How New Insights into Pharmacogenomics Lead to Rev

1、1 how new insights into pharmacogenomics lead to revisions of product labels shiew-mei huang, ph.d. deputy director for science office of clinical pharmacology however, clinical results have been variable and such patients have been shown to tolerate normal starting doses. 13 if individuals with cer

2、tain genetic makeup are more sensitive to one of the life threatening adverse events that may not be managed via dose reduction example: thioridazine 14 thioridazine contraindications elevated levels of thioridazine would be expected to augment the prolongation of the qtc interval associated with th

3、ioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias. . therefore, thioridazine is contraindicated . in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced le

4、vels of activity of p450 2d6 (see warnings and precautions ). action- recommendations 15 if individuals with certain genetic makeup had a higher rate of adverse reactions example: atomoxetine 16 atomoxetine adverse event adrpmem decreased appetite23% 16% insomnia 13% 7% sedation 4% 2% depression 6%

5、2% tremor4% 1% early morning awakening 3% 1% pruritus 2% 1% mydriasis2% 1% descriptive info- 17 when a specific laboratory test is available. examples: atomoxetine azathioprine 18 atomoxetine laboratory test laboratory tests : laboratory tests are available to identify cyp2d6 pms .higher blood level

6、s in pms lead to higher rate of some adverse effects of strattera. 19 azathioprine laboratory tests: tpmt testing: it is recommended that consideration be given to either genotype or phenotype patients for tpmt. phenotyping and genotyping methods are commercially available. the most common non- func

7、tional alleles associated with reduced levels of tpmt activity are tpmt*2, tpmt*3a and tpmt*3c. patients with two non-functional alleles (homozygous) have low or absent tpmt activity and those with one non-functional allele (heterozygous) have intermediate activity. 20 device labeling intended use s

8、ummary & explanation of the test test procedure limitations summary of expected results or performance characteristics 21 .an in vitro diagnostic test for detection and genotyping of the *1 (ta6) and *28 (ta7) alleles of .the ugt1a1 gene. .aid in identification of patients with greater risk for decr

9、eased ugt activity example: ugt1a1 molecular assay 22 .can be used to identify patients that may require dose modifications for drugs that are metabolized by ugt1a1 .patients who possess the ugt1a1*28 genotype are at greater risk for irinotecan-induced toxicities example: ugt1a1 molecular assay 23 l

10、abeling questions 1. what is the best way to present genetic information in the labeling (section and content) for use by providers and patients? progression of labeling (recent examples): - atomoxetine: cyp2d6 pm (2003) - 6-mp: tpmt*2, *3a, *3c (2004) - irinotecan: ugt1a1*1, *28 (2005) - thioridazine: genetic defect reduced activity of 2d6 (2003) - azathioprine: tpmt*2, *3a, *3c (2005) 24 labeling questions 2. how should the results of a genotype test be reported when technology allows measurement of genotypes where cli