23 Pharmacogenomics Louie

Question 1

What is Therapeutic Index?

Answer 1

A measure of how far apart the dose that produces a desired efficacious effect is from the dose that will likely produce a serious unwanted, but predictable toxic effect

Question 2

When should a patient on 5-FU be changed to another treatment regimen?

Answer 2

Patients with verified DPD deficiency. Patients w/ DPD deficiency develop significantly earlier than patients with normal DPD activity. Increased TC activity linked to poor outcomes in patients treated with 5-FU and its derivatives

Question 3

What are the general characteristics of Thiopurines?

Answer 3

Purine analogs. Includes: 6-MP, thioguanine, and azathioprine. 6-MP has been used in the treatment of childhood ALL. This class of drugs is now used more for autoimmune disorder and to prevent organ rejection. Thiopurine Methyltransferase (TPMT) inactivates thiopurines

Question 4

Why is TPMT genetic testing done?

Answer 4

Low TPMT: Increased thiopurine toxicity. High TPMT: Decreased therapeutic effect

Question 5

What are the general characteristics of CYP2D6 and Tamoxifen?

Answer 5

Tamoxifen is a prodrug that is converted to its active metabolites endoxifen and 4-OH-TAM (4-OH-TAM is 30x more active, Endoxifen is 100x more active). CYP2D6 metabolizes Tamoxifen to endoxifen

Question 6

What happens with CYP2D6 polymorphisms and Tamoxifen?

Answer 6

Number of inactive alleles affects metabolism: Homozygous carriers (ex. 4/4) are poor metabolizers. Heterozygous carriers (ex. 1/4) are either intermediate or extensive metabolizers. There is concern that decreased CYP2D6 activity will lead to undertreatment with Tamoxifen

Question 7

What are UGT1A1*28 polymorphisms involved with?

Answer 7

Associated with increased risk of toxicity with Irinotecan. This polymorphism occurs in the promoter region. Individuals homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of Irinotecan

Question 8

How are UGT1A1*28 Polymorphisms associated with SN-38?

Answer 8

Hetero/Homozygous patients had lower glucuronidation of SN-38 and higher levels of SN-38 levels. Hetero/homozygous patients had higher grades of diarrhea and neutropenia