Adverse drug reactions (ADRs) are one of the major causes of morbidity and mortality worldwide. It is well-known that individual genetic make-up is one of the causative factors of ADRs. Approximately 14 million single nucleotide polymorphisms (SNPs) are distributed throughout the entire human genome and every patient has a distinct genetic make-up which influences their response to drug therapy. Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of antiretroviral, antimalarial, anticancer, and antidepressant drugs. These drug classes are commonly in use worldwide and face specific population variability in side effects and dosing. Parts of this variability may be caused by single nucleotide polymorphisms (SNPs) in the CYP2B6 gene that are associated with altered protein expression and catalytic function. Population variability in the CYP2B6 gene leads to changes in drug metabolism which may result in adverse drug reactions or therapeutic failure. So far more than 30 non-synonymous variants in CYP2B6 gene have been reported. The occurrence of these variants show intra and interpopulation variability, thus affecting drug efficacy at individual and population level. Differences in disease conditions and affordability of drug therapy further explain why some individuals or populations are more exposed to CYP2B6 pharmacogenomics associated ADRs than others. Variabilities in drug efficacy associated with the pharmacogenomics of CYP2B6 have been reported in various populations. The aim of this review is to highlight reports from various ethnicities that emphasize on the relationship between CYP2B6 pharmacogenomics variability and the occurrence of adverse drug reactions. In vitro and in vivo studies evaluating the catalytic activity of CYP2B6 variants using various substrates will also be discussed. While implementation of pharmacogenomic testing for personalized drug therapy has made big progress, less data on pharmacogenetics of drug safety has been gained in terms of CYP2B6 substrates. Therefore, reviewing the existing evidence on population variability in CYP2B6 and ADR risk profiles suggests that, in addition to other factors, the knowledge on pharmacogenomics of CYP2B6 in patient treatment may be useful for the development of personalized medicine with regards to genotype-based prescription.

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Ketamine and its enantiomer S‐ketamine (esketamine) are known to produce rapid‐onset antidepressant effects in major depression. Intranasal esketamine has recently come onto the market as an antidepressant. Besides experience from short‐term use in anaesthesia and analgesia, the experience with ketamine as long‐term medication is rather low. The use of ketamine and esketamine is limited due to potential neurotoxicity, psychotomimetic side effects, potential abuse and interindividual variability in treatment response including cessation of therapy. Therefore, taking a look at individual patient risks and potential underlying variability in pharmacokinetics may improve safety and dosing of these new antidepressant drugs in clinical practice. Differential drug metabolism due to polymorphic cytochrome P450 (CYP) enzymes and gene‐drug interactions are known to influence the efficacy and safety of many drugs. Ketamine and esketamine are metabolized by polymorphic CYP enzymes including CYP2B6, CYP3A4, CYP2C9 and CYP2A6. In antidepressant drug therapy, usually multiple drugs are administered which are substrates of CYP enzymes, increasing the risk for drug–drug interactions. We reviewed the potential impact of polymorphic CYP variants and common drug–drug interactions in antidepressant drug therapy affecting ketamine pharmacokinetics, and the role for dose optimization. The use of ketamine or intranasal esketamine as antidepressants demands a better understanding of the factors that may impact its metabolism and efficacy in long‐term use. In addition to other clinical and environmental confounders, prior information on the pharmacodynamic and pharmacokinetic determinants of response variability to ketamine and esketamine may inform on dose optimization and identification of individuals at risk of adverse drug reactions.