We have updated the pathway: Tamoxifen PK pathway.

Tamoxifen is a selective estrogen receptor modulator. It is used to treat estrogen receptor positive breast cancer, and has been shown to decrease disease recurrence and mortality rates by 50% and 30%, respectively.

PharmGKB's Tamoxifen PK pathway describes the metabolism of tamoxifen from what can be classified as a pro-drug, to a more potent estrogen receptor inhibitor, and finally to its inactivation.

View or download the pathway here: Tamoxifen PK pathway.

View all pathways at PharmGKB.

Personalized Medicine World Conference 2013

PharmGKB curators attended the PMWC this week, featuring talks covering different areas and aspects of personalized medicine, including pharmacogenetics, co-drug and diagnostics development, adaptation of clinical trials, systems medicine, wellness, sequencing technologies, and implementation.

CPIC guidelines for TPMT and Thiopurine dosing: Update 2013

The 2013 update of the CPIC guidelines for TPMT and Thiopurine dosing is now available online, as an accepted article preview. CPIC genotype-based dosing guidelines are reviewed and updated every two years in order to be clinically current - this is the first update to be released.

After an extensive literature review, CPIC concluded that there is no new evidence that would result in changes to the original guidelines, published in 2011 and available to read or download from PharmGKB.

Read the 2013 update:

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for thiopurine methyltransferase (TPMT) genotype and thiopurine dosing: 2013 update 

Mary V. Relling, Eric E. Gardner, William J. Sandborn, Kjeld Schmiegelow, Ching-Hon Pui, Sook Wah Yee, Charles M. Stein, Michelle Carrillo, William E. Evans, J. Kevin Hicks, Matthias Schwab and Teri E. Klein. 
Clin Pharmacol Ther doi:10.1038/clpt.2013.4; accepted article preview online January 17, 2013.

View the CPIC gene-drug pairs table with the current status of guidelines and updates.

Additional EMA drug labels released on PharmGKB

Our collection of drug labels containing pgx information from the European Medicines Agency has been extended:

Boceprevir and IL28

Brentuximab vedotin and CD30 (TNFRSF8)

Capecitabine and DYPD

Cetuximab and KRAS

Crizotinib and ALK

Dasatinib and the Philadelphia chromosome

Eltrombopag and F5, SERPINC1 

Everolimus and ERBB2 (HER2)

Fulvestrant and estrogen receptor

View a complete list of available FDA and EMA drug labels with highlighted pgx information.

Tailored therapy in asthma? ADRB2 genotype in the context of salmeterol therapy

In a recent trial, asthmatic children homozygous for the beta2-adrenergic receptor Arg16 variant (ADRB2 gene, rs1042713 genotype AA) were randomized and treated with either salmeterol (a beta2-adrenergic receptor agonist) or montelukast (a leukotriene receptor antagonist), both combined with fluticasone. Those in the montelukast treatment group displayed significantly better responses in several symptom categories, had fewer school absences, and overall had significantly higher quality of life scores over the 1 year period compared to those treated with salmeterol. [Click here for Further details]

Tailored second line therapy in asthmatic children with the arginine-16 genotype. Lipworth BJ, Basu K, Donald HP, Tavendale R, Macgregor DF, Ogston SA, Palmer CN, Mukhopadhyay S. Clinical Science (2013) 124, (517-519).

This trial was based on previous studies from the same group showing an increased risk of asthma exacerbations in children with daily exposure to beta2-adrenergic receptor agonists who have the ADRB2 Arg16 variant: 

• "Arginine-16 beta2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol" Palmer et al, (2006). 
• "Adrenergic beta(2)-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol" Basu et al, (2009).

These studies suggest that alternative treatments may be more beneficial in children with the Arg16/Arg16 genotype compared to using beta2 adrenergic receptor agonists.

Learn more about Beta-agonist action on ADRB2:

PharmGKB Beta-agonist/Beta-blocker Pathway, Pharmacodynamics

Learn more about the ADRB2 gene:

ADRB2 Very Important Pharmacogene summary

CP&T Issue Focuses on Personalized Medicine

The October 2012 issue of Clinical Pharmacology & Therapeutics focuses on individualized medicine including articles that discuss, reveal and tackle key issues in the field of PGx, and provides examples of current clinical implementation projects. Clinical Pharmacology & Therapeutics Volume 92, Issue 4 (October 2012)

Amongst these are articles by past and present members of the PGRN:

• Ready when you are: easing into preemptive pharmacogenetics.   He YJ, McLeod HL.
• Pharmacogenomics and individualized medicine: translating science into practice. Crews KR, Hicks JK, Pui CH, Relling MV, Evans WE.
• The relevance of "missing heritability " in pharmacogenomics. Sadee W.
• Strategies for personalized medicine-based research and implementation in the clinical workflow. Lieb W, Völzke H, Pulley JM, Roden DM, Kroemer HK.

and articles we have announced in previous blogs:

• Pharmacogenomics Knowledge for Personalized Medicine. M Whirl-Carrillo, E M McDonagh, J M Hebert, L Gong, K Sangkuhl, C F Thorn, R B Altman and T E Klein.
  
• The 1200 Patients Project: Creating a New Medical Model System for Clinical Implementation of Pharmacogenomics. P H O'Donnell, A Bush, J Spitz, K Danahey, D Saner, S Das, N J Cox and M J Ratain.
  
• Implementing Personalized Medicine: Development of a Cost-Effective Customized Pharmacogenetics Genotyping Array. J A Johnson, B M Burkley, T Y Langaee, M J Clare-Salzler, T E Klein and R B Altman.

CPIC publishes guidelines on interpreting genetic test results for HLA-B*5801 when prescribing allopurinol therapy.

Allopurinol is an analog of the purine base hypoxanthine. It inhibits the conversion of hypoxanthine and xanthine to uric acid by XDH and is used in the treatment of gout.  Severe cutaneous adverse reaction, SCAR, also known as allopurinol hypersensitivity syndrome, is a rare serious and sometimes fatal side effect that occurs in an estimated 0.1 to 0.4% of allopurinol-treated patients.  SCAR is manifested by Stevens-Johnsons Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) or drug reaction with eosinophilia and systemic symptoms (DRESS). 

There is substantial evidence linking HLA-B*5801 with allopurinol-induced SCAR [see Articles: 15743917, 18192896, 19018717, 19696695, 21301380, 21393610, 21545408].  A recent meta-analysis pooling all the published studies gave the odds ratios for allopurinol induced SCAR in HLA-B*5801 carriers as 73 and 165 for studies using healthy controls and allopurinol tolerant controls, respectively [Article: 21906289]. 
A multinational team of rheumatologists, clinicians and pharmacogenomics researchers evaluated the evidence on HLA-B*5801 and allopurinol-induced SCAR. The CPIC guidelines recommend that allopurinol not be used in patients who are known carriers of HLA-B*5801.

To find out more:

Please click here to see excerpts from the guideline and access downloads of the article and supplement . 

Please click here for a complete list of CPIC publications.