Pharmacogenomics in the Intensive Care Unit: Focus on Potential Implications for Clinical Practice

Abstract

Critically ill patients often are at high-risk for adverse drug reactions (ADRs), mainly due to alterations in pharmacokinetic and pharmacodynamic (PK/PD) parameters. These PK/PD differences in can also lead to inadequate therapeutic response to many commonly used drugs in this patient population. Frequently in the critically ill patient, medications are utilized based on a "trial-and-error" approach. Furthermore, drug dosing in the critically ill largely remains a "one-size-fits-all" phenomenon, utilizing dosing based on PK studies in healthy volunteers. Known differences in gene variation among the general population can greatly alter response to drug therapy. The use of pharmacogenomics (PGX) to aid in the development of individualized pharmacotherapeutic regimens, potentially may reduce ADRs and increase therapeutic efficacy. Potential uses of PGX include: identification of patients who are particularly susceptible to ADRs; and patients whom are more likely to benefit from a particular drug therapy, based on the patient's own genetic profile. This review will focus on potential applications of PGX in the critically ill, including management of acute coronary syndromes (ACS), invasive fungal infections, and pain management. Current barriers to PGX-guided therapy in the critically ill and recent patent developments in the clinical application of PGX will also be discussed.

Utilisation de la pharmacogénomique et de la pharmacogénétique à l’unité de soins intensifs: un compte rendu narratif

“…It is estimated that 15% of Caucasians and Africans and 30% of the Asian population have the CYP2C19*2 allele, which is most often implicated in loss of function and poor metabolism. 23 In the case of the proton pump inhibitors, the presence of this allele may lead to excess acid suppression, which in the ICU has been associated with an increased risk of pneumonia. 68 In contrast, omeprazole concentration was significantly elevated in EMs in the presence of clopidogrel -likely through clopidogrelinduced inhibition of CYP2C19.…”

“…17,24,25 In addition, alterations in drug pharmacokinetics due to changes in bioavailability, volume of distribution, and drug-and disease-induced changes in drug metabolism and clearance that occur because of the nature of critical illness 26 make it difficult to attribute observed differences in drug effects to alterations in genomic variability alone. Herein, we expand on the observations of Allen and Gelot 23 and use the concepts of pharmacogenetics (i.e., application of a single genetic variant to describe an alteration in drug effect) and pharmacogenomics (i.e., the broader application of an individual's genome to predict his or her response to medications) to explain some of the variability in clinical Table 1 Factors necessary for pharmacogenomics to result in a clinically important change in drug effect 1. The effect of the polymorphism on the total active drug moiety should be considerable.…”

“…Despite the forgoing, the application of genetic variation to predict altered responses to drug therapy in patients in the intensive care unit (ICU) has received relatively little study. 23 In part, it may be because diagnostic tests for genomic variability, until recently, have not been available within the short time frame necessary for decision making in the ICU. 17,24,25 In addition, alterations in drug pharmacokinetics due to changes in bioavailability, volume of distribution, and drug-and disease-induced changes in drug metabolism and clearance that occur because of the nature of critical illness 26 make it difficult to attribute observed differences in drug effects to alterations in genomic variability alone.…”

Personalized Critical Care Medicine: How Far Away Are We?

“…8 About 10% of drugs currently have pharmacogenomics information or recommendations included in their FDA-approved product labeling. 8,9 The most studied drugrelated genetic variations have been single nucleotide polymorphisms (SNPs) in the cytochrome P450 (CYP) genes, since roughly 75% of all genes use this pathway in primary hepatic metabolism, and genetic variations may affect a variety of pharmacokinetic (PK) variables such as absorption, distribution, and elimination. 9 More than 30 families of enzymes involved in drug metabolism have been identified, and functional polymorphisms resulting in clinically significant alterations in drug effects have been described in the genes encoding many of these.…”

“…8,9 The most studied drugrelated genetic variations have been single nucleotide polymorphisms (SNPs) in the cytochrome P450 (CYP) genes, since roughly 75% of all genes use this pathway in primary hepatic metabolism, and genetic variations may affect a variety of pharmacokinetic (PK) variables such as absorption, distribution, and elimination. 9 More than 30 families of enzymes involved in drug metabolism have been identified, and functional polymorphisms resulting in clinically significant alterations in drug effects have been described in the genes encoding many of these. 10 While some drugs are metabolized through a single pathway under the control of only one gene, most drugs exhibit so-called Gaussian behavior with many enzymes involved at various points in the drug's metabolism and action.…”