropriate preservation conditions of the sample;
7) risk of contamination and difficulty of repeated sampling using some methods.
3.
Should read:
3) potential increase in the LLOQ due to the limited sample volume;
What does ICH stand for?
International Council for Harmonization
Minimizing volume of blood collection:
A. Can minimize pain and distress in animals (improvement of the animal welfare: refinement).
B Can reduce or eliminate the number of required animals in a TK satellite group for rodents (reduction), particularly for mice.
C Can make evaluation of the relationship between safety data and drug exposure in the same animals, when performing on main study group.
Choices:
1. A.
2. B and C only
3. A and B only
4. All of the above
5. None of the above
- All of the above.
True or False:
In the few situations where a dose of 1000 mg/kg/day does not result in a mean exposure margin of 10-fold to the clinical exposure and the clinical dose exceeds 1 g per day, then the doses in the toxicity studies should be limited by a 10-fold exposure margin or a dose of 2000 mg/kg/day or the MFD, whichever is lower.
True
Ture or False:
Nonclinical characterization of a human metabolite(s) is only warranted when that metabolite(s) is observed at exposures greater than 10% of total drug-related exposure and at significantly greater levels in humans than the maximum exposure seen in the toxicity studies.
True
What is the definition and calculation method of 10% threshold?
The 10% threshold refers to when a human metabolite comprises greater than 10% of the measured total exposure to drug and metabolites, usually based on group mean AUC (e.g., AUC 0-inf).
The 10% threshold refers to when a human metabolite comprises greater than 10% of the measured total exposure to drug and metabolites, usually based on group mean AUC (e.g., AUC 0-inf).
It is general practice to use contraception in males until the potential for reproductive and developmental risk has been addressed
According to the ICH Guideline section M4: The Common Technical Document, which of the following topics is not a component?
1. Organization
2. Quality
3. Safety
4. Efficacy
5. Reproducibility
- Reproducibility
What is the ICH Q3A reporting threshold for degradation products?
Below 1%
True or False:
A TTC-based acceptable intake of a mutagenic impurity of 1.5 µg per person per day is considered to be associated with a negligible risk (theoretical excess cancer risk of <1 in 100,000 over a lifetime of exposure) and can in general be used for most pharmaceuticals as a default to derive an acceptable limit for control.
True
What is an acceptable intake?
An intake level that poses negligible cancer risk, or for serious/life-threatening indications where risk and benefit are appropriately balanced.
What is an acceptable limit?
Maximum acceptable concentration of an impurity in a drug substance or drug product derived from the acceptable intake and the daily dose of the drug.
What is acceptance criterion?
Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures.
What is a control strategy?
A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.
What is the total intake of a substance that a person is exposed to over time.
Cumulative intake
What is a degradation product?
A molecule resulting from a chemical change in the drug molecule brought about over time and/or by the action of light, temperature, pH, water, or by reaction with an excipient and/or the immediate container/closure system.
If something is DNA-reactive, it has the potential to do what?
The potential to induce direct DNA damage through chemical reaction with DNA.
What is the definition of genotoxicity?
A broad term that refers to any deleterious change in the genetic material regardless of the mechanism by which the change is induced.
What is Any component of the drug substance or drug product that is not the drug substance or an excipient.
Impurity
What is QSAR/SAR?
The relationship between the molecular (sub) structure of a compound and its mutagenic activity using (Quantitative) Structure-Activity Relationships derived from experimental data.
What is a purge factor?
Purge reflects the ability of a process to reduce the level of an impurity, and the purge factor is defined as the level of an impurity at an upstream point in a process divided by the level of an impurity at a downstream point in a process. Purge factors may be measured or predicted.
What mutagenic impurity added to ICH M7 is mutagenic in hypoxantine-phosphoribosyl-transferase (HPRT) assay in mammalian cells while negative in the Ames test?
Acetaldehyde
What mutagen is on carcinogenic in rats orally, but is via inhalation (nasal adenocarcinoma), and is exposed to humans through food (and is endogenously formed as metabolite of carbohydrates)
Acetaldehyde
What is the oral PDE of acetaldehyde?
2 mg/day.
(All other routes is 185 ug/day)
What mutagenic impurity added to ICH M7 is mutagenic in Ames test and HPRT test in Chinese hamster ovary, is and carcinogenic orally and via inhalation in the rat?
1,2 Dibromoethane (2ug/day)
What mutagenic impurity added to ICH M7 is mutagenic in the Ames and mouse lymphoma test, and is carcinogenic at the site of contact (i.e. stomach following oral, nasal following inhalation, subq following injection)
Epichlorohydrin (3 ug/day)
What mutagenic impurity added to ICH M7 is mutagenic in the ames test as a gas and is an alkylating agent?
Ethyl Bromide (32 ug/day)
What mutagenic impurity added to ICH M7 is mutagenic is mutagenic in the Ames test and in the HPRT test in mammalian TK6 cells?
Formaldehyde
What mutagenic impurity added to ICH M7 is mutagenic is considered to be a site-of-contact carcinogen acting by cytolethality/regenerative cellular proliferation? a
Formaldehyde
inhalation (8mg /day or 215 ppb, whichever is lower)
other routes PDE 10mg/day
What mutagenic impurity added to ICH M7 is mutagenic in the Ames test only with metabolic activation and in vivo in lymphocyte of exposed workers?
Styrene 154 ug/day
Metabolite styrene 7,8-oxide is a mutagenic compound
What mutagenic impurity added to ICH M7 is not mutagenic in the Ames test, but genotoxic causing chromosomal damage in human lymphocytes?
Vinyl Acetate
Oral PDE 2mg/day
Other PDE 758 ug/day
What mutagenic impurity added to ICH M7 undergoes rapid hydrolysis to form acetic acid and aldehyde?
Vinyl Acetate
What is the new, updated duration of HIV treatment?
> 10 years - lifetime
