Tramadol pathway summary published in PG&G

Tramadol is a centrally acting opioid analgesic used to relieve moderate to severe pain.  It is administered as a racemic mixture of (+) and (-) enantiomers and exerts its analgesic effect via activating the µ-opioid receptor and inhibiting the neurotransmitter reuptake. Tramadol metabolism to its major active metabolite O-desmethyl tramadol (M1) is predominantly mediated via CYP2D6. Genetic variations of CYP2D6 have been shown to affect not only the pharmacokinetics of tramadol and M1, but also the analgesic efficacy as well as pharmacodynamic responses.

We have published the
PharmGKB summary: tramadol pathway in the Pharmacogenetics and Genomics Journal. This review summarizes the metabolism and transport of tramadol and discusses genetic variations affecting the pharmacokinetics, efficacy and toxicity of tramadol and their clinical significance.

Find out more...
View our Tramadol pathway on PharmGKB.

Read our new publication: 
PharmGKB summary:tramadol pathway
Gong L, Stamer UM, Tzvetkov MV, Altman RB, Klein TE.
Pharmacogenet Genomics. 2014 May 20. [Epub ahead of print]
PMID: 24849324

View all pathways on PharmGKB.

Big Data Conference 2014

Stanford University are hosting the second Big Data in Biomedicine conference this week, featuring speakers across academia, industry and government.

PharmGKB's Associate Director will be discussing Genomic Medicine on Friday 23rd May with other speakers leading in this field.

Watch the live stream of the Big Data in Biomedicine talks.

Update: CPIC ivacaftor-CFTR guideline

The CPIC guideline for ivacaftor treatment based on CFTR genotype has been updated on PharmGKB, in light of changes to the FDA-approved drug label.

Originally, ivacaftor was indicated only in patients with the G551D variant. This has now been extended to other variants that result in CFTR gating defects:

• G1244E (rs267606723)
• G1349D (rs193922525)
• G178R (rs80282562)
• G551S (rs121909013)
• S1251N (rs74503330)
• S1255P (rs121909041)
• S549N (rs121908755)
• S549R (rs121909005, rs121908757)

> View the updated CPIC ivacaftor-CFTR guideline.

Figure 1: Treatment algorithm for clinical use of ivacaftor for cystic fibrosis patients based on CFTR genotype.

New CPIC Guideline: G6PD & Rasburicase

CPIC has published therapeutic guidelines for rasburicase based on G6PD genotype.

Rasburicase is a drug that lowers uric acid levels and is used to treat or prevent hyperuricemia in cancer patients undergoing chemotherapy, and in newborns to prevent kidney damage. It is contraindicated for use in patients with G6PD deficiency due to an increased risk of acute hemolytic anemia and possibly also methemoglobinemia. Reduced G6PD enzyme activity is caused by underlying genetic variants in the G6PD gene. There are more than 180 G6PD variants, each categorized class I to V depending on the level of deficiency in red blood cells conferred and the associated resulting clinical manifestations.  

To our knowledge, this is the first published guideline to fully address therapeutic recommendations for patients who have pre-emptive G6PD genotyping or sequencing results in both men and women, for a large collection of variants.

CPIC contraindicate the use of rasburicase in males or females who are hemi/homozygous for class I-III G6PD variants, respectively. For females heterozygous for class I-III G6PD variants, phenotype is variable due to X-linked mosaicism and thus an enzyme test is recommended prior to rasburicase use. An enzyme test to determine G6PD phenotype is also the recommendation for patients who have negative or inconclusive genetic results.

> View the CPIC guidelines for G6PD variants & rasburicase.

> Read the accepted article preview of the guideline manuscript:
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Rasburicase Therapy in the context of G6PD Deficiency Genotype.
Relling MV, McDonagh EM, Chang T, Caudle KE, McLeod HL, Haidar CE, Klein T, Luzzatto L.
Clin Pharmacol Ther. Accepted article preview online 02 May 2014 doi:10.1038/clpt.2014.97.

> Learn more about G6PD and drug response.

> Learn more about the mechanism underlying rasburicase-induced hemolytic anemia. 

CPIC featured in the clinical pharmacology podcast

Clinpharmpod  is the clinical pharmacology podcast from the journal Clinical Pharmacology and Therapeutics produced in association with Nature Publishing Group. In the March 25th episode from Clinpharmpod, host Geoff Marsh interviews Dr. Mary Relling on the history and future plans for the Clinical Pharmacogenetics Implementation Consortium (CPIC). A joint effort between the Pharmacogenomics Research Network (PGRN) and PharmGKB, CPIC was established in 2009 to develop gene-drug dosing guidelines that enable the translation of genetic test results into actionable prescribing decisions. Dr. Relling addressed many questions regarding the origin of CPIC, the roles of CPIC members, how CPIC guidelines differ from other clinical guidelines,  how gene/drug pairs are chosen and prioritized, the format and essential components of CPIC guidelines, and the future directions for CPIC.

PharmGKB has been intimately involved in the CPIC development from the very beginning. To date, twelve CPIC gene/drug guidelines have been published in journal Clinical Pharmacology and Therapeutics and a few more in the plan. All CPIC guidelines and updates are posted and maintained on PharmGKB in an interactive format. An article describing the CPIC guideline development process was also published recently in journal Current Drug Metabolism.

• Listen to the interview with Dr. Relling at clinpharmpod 
• Read more about CPIC
•  View all CPIC gene-drug dosing guidelines on PharmGKB
• View the list of CPIC guideline gene-drug pairs that have been published or are in progress

To Replicate or Not to Replicate

Dr. Aslibekyan and colleagues propose that an alternative to replication of genetic association studies be considered in an article titled “To Replicate or Not to Replicate: The Case of Pharmacogenetic Studies” in Circulation: Cardiovascular Genetics (2013).  It is understandable why replicating the positive results of a genetic association study is, as the authors state, “the gold standard” of validation. Replication is a useful tool to confirm the likelihood of an association from a previous genetic association study.

However, the results of genetic association studies, including genome wide association studies (GWAS), are often difficult to reproduce as evidenced in pharmacogenomics. The authors provide multiple reasons why false positives and false negatives in genetic association studies prevent results from being reproduced. Much of the data in pharmacogenomic studies come from groups of patients who may have differing drug regimens and intervention strategies. Other factors include low minor allele frequencies, small effect size of the variants, limited sample sizes, and differences in phenotype definitions.

The authors conclude that as an alternative to replication a combination of methods should be used to validate results. They’ve termed this multi-method validation of genetic association studies “triangulation”. They propose to validate results through a combination of functional validation in vitro and in animal models, joint analyses of several populations, and simulation-based methods, and cite a precedent for methodological triangulation in the social sciences. Social science research involves highly complex systems, and the inherent ethical limitations in human subjects research render reproducibility an impractical method of validation.

In a rebuttal, Dr. John Ioannidis argues that what pharmacogenetic association studies actually require are “better, more rigorous methods, and even more stringent replication, and clinical validation”. He proposes several strategies to yield better results from pharmacogenetic association studies including mining data from biobanks and electronic medical records, more stringent criteria for replication, improved methods of detecting and validating rare variants, focus on polygenic markers rather than on single genes, and validation with large, randomized clinical trials.

In a response, Dr. Aslibekyan and colleagues agreed with much of Dr. Ioannidis’ argument. They did, however, reiterate the concern that lowering P-value thresholds for single nucleotide variants could cause many single gene variants with true associations to be overlooked due to factors such as gene-environment interactions and epistasis.

Read the articles here:

To Replicate or Not to Replicate: the Case of Pharmacogenetic Studies: Establishing Validity of Pharmacogenomic Findings: From Replication to Triangulation. Circulation: Cardiovascular Genetics (2013)

Aslibekyan S, Claas SA, Arnett DK

To Replicate or Not to Replicate: the Case of Pharmacogenetic Studies: Have Pharmacogenomics Failed, or Do They Just Need Larger-Scale Evidence and More Replication? Circulation: Cardiovascular Genetics (2013)

Ioannidis John PA