Personalized Prescriptions: Russ Altman's TEDx Talk

The mission of PharmGKB and the role of CPIC's therapeutic guidelines are nicely introduced in Russ's TEDxStanford talk, in which he uses the commonly prescribed drug codeine as an example to explain pharmacogenetics.

4 basic lessons are outlined:
1. People don't respond in the same way to drugs.
2. Genetics is behind our response to drugs and these differences.
3. PharmGKB is a resource for this information.
4. Physicians want to use PGx in their practice...CPIC writes evidence-based guidelines to enable this to happen.

• Watch the talk
• For more information on PharmGKB read Whirl-Carrillo et al, 2012
• Learn more about codeine and CYP2D6
• Read the CPIC CYP2D6 genotype-based therapeutic recommendations for codeine

New Pathway for Abacavir

We have posted a new pathway on PharmGKB summarizing the pharmacokinetics, pharmacodynamics and pharmacogenetics of abacavir.

Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) pro-drug, used for treating human immunodeficiency virus (HIV) infection. Abacavir is converted through several enzymatic steps into its active form, carbovir 5’-triphosphate (CBV-TP), which works by blocking the action of HIV reverse transcriptase. Approximately 5-8% of patients experience a hypersensitivity reaction (HSR) within the first 6 weeks of abacavir treatment. These HSRs can be severe and even fatal, particularly if the drug is discontinued then rechallenged. Abacavir HSRs have been strongly linked with the presence of the HLA-B*57:01 allele. For more information on the pharmacogenetics of abacavir, as well as the pharmacokinetics and pharmacodynamics, please view the entire pathway description.

View all pathways on PharmGKB.

Update to CYP2C19 TPP lookup table

We have verified that position rs3758581 in CYP2C19*1 is allele A. The CYP2C19 TPP lookup table has been updated accordingly.

View CYP2C19 haplotypes.

CPIC publishes guidelines for HLA-B*15:02 Genotype and Carbamazepine Use

The Clinical Pharmacogenomics Implementation Consortium (CPIC) has published guidelines for the use of genetic test results for HLA-B*15:02 and carbamazepine in Clinical Pharmacology and Therapeutics.  In cases where a patient is known to carry at least one HLA-B*15:02 allele, the guideline recommends that the clinician use another drug due to the increased risk of carbamazepine-induced Stevens-Johnson Syndrome (SJS)/toxic epidermis necrolysis (TEN) associated with that allele.

Carbamazepine is an aromatic anti-convulsant used in the treatment of epilepsy and other seizure disorders.  However, there is a risk of dangerous, even fatal, skin reactions such as SJS and TEN for patients taking the drug.  An association with the HLA-B*15:02 allele and increased risk for these carbamazepine-induced reactions has been established.  The FDA recommends testing for this allele in certain populations where the allele is most common.  The CPIC guidelines recommend an alternative treatment for anyone carrying the HLA-B*15:02 allele regardless of ethnicity.

See the excerpts and recommendations from the guidelines and download the CPT article and supplement here.

Tacrolimus/Cyclosporine Pathways, Pharmacokinetics and Pharmacodynamics

We have added two new pathways to our collection, in collaboration with Dr. Christine Staatz from the University of Queensland and Dr. Raman Venkataramanan from the University of Pittsburgh. These pathways cover the pharmacokinetics and pharmacodynamics of tacrolimus and cyclosporine. Both drugs are immunosuppressants given to solid organ transplant recipients in order to prevent allograft rejection. They differ in structure, but have highly similar metabolisms and immunosuppressive actions. Given these similarities, the drugs are combined on the pharmacokinetic and pharmacodynamic pathways. The pharmacokinetics pathway shows the metabolism of these two drugs and the genes and cells involved, and the pharmacodynamics pathway shows the mechanisms by which the drugs inhibit immune responses within T cells.

A large number of genes are involved in the pharmacogenetics of these drugs. Please visit the tacrolimus/cyclosporine pharmacokinetics or tacrolimus/cyclosporine pharmacodynamics pathway pages to find out more and to view or download these pathways.

View all pathways at PharmGKB

Novel SNP in CYP2C cluster associated with warfarin dose in African Americans

The International Warfarin Pharmacogenetics Consortium (IWPC),  which involves investigators from eight institutions including Stanford University, has identified a SNP that is associated with warfarin dose requirement in the African American population. As described in Lancet, rs12777823, located in the CYP2C cluster, shows an effect in African Americans that is independent from those of CYP2C9*2 and CYP2C9*3.  In this first investigation of warfarin dose requirements in African Americans, this new association reached genome-wide significance in a GWAS and was also found to be significant in a replication cohort.  Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous for this allele need reduction in dose of 9·34 mg/week.

The data used in these studies are available on the PharmGKB.

New VIP Summary for CYP2C8

A new VIP summary is available for CYP2C8, a member of the cytochrome P450 family of drug metabolizing enzymes. CYP2C8 accounts for 7% of CYP content in the liver, and is expressed to a lesser extent in the kidney, adrenal gland, mammary gland, brain, ovary, uterus, and duodenum.  CYP2C8 plays a major role in the metabolism of many commonly used drugs [Article:15900280]. Several CYP2C8 SNPs have functional consequences [Article: 20459297] and have been associated with variability in CYP2C8-mediated metabolism and altered disposition and response for many commonly used drugs such as repaglinide, rosiglitazone, pioglitazone,paclitaxel, bisphosphonates, amiodarone and amodiaquine [Articles:12429347, 11668219, 17361129, 23536207, 11767116, 12530467, 18769365]. As a result, CYP2C8 has emerged as a significant pharmacogene. 

For more information on this VIP gene and its variants see the VIP tab for CYP2C8.

For all VIP gene summaries on pharmgkb, see here.