Abstract
Much of the inter-individual variability in drug efficacy and risk of adverse reactions is due to polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics or immunological responses. Pharmacogenetic research has identified a multitude of gene-drug response associations, which have resulted in genetically guided treatment and dosing decisions to yield a higher success rate of pharmacological treatment. The rapid technological developments for genetic analyses reveal that the number of genetic variants with importance for drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to millions of rare mutations. Here, we review the evolutionary background of genetic polymorphisms in drug-metabolizing enzymes, provide some important examples of current use of pharmacogenomic biomarkers, and give an update of germline and somatic genome biomarkers that are in use in drug development and clinical practice. We also discuss the current technology development with emphasis on complex genetic loci, review current initiatives for validation of pharmacogenomic biomarkers, and present scenarios for the future taking rare genetic variants into account for a true personalized genetically guided drug prescription. We conclude that pharmacogenomic information for patient stratification is of value to tailor optimized treatment regimens particularly in oncology. However, the routine use of pharmacogenomic biomarkers in clinical practice in other therapeutic areas is currently sparse and the prospects of its future implementation are being scrutinized by different international consortia.
Highlights
Differential response to pharmacological treatment constitutes a major source of patient morbidity and mortality
These severe adverse drug reactions (ADRs) prompted the Food and Drug Administration (FDA) to require boxed warnings on all codeine-containing medications to highlight the risks for pediatric patients
In Zimbabwe, 20% of the population are homozygous for the reduced functionality allele CYP2B6*6 which entails that efavirenz plasma concentrations exceed the recommended therapeutic levels, resulting in the local failure of a globally established dosing regimen [87]
Summary
Differential response to pharmacological treatment constitutes a major source of patient morbidity and mortality. Various patient-specific factors, including age, polypharmacy, concomitant diseases, and diet as well as heritable factors contribute to these inter-individual differences with genetic polymor-. The liver as the central organ of drug metabolism is involved in the clearance of around 70% of drugs [5]. Enzymes encoded by the cytochrome P450 (CYP) superfamily of genes are responsible for > 75% of phase 1 drug metabolism and constitute major modulators of drug response [6]. CYP genes are highly polymorphic between individuals and across populations, which can have important implications for the bioactivation and/or detoxification of medications [7]. Epigenetic modifications of DNA or histones have been linked to differences in drug response.
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