New PharmGKB pathway: Paroxetine

The paroxetine PK pathway is the newest addition to PharmGKB's pathway summaries.

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) used for the treatment of multiple psychiatric disorders including mood, panic, anxiety, and obsessive compulsive disorders. The pathway diagram depicts candidate genes mediating the transformation of paroxetine into its metabolites. The main enzyme responsible for the metabolism is cytochrome P450 2D6 (CYP2D6).

View the Paroxetine Pathway at PharmGKB for a summary of genetic variations in pharmacokinetic and pharmacodynamic genes that might affect paroxetine's metabolism and response. 

View all pathways at PharmGKB.

New PharmGKB VIP Summary: HLA-B

Human leukocyte antigen B (HLA-B) is a cell-surface molecule responsible for the presentation of endogenous peptides to cytotoxic CD8+ T cells. This presentation of peptides allows for the recognition of pathogens, and leads to an immune reaction that destroys the infected cell. Variations within the HLA-B gene affect which peptides the molecule can present, but allelic changes have also been associated with susceptibility and resistance to numerous diseases and adverse reactions to a wide range of pharmaceuticals. Some of these pharmaceutical associations have been well-studied, such as HLA-B*57:01 and abacavir hypersensitivity, HLA-B*58:01 and allopurinol-induced severe cutaneous adverse reactions (SCARs), and HLA-B*15:02 and carbamazepine-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, many other variants within the HLA-B gene also show associations with drug phenotypes. 

The VIP summary posted on PharmGKB provides background on HLA-B and its role in the immune system, as well as discussing the roles of HLA-B alleles in diseases and pharmacogenetics, with a particular focus on the *57:01, *58:01 and *15:02 alleles. 

For more information, please read the entire HLA-B VIP summary and its associated variant summaries on PharmGKB.

View all VIP gene summaries at PharmGKB.

European approval of additional CFTR variants listed for ivacaftor use

The drug Ivacaftor (Kalydeco) was originally indicated for use in cystic fibrosis (CF) patients with one or two copies of the G551D variant (rs75527207) in the CFTR gene. The European Commission has approved the use of ivacaftor in patients with an expanded list of CFTR variants that all result in a defect in CFTR gating (announced in a press release by the company).

The additional variants are: G178R (rs80282562), S549N (rs121908755), S549R (rs121908757 and rs121909005), G551S (rs121909013), G1244E (rs267606723), S1251N (rs74503330), S1255P (rs121909041) and G1349D (rs193922525). 

These additional variants were approved by the FDA earlier this year, and added to the ivacaftor drug label indication section. In light of these changes, the CPIC therapeutic guidelines for ivacaftor were updated. 

The variants are listed in Table 2 of the PharmGKB CFTR VIP summary - view to read more about targeting CFTR variants to treat CF.

Praise for PharmGKB

PharmGKB is “the Holy Grail” for DNA STAT, a company that provides pharmacogenomics testing for patients. DNA STAT goes on to praise PharmGKB’s “accessibility and comprehensiveness” and highlights its “interactive SNP features and tools for education and clinical implementation of genetic data.”

Ifosfamide PK and PD pathways published in PG&G

Ifosfamide is a produg used in combination chemotherapy for the treatment of solid tumors. Around 20% of patients experience toxicity. Pathways depicting the genes involved in the pharmacokinetics and pharmacodynamics of ifosfamide have been published in PG&G. Variants in these genes that are associated with toxicity and drug resistance are discussed.

Click on the pictures to view the pathways:

Pharmacokinetics

Pharmacodynamics

Read the publication:

PharmGKB summary: ifosfamide pathways, pharmacokinetics and pharmacodynamics.
Lowenberg D, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE.

Pharmacogenetics & Genomics. 2014 Feb;24(2):133-8.

New PharmGKB VIP Summary: CYP4F2

Cytochrome p450, family 2, subfamily F, polypeptide 2 (CYP4F2) is known to catalyze multiple biological reactions.  It is predominantly expressed in the liver and kidneys, although there is evidence that it is also expressed in the intestines. Of specific interest in pharmacogenetics, hepatic CYP4F2 regulates the bioavailability of vitamin K and vitamin E and is currently studied to determine how polymorphisms in CYP4F2 affect warfarin dosing in patients. A single variant in CYP4F2 (rs2108622) is significantly associated with small, but significant alterations in warfarin dosage in Asian and Caucasian populations.

For more information on this VIP gene and variant, please see the VIP tab for CYP4F2.

Introducing CFTR as a Very Important Pharmacogene (VIP)

Variants within the CFTR gene underlie Cystic Fibrosis (CF). Traditionally, drugs used in the treatment of this disease have focused on ameliorating symptoms, fighting infection, thinning mucus and dampening inflammation. Now, drug development is focusing on pharmaceuticals that correct the underlying CFTR defect. The PharmGKB CFTR VIP summary describes potential treatment strategies that target defects conferred by particular classes of CFTR variants.

Read VIP information about these CFTR variants: 

• F508del-CFTR is prematurely degraded, failing to reach the plasma membrane. 

          Variants resulting in CFTR gating defects:

• G551D
• S549N
• G1244E 
• G1349D
• G178R
• G551S
• S1251N
• S1255P
• S549R(A>C) and S549R(T>G)