Genetic Variation in Prediction of Drug Efficacy and Toxicity

Abstract

Personalized medicine is currently transitioning from its maturation into the clinical practice [1]. The individual response difference to the drug is attributable to the pharmacogenomics make up of each individual, or to the pharmacokinetic difference in its ADME property as absorption, distribution, metabolism and excretion. The pharmacogenomics make up and genetic variation can be categorized into single nucleotide polymorphisms (SNPs), insertion, deletion, translocation or duplication of the genome sequence. Extensive work has been carried out to test the effect of gene SNPs on the drug disposition, efficacy or toxicity of the drug, and there are successful examples in the drug regulation in terms of appreciable pharmacogenomics on the drug dosage and effect. For example, the United States Food and Drug Administration (FDA) has modified the dosage of irinotecan in the population of homozygous UGT1A1*28 allele with reduced UGT1A1 activity. The patients’ plasma concentration of isoniazid which is an anti-tuberculosis drug had a bimodal distribution pattern. The difference in genomic make up of N-acetyltransferase gene differentiated the population into rapid vs. slow acetylators. The slow acetylators had higher isoniazid drug concentration, and the rapid acetylators had lower plasma drug concentration which in turn leads to diverse response/toxicity in these different populations [2].