Drug development and quantitative bioanalysis
24 important questions on Drug development and quantitative bioanalysis
Why performing bioanalysis during drug development?
- It tells you something about pharmacodynamics of the drug (concentrations of endogeneous compounds e.g.)
What are the purposes of the preclinical phase?
- to help decide which compounds will be further developed.
- to determine safe starting dose for human administration
- it is typically performed with rats, mice, dogs and less frequently with rabbits and monkeys.
What kind of studies are performed during the preclinical phase?
- animal kinetic studies (bionanalysis for pharmacokinetics)
- pharmacology studies (mostly no bioanalysis)
- safety studies (mostly no bioanalysis)
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What is typical for the bioanalysis during the preclinical phase?
- Sample volumes are typically much lower than in humans (25 - 50 ul)
- The differences between individual animals is smaller than the differences between individual humans, so less variability in sample composition is expected. however, to obtain a PK curve most of the time, for every time point a different animal needs to be used due to the fact that small animals do not contain enough blood for collection of all the samples.
What is the purpose of phase 0 studies?
- to speed up the drug development process by pre-selecting drugs with favourable PK characteristics.
- no information on safety or efficacy possible.
- it is usally performed with radioactive labeled drugs.
What is the role of bioanalysis during phase 0?
- extreme sensitive methods are needed (concentrations down to 1 pg/ml or below).
- A tecnique that is often used to analyse these samples is accelerator mass spectrometry (AMS). This method can determine very low levels of radioactivity.
- with the newest LC-MS equipment, the required sensitivyt comes within reach.
What is an example of an phase 0 study?
- it is administered both iv and single oral.
- 4 different healthy male volunteers are needed. (they are exposed to all different compounds during different periods)
- blood samples are collected at several time points and with HPLC they are analysed.
- Nice PK curves are obtained for the different drug candidates.
- when drug candidates show a similar PK profile as the conventional drug, this is fine.
What is the purpose of phase 1 studies?
- to establish the appropriate dose(s) for further research in patients.
- usually performed with small groups of healthy volunteers
What kind of studies can be performed during phase I?
- Multiple ascending dose (MAD) studies
- Food effect (FE) studies
- Interaction studies
- Bioequivalence studies
- phenotyping studies
What are single ascending dose studies?
- single doses of certain drug are used.
- they start with a very low dose but this dose is increased step by step.
- it is placebo-controlled
- it is mostly performed with groups of healthy young male volunteers.
- The decision to continue or to stop is also based on PK.
What is the role of bioanalysis during SAD?
- the concentration range that needs to be covered is relatively large because of large difference in dose levels.
- the lower limit of quantification is often in the ng/ml range.
- the sample volume is often not limiting. (1-2 ml is avaiable)
- Results need to be known quick to allow weekly dosing.
What is an example of a SAD study?
several time points to monitor the blood levels.
such a study is started with one single dose to small group of male healthy volunteers. (so once administered) if PK values are fine, the dose can be increased (2X) either in the same group or a new group.
- if unaccepted toxicity is occurring, a new group is treated with the same dose. In this way the maximum tolerated dose is determined.
What is an important parameter to evaluate in a SAD study?
If this is not the case a kind of saturation might be the explanation (for absorption e.g.)
On which time points, samples are collected for a MAD study?
What is a food effect study?
- a single oral dose of an ivestigational drug is applied.
- there are 2 periods (with and without food).
- Groups of healthy young male volunteers are used. ( all of the volunteers have to undergo both periods (cross-over study).
- it is placebo-controlled.
What is the standardized FDA breakfast that is used in food studies?
2 fried eggs in margarine
1 portion of bacon
1 portion of fried potatoes
1 glass of high fat milk
total calories 842 kcal
How do you explain obtained results of a food effect study?
What are interaction studies?
- a single or a multiple dose of an investigational drug and/or another drug is applied.
- there are 3 periods (drug A alone, drug B alone and drug A + B combined)
- it is a cross-over study.
- blood sampling can be done in a similar way as in the MAD study.
- 2 curves are the results, one of drug A and one of drug B. (in both curves the combined curve is visible as well).
What are bioequivalence studies?
- 2 pharmaceutical products are bioequivalent if their bioavailabilities (rate and extent of adsorption) are similar after administration of the same dose.
Cmax and AUC values are determined
It is assumed that their effects, both with regard to safety and efficacy are the same.
How is determined if 2 drugs (or formulations) are bioequivalent or not?
- as long as the CI fits into the acceptable range (CI) it is fine. If one or both (Cmax or AUC) are not within the CI, the entire study needs to be repeated for example with a different formulation.
What is the purpose of a phase II study?
- phase 2a: to establish the appropriate dose(s) for patients
- phase 2b: to establish drug efficacy and short-term side effects in patients.
- usually performed with medium-sized groups of patients (smaller than 300) at a limited numver of clinical sites.
- The bioanalysis is important to support the conclusions.
How can a stimulation assay be performed?
Then the supernatant is harvested and an assay of cytokines in supernatant is performed. (e.g. ELISA)
- additionally, an anti-inflammatory drug can be added to test the inhibitory effect on cytokine production.
In which 3 ways stimulation assays can be performed?
ex vitro: endotoxin is added to whole blood from a subject that was dosed with a drug.
in vivo: whole blood from subject dosed with both drug and endotoxin.
What is the purpose of phase III studies?
- to evaluate risk-benefit relationship and compare to existing drugs.
- it is performed with large groups of patients (100-1000) at many clinical sites.
- bioanalysis is less important.
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