Drug development (an overview with real drugs)
18 important questions on Drug development (an overview with real drugs)
What is background information about chronic myelogenous leukaemia?
- In this way CML must be distingquised from a leukomoid reaction that can give the same results in a routine laboratory test.
- Symptoms of CML could be: a large spleen with pain on the left side, malaise (feeling uncomfortable), joint and/or hip pain, low-grade fever, anemia, increased susceptibility to infections, thrombocytopenia with easy bruishing (kneuzingen)
How does the progress of CML go?
Then the advance phase dawns consisting of 2 phases; the first phase takes 1 year the second phase is the blastic phase and patients often survive 3 to 6 months in this last phase.
So what is the biggest feature of CML?
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What are genetic aspects of CML?
What are the molecular mechanisms behind CML?
A dysregulation of this kinase is linked to a variety of human cancers.
What are aspects for CML disease in such a way that it can be studied?
- It is easy measurable in vitro biochemical and cellular assays. (ATP meassurements)
- There are cell lines available with same chromosomal abnormalities.
This together means that is ideal for in vitro and animal studies.
What was the bioavailability of Glivec?
monkey: 19 - 55%
humans: more than 98%
What are the five difficulties when we try to extrapolate data from in vivo animal models to in vivo human models?
2) substrate specificity
3) regulation
4) organ specificity
5) toxicity
How was the distribution of Glivec in rats and mice?
- placental transfer
- It can also come into the milk
Mice:
- Almost no brain distribution
- Highest levels in kidney, liver and lung
What is the protein binding in rats, humans, mice and monkey's?
humans: 98%
Mice: 98%
monkey's: 90%
How is the metabolism of glivec?
In addition human in vitro microsome studies show that Glivec is a competitive inhibitor of cyp3A4/5, CYP2D6 as well as CYP2C9.
What is the NOAEL in rats and monkey's of Glivec?
monkey: 15 mg/kg/day
in a 13 weeks orally toxicity study.
How does the discovery pathway of glivec go?
2) Pharmacological or biochemical target
3) Molecular target
4) Structure elucidation
5) Drug design
6) Screening assay
7) Chemical leads
What were other targets of Gleevec found by in vitro screening?
- PDGF receptor: it probably has a role in the tumorigenisis and in the fibrosis.
What is drug targeting?
- less site effects
- increasing local concentrations at the target site
- Providing slow local drug release
What are cells frequent cells in the liver?
- Kupffercells
- stellate cells: it is involved in liver fibrosis
- endothelial cells
How does liver fibrosis occur?
2) This hepatocyte activates endothelial cells, stellate cells and Kupffer cells.
3) Both endothelial cells and Kupffercells also activate Stellate cells.
4) Once a stellate cell is activated it becomes a myofibroblast
5) The collagen production is activated and fibrosis starts
6) In the liver fibrosis can turn into cirrhosis in which stage a patient needs a donor organ.
What are the mechanisms of resistance to Glivec in CML?
- Protein binding of Glivec for example to circulating AGP
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