Clinical pharmacogenetics implementation: Approaches, successes, and challenges

Abstract

Current challenges exist to widespread clinical implementation of genomic medicine and pharmacogenetics. The University of Florida (UF) Health Personalized Medicine Program (PMP) is a pharmacist-led, multidisciplinary initiative created in 2011 within the UF Clinical Translational Science Institute. Initial efforts focused on pharmacogenetics, with long-term goals to include expansion to disease-risk prediction and disease stratification. Herein we describe the processes for development of the program, the challenges that were encountered and the clinical acceptance by clinicians of the genomic medicine implementation. The initial clinical implementation of the UF PMP began in June 2012 and targeted clopidogrel use and the CYP2C19 genotype in patients undergoing left heart catheterization and percutaneous-coronary intervention (PCI). After 1 year, 1,097 patients undergoing left heart catheterization were genotyped preemptively, and 291 of those underwent subsequent PCI. Genotype results were reported to the medical record for 100% of genotyped patients. Eighty patients who underwent PCI had an actionable genotype, with drug therapy changes implemented in 56 individuals. Average turnaround time from blood draw to genotype result entry in the medical record was 3.5 business days. Seven different third party payors, including Medicare, reimbursed for the test during the first month of billing, with an 85% reimbursement rate for outpatient claims that were submitted in the first month. These data highlight multiple levels of success in clinical implementation of genomic medicine.

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

“…Approximately 25–35% of individuals of European and African ancestry and ~ 60% of Asians carry at least one copy of no function allele [33]. CYP2C19 *3, *4, *5, *6, *7, and *8 are other less frequent no function alleles, with *3 and *8 being the most common among this group [34]. Poor metabolizers (PM), carrying two copies of CYP2C19 no function alleles make up about 2–5% of European and African individuals and 15% of Asians [35].…”

“…On the other hand, the identified increased function polymorphism in CYP2C19 (*17: rs12248560) contributes to enhanced clearance of drugs metabolized by CYP2C19. This is also a common polymorphism in CYP2C19 with approximately 30% of individuals of European and African ancestry [34,36] and ~ 2–4% of Asians carrying at least one copy of CYP2C19*17 [37]. Individuals with two copies of the normal function allele are classified as CYP2C19 normal metabolizer status (NM) while individuals with one normal function allele and one increased function allele (*17) are rapid metabolizers (RM).…”

Evidence for Extensive Pleiotropy Among Pharmacogenes

“…In the past decade, candidate gene and genomewide association studies (GWAS) have identified specific genetic variants underlying the physiological response to highly prescribed medications, including warfarin [2][3][4][5], clopidogrel [6] and statins [7], to name a few. The appeal of personalized or precision medicine has prompted many clinics to implement genetic testing for these variants [8][9][10][11][12], often despite little [13,14] or even contrary [15] evidence regarding clinical utility. Among the consequences of this recent rise in clinical genotyping and sequencing has been the growing recognition that pharmacogenetic variants regularly display pleiotropic effects [16] incidental to the original purpose of testing [17][18][19].…”

Iterative Development and Evaluation of a Pharmacogenomic-Guided Clinical Decision Support System for Warfarin Dosing

“…[1] Nonetheless, the translation of pharmacogenomic testing into routine clinical practice has been slow due to several obstacles towards its implementation [2][3][4]. Currently, the routine use of clinical pharmacogenomics is limited to centers with resources to overcome these obstacles [5][6][7][8][9].…”