spa meeting reviews

Pharmacogenomics

By Connie Monitto, MD, FAAP
Johns Hopkins University School of Medicine

Bruce Carleton PharmD, (Professor and Chair, Division of Translational Therapeutics, University of British Columbia, Vancouver), opened the meeting with a fascinating talk titled “Pharmacogenomics and the Transformation of Practice.” Dr. Carleton began his presentation by reminding the audience that individual variability in drug response can have serious clinical consequences. Adverse drug reactions are a leading cause of death in the USA, cost hundreds of billions of dollars annually, and account for 7% of all hospital admissions. While modern drug development is often based on clinical trials that provide evidence of efficacy and safety at “usual doses” in populations, physicians treat individual patients whose responses to drug therapy can vary widely.  Drug response and risk of an adverse reaction can both be influenced by a patient’s genotype. Hence, incorporating pharmacogenomics into clinical practice should help stratify the risk of therapy. Of note, children may be at increased risk of severe adverse drug reactions as many of the medications we prescribe were never clinically evaluated in children and age-related variability in drug metabolism may play an important role in these events.

In light of these issues the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) project was developed with the goal of developing genotype-based dosing guidelines to predict safety and avoid severe adverse drug reactions. The CPNDS clinical surveillance network consists of 26 (13 adult and 13 pediatric) sites where patients with well characterized drug reactions can be identified, extensively phenotyped, and matched to patients who receive the same medication but do not develop a drug reaction. Genetic testing, often with SNP arrays, is then performed to look for genetic variation in key drug metabolizing enzymes. Using this paradigm the network has been able to identify genetic variants associated with lethal reactions to codeine in newborns, as well as candidate polymorphisms and risk stratification in anthracycline-associated cardiotoxicity. These discoveries have been possible in part because of the advances in genomics technology that have occurred over the past decade. Translation of these results from the bench to clinical research teams will ultimately help physicians develop individualized therapeutic plans that can benefit patients by maximizing drug efficacy while minimizing toxicity.

In keeping with the theme of Pharmacogenomics, Lena Sun, MD (Emanuel M. Papper Professor of Pediatric Anesthesiology, Columbia University, New York), spoke on “Pharmacogenomics and Malignant Hyperthermia.” The objectives of Dr. Sun’s presentation were to describe the phenotypes of malignant hyperthermia (MH) susceptibility, and to discuss the genetics of and susceptibility testing in MH. As with Dr. Carleton’s examples, MH is a prototype disease that gains from the application of pharmacogenomics as well as the ability to identify and characterize at-risk subpopulations. This approach allows for the development of personalized strategies to individualize anesthetic management and predict and prevent MH reactions. Interestingly, while the prevalence of MH is 1 in 50,000 adult anesthetics and one in 15,000 pediatric anesthetics, MH susceptibility is estimated to be much higher –  around 1 in 2,000.    Diagnosis consists of muscle biopsy and caffeine halothane contracture testing. Risk factors include a prior history of MH, a diagnosis of an associated “at risk” disease (e.g., those associated with ryanodine receptor mutations like central core disease), a family history of MH, a history of muscle rigidity, and possibly exertional rhabdomyolysis. Clinical manifestations of the disease are related to calcium dysregulation, which can be associated with mutations in at least three genes:  RYR1 (ryanodine receptor 1), CACNA1S (a voltage gated L-type calcium channel), and STA3 (a gene associated with Native American myopathy). Genetic testing has been done using both targeted gene screening and whole exon sequencing. Multiple studies looking at patients in various countries have identified causative mutations in between 29 and 86% of those screened, but in general causative mutations are not found in all screened individuals. As a result, when testing for MH muscle biopsy remains the first line in testing, while genetic screening is the second line, and negative screen does not rule out a diagnosis of MH.

Mindy Cohen, MD (Children’s Hospital, Colorado) concluded the session with a talk titled
“Analgesics and the Effects of Pharmacogenomics.” The goals of her presentation were to review genetic variations that influence analgesic pharmacotherapy in children, identify the most common polymorphisms in drug metabolizing enzymes, and describe strategies for modifying analgesic regimens based on pharmacogenomics. Dr. Cohen began her presentation by reviewing how our genetic background can influence both our sensitivity to pain as well as our response to analgesics. Genetic influences on the response to noxious thermal and chemical stimuli as well as mu agonists have been demonstrated in twin studies. Furthermore, genetic mutations, such as loss of function mutations in voltage-gated sodium channels, can produce insensitivity to pain. Genetic variation can also affect pharmacokinetics by impacting drug absorption, distribution, metabolism, and/or elimination. For example, polymorphisms in the cytochrome P450 isoenzymes 3A4/5 and 2D6 and the UGT enzymes play a role in the efficacy and toxicity of many drugs including the “prodrugs” codeine and tramadol, as well as morphine. The clinical relevance of these effects has been highlighted recently by reports of codeine-related deaths in ultra-rapid metabolizers.  Similarly, genetic polymorphisms can impact pharmacodynamics, i.e., the response to a drug, by altering target site concentration, receptor morphology, receptor number, or downstream events in signal transduction pathways. Some of the genes that may play a role in these events include the mu-receptor OPRM1 and the melanocortin-1 receptor MC1R (receptor morphology), the ABCB1/MDR1 transporter (target site concentration), and catechol-O-methyltransferase. Interestingly, polymorphisms in these genes can work “in tandem” when genotypes are combined.

Dr. Cohen concluded by pointing out that as we move forward a better understanding of the role of genetic variants in the perception and treatment of pain will help clinicians appreciate how available genetic test results can be used to optimize drug therapy, a goal endorsed by the Clinical Pharmacogenetics Implementation Consortium (https://www.pharmgkb.org/page/cpic).