Cyrine E. Haidar

Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 Update

Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.

The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin‐Induced Myopathy: 2014 Update

Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single‐nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin‐induced myopathy.

Development and use of active clinical decision support for preemptive pharmacogenomics

Background Active clinical decision support (CDS) delivered through an electronic health record (EHR) facilitates gene-based drug prescribing and other applications of genomics to patient care. Objective We describe the development, implementation, and evaluation of active CDS for multiple pharmacogenetic test results reported preemptively. Materials and methods Clinical pharmacogenetic test results accompanied by clinical interpretations are placed into the patients EHR, typically before a relevant drug is prescribed. Problem list entries created for high-risk phenotypes provide an unambiguous trigger for delivery of post-test alerts to clinicians when high-risk drugs are prescribed. In addition, pre-test alerts are issued if a very-high risk medication is prescribed (eg, a thiopurine), prior to the appropriate pharmacogenetic test result being entered into the EHR. Our CDS can be readily modified to incorporate new genes or high-risk drugs as they emerge. Results Through November 2012, 35 customized pharmacogenetic rules have been implemented, including rules for TPMT with azathioprine, thioguanine, and mercaptopurine, and for CYP2D6 with codeine, tramadol, amitriptyline, fluoxetine, and paroxetine. Between May 2011 and November 2012, the pre-test alerts were electronically issued 1106 times (76 for thiopurines and 1030 for drugs metabolized by CYP2D6), and the post-test alerts were issued 1552 times (1521 for TPMT and 31 for CYP2D6). Analysis of alert outcomes revealed that the interruptive CDS appropriately guided prescribing in 95% of patients for whom they were issued. Conclusions Our experience illustrates the feasibility of developing computational systems that provide clinicians with actionable alerts for gene-based drug prescribing at the point of care.

A Clinician-Driven Automated System for Integration of Pharmacogenetic Interpretations Into an Electronic Medical Record

Advances in pharmacogenetic testing will expand the number of clinically important pharmacogenetic variants. Communication and interpretation of these test results are critical steps in implementation of pharmacogenetics into the clinic. Computational tools that integrate directly into the electronic medical record (EMR) are needed to translate the growing number of genetic variants into interpretive consultations to facilitate gene‐based drug prescribing. Herein, we describe processes for incorporating pharmacogenetic tests and interpretations into the EMR for clinical practice.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing

The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin‐related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).

PharmGKB summary: very important pharmacogene information for UGT1A1.

The uridine diphosphate glucuronosyltransferase (UGT) enzymes are a superfamily of enzymes responsible for the glucuronidation of target substrates. The transfer of glucuronic acid renders xenobiotics and other endogenous compounds water soluble, allowing for their biliary or renal elimination [1]. The UGT family is responsible for the glucuronidation of hundreds of compounds, including hormones, flavonoids, and environmental mutagens [1]. Most of the members of the UGT family are expressed in the liver, as well as in other types of tissues, such as intestinal, stomach, or breast tissues. A few members are expressed only extrahepatically, such as UGT1A7, UGT1A8, UGT1A10, and UGT2A1 [2]. Four families exist within the UGT superfamily: UGT1A, UGT2, UGT3, and UGT8 [3]. UGT2 is further divided into two subfamilies, UGT2A and UGT2B, both of which are present on chromosome 4 [2]. UGT2A enzymes are involved in the glucuronidation of compounds such as phenolic odorants and polycyclic aromatic hydrocarbon metabolites, although limited studies have been carried out on this subfamily [4]; UGT2B proteins are mainly responsible for the metabolism of steroids [5]. The roles of UGT3 and UGT8 family members have not been well characterized [3]. The UGT1A family is located on chromosome 2q37, and the members of this group glucuronidate a large variety of compounds. Pharmaceutical drugs are a common substrate of the UGT1A family [1], making the enzymes in this group relevant to pharmacogenetic research. This very important pharmacogene summary on UGT1A1 is available with interactive links to genetic variants and drugs on the PharmGKB website at http://www.pharmgkb.org/gene/PA420.

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for rasburicase therapy in the context of G6PD deficiency genotype.

Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia (AHA) induced by a number of drugs. We provide guidance as to which G6PD genotypes are associated with G6PD deficiency in males and females. Rasburicase is contraindicated in G6PD‐deficient patients due to the risk of AHA and possibly methemoglobinemia. Unless preemptive genotyping has established a positive diagnosis of G6PD deficiency, quantitative enzyme assay remains the mainstay of screening prior to rasburicase use. The purpose of this article is to help interpret the results of clinical G6PD genotype tests so that they can guide the use of rasburicase. Detailed guidelines on other aspects of the use of rasburicase, including analyses of cost‐effectiveness, are beyond the scope of this document. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are published and updated periodically on https://www.pharmgkb.org/page/cpic to reflect new developments in the field.

The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems

Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real‐world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene–drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease

After postoperative deaths in children who were prescribed codeine, several pediatric hospitals have removed it from their formularies. These deaths were attributed to atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics, which is also implicated in poor analgesic response. Because codeine is often prescribed to patients with sickle cell disease and is now the only Schedule III opioid analgesic in the United States, we implemented a precision medicine approach to safely maintain codeine as an option for pain control. Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June 2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultra-rapid metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized pediatric populations.

Voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes.

AIM Our objective was to describe the association between voriconazole concentrations and CYP2C19 diplotypes in pediatric cancer patients, including children homozygous for the CYP2C19*17 gain-of-function allele. MATERIALS & METHODS A linear mixed effect model compared voriconazole dose-corrected trough concentrations (n = 142) among CYP2C19 diplotypes in 33 patients (aged 1-19 years). Voriconazole pharmacokinetics was described by a two-compartment model with Michaelis-Menten elimination. RESULTS Age (p = 0.05) and CYP2C19 diplotype (p = 0.002) were associated with voriconazole concentrations. CYP2C19*17 homozygotes never attained therapeutic concentrations, and had lower dose-corrected voriconazole concentrations (median 0.01 μg/ml/mg/kg; p = 0.02) than CYP2C19*1 homozygotes (median 0.07 μg/ml/mg/kg). Modeling indicates that higher doses may produce therapeutic concentrations in younger children and in those with a CYP2C19*17/*17 diplotype. CONCLUSION Younger age and the presence of CYP2C19 gain-of-function alleles were associated with subtherapeutic voriconazole concentrations. Starting doses based on age and CYP2C19 status could increase the number of patients achieving therapeutic voriconazole exposure.