In pediatric oncology, pharmacogenetic guidelines are underutilized and the potential impact of pre-emptive pharmacogenetic screening remains largely unexplored despite this field's need for individualized approaches. While comprehensive pharmacogenetic guidelines are not yet available for all anticancer drugs, evidence-based recommendations exist for a subset of supportive care drugs and anticancer drugs, including thiopurines, irinotecan, capecitabine, and 5-fluorouracil. In this study, we evaluate the potential impact of pre-emptive pharmacogenetic screening by retrospectively identifying opportunities for dose or treatment adjustments within a national pediatric oncology cohort. Our analysis focused on ten genes and 28 drugs relevant to pediatric oncology, which are included in the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group guidelines. In a cohort of 1,151 pediatric oncology subjects, we identified that 16% of individuals could have benefited from altered drug dosing or treatment. These include dose and treatment recommendations for allopurinol, nonsteroidal anti-inflammatory drugs, phenytoin, amitriptyline, proton pump inhibitors, voriconazole, tramadol, codeine, paroxetine, tacrolimus, rasburicase, and 6-mercaptopurine. As genetic data increasingly becomes available through molecular diagnostics in pediatric oncology, there is a unique opportunity to re-utilize this data for pre-emptive pharmacogenetic screening. Leveraging genetic profiles to guide clinicians in drug selection and dose optimization can improve patient outcomes by enhancing the safety and efficacy of treatments. We therefore recommend incorporating pharmacogenetic screening into clinical workflows to advance personalized medicine in pediatric oncology.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU), significantly impacts quality of life. Despite significant advances in the management of the conditions, responses to treatments vary greatly, and this is due partly to our natural genetic variation. Here we will review the evidence for whether single nucleotide polymorphisms (SNPs) have the potential to guide treatment decisions for people with IBD. We will first consider SNPs that exhibit strong associations with IBD pathogenesis and their relevance to epithelial barrier integrity, cytokine production, and immune system function. Then, we will cover those SNPs implicated in altering response to our various current IBD therapeutics, including the recently implemented drugs ustekinumab and tofacitinib. Finally, we will explore lesser-known SNPs that exhibit complex relationships with the disease and which may be undervalued as pharmacogenetic tools. Overall, it will be demonstrated that SNPs associated with IBD pathology are largely distinct from those predicting response to treatments and that new discoveries of clinically useful tools can be expected from therapy-focused investigations. Given the growing list of treatments available, we argue that beneficial personalization of treatments based on SNPs is still underutilized.

Background/Objectives: Solid organ transplant (SOT) recipients are exposed to multiple medications, many of which have pharmacogenetic (PGx) prescribing recommendations. This study leveraged data from a population-scale biobank and an enterprise data warehouse to determine the prevalence of actionable exposures to PGx medications among kidney, heart, and lung transplant recipients during the first six months post-transplant. Methods: We conducted a retrospective analysis of adult SOT patients with genetic data available from the Colorado Center for Personalized Medicine (CCPM) biobank and clinical data from Health Data Compass (HDC). We evaluated 29 variants in 13 pharmacogenes and 42 Clinical Pharmacogenetics Implementation Consortium (CPIC) level A or B medications (i.e., sufficient evidence to recommend at least one prescribing action based on genetics). The primary outcome was actionable exposure to a PGx medication (i.e., actionable phenotype and a prescription for an affected PGx medication). Results: The study included 358 patients. All patients were prescribed at least one PGx medication, and 49.4% had at least one actionable exposure to a PGx medication during the first six months post-transplant. The frequency of actionable exposure was highest for tacrolimus (15.4%), followed by proton pump inhibitors (PPIs) (15.1%) and statins (12.8%). Statin actionable exposures significantly differed by transplant type, likely due to variations in prescribing patterns and actionable phenotypes for individual statins. Conclusions: Our findings highlight the potential clinical utility of PGx testing among SOT patients. Further studies are needed to address the impact on clinical outcomes and the optimal timing of PGx testing in the SOT population.

The prevalence of inflammatory bowel disease among Hispanic/Latine communities is increasing. Pharmacogenomic studies reveal genetic markers that influence treatment decisions. The aim of our study was to examine the frequency and impact of genetic polymorphisms on thiopurine-associated leukopenia (NUDT15, TPMT) and anti-tumor necrosis factor (TNF) immunogenicity (HLA-DQA1∗05) in a cohort of Hispanic patients of diverse ancestral backgrounds.

We performed a multicenter, retrospective cohort study comprising 2225 Hispanic participants. We measured the frequency of variation affecting drug response in NUDT15, TPMT, and HLA-DQA1∗05; their ancestral origin (European, African, or Amerindian); and the rate of development of myelosuppression and immunogenicity to thiopurines and anti-TNFs, in exposed patients.

NUDT15 and TPMT variants were rare, except for rs116855232 in NUDT15, which was common only in alleles of Amerindian origin. All NUDT15 variant alleles were inherited on an Amerindian haplotype, and among the Amerindian allele subset, the variant frequency of NUDT15∗4 (rs147390019) was a remarkable 23% in patients with leukopenia but only 3% in patients without leukopenia. HLA-DQA1∗05 and its European tagging variant rs2097432 were common in alleles from all ancestral origins and demonstrated association with immunogenicity to anti-TNFs. However, rs2097432 was only correlated with HLA-DQA1∗05 in the European allele subset.

These findings indicate that NUDT15 testing should become standard clinical practice before prescribing thiopurines in individuals with Amerindian/Alaska Native ancestry, including Hispanic individuals. Additionally, rs2097432 should not be used as a surrogate for HLA-DQA1∗05 testing for diverse populations. Ultimately, incorporating ancestry in personalized therapeutic approaches is important for treatment of Hispanic patients with inflammatory bowel disease.

The importance of the intestinal microbita in a multitude of physiological processes is well-evidenced. These include metabolism of nutrients and xenobiotics, biosynthesis of vitamin K and vitamin B12, immunomodulation, maintenance of the gut mucosal barrier integrity and protection against some pathogens. Interindividual differences in the intestinal microbiota composition have impacts on health. The bioavailability and activity of some pharmaceuticals are heavily influenced by interindividual variability in metabolism, which has a genetic basis. This variability, primarily occurring in the liver but also in the intestine, has been studied extensively. Despite the advancement of this field - pharmacogenetics - its integration into clinical practice remains limited for reasons discussed herein. This highlights the even greater challenge of applying emerging knowledge on variability in the gut microbiota to drug therapy. However, ignoring these opportunities would be a mistake. While clinical applications of microbiota-guided drug therapy are currently absent and the ideas in this article are largely theoretical, research is uncovering that in cases where a substantial portion of a drug or its metabolites reaches the colon, or where drugs are formulated for colonic delivery, the gut microbiota can significantly affect drug metabolism and activity. Greater focus should be placed on research into how interindividual variability in the intestinal microbiome can modify pharmaceutical bioavailability and activity. This article is deliberately speculative and exploratory but proposes that, though there are still no clinical examples of microbiome-guided drug therapy, these interactions could afford opportunities for improvements in personalised medicine and also for drug design.

Thiopurines are a class of immunosuppressant and antineoplastic agents. They are widely used in the treatment of inflammatory bowel disease, haematological malignancies and autoimmune diseases, but can cause significant toxicity. Inherited gene mutations are now recognized as independent risk factors for severe adverse drug reactions to thiopurines even at 10-fold dose reductions. We present a case of thiopurine toxicity resulting in severe myelosuppression, hepatotoxicity and alopecia in an individual with homozygous *3/*3 loss-of-function alleles in the NUDT15 gene. Our case highlights important differences in gene mutation frequencies between races that can help guide pharmacogenomic testing.

Pharmacogenomics remains underutilized in pediatric oncology, despite the existence of evidence-based guidelines. Implementation of pharmacogenomics-informed prescribing could improve medication safety and efficacy in pediatric oncology patients, who are at high risk of adverse drug reactions. This study examines the prevalence of high-risk pharmacogenomic phenotypes and the prescription of relevant medications in a diverse Australian pediatric oncology cohort, highlighting the potential impact of pharmacogenomic testing in this unique population. Whole genome sequencing data from 180 patients were analyzed to assess 14 genes with evidence-based pharmacogenomic guidelines relevant to pediatric oncology. Over 90% of patients had at least one high-risk phenotype, with 20% presenting four or more. Ondansetron, mercaptopurine, omeprazole, pantoprazole, and voriconazole were commonly prescribed medications that have pharmacogenomic prescribing recommendations, with the latter three showing the highest actionability rates. High-risk phenotypes were most frequently observed for CYP2C19 and CYP2D6, with 30% of patients having a high-risk phenotype for both genes. This study underscores the potential utility of pharmacogenomics in pediatric oncology patients across a range of pharmacogenes and commonly prescribed medications. The findings support advocacy for implementing broad, pre-emptive pharmacogenomic testing in oncology patients to improve treatment safety and efficacy.

Background: Childhood cancers represent a heterogeneous group of malignancies and remain one of the leading causes of mortality among children under 14 years of age, ranking second only to accidental injuries, and fourth among individuals aged 15 to 19 years. Despite notable improvements in cure rates, a substantial proportion of patients experience acute or long-term toxicities associated with treatment. Methotrexate (MTX), a chemotherapeutic agent, has been employed effectively for over six decades in the management of pediatric malignancies. High-dose methotrexate constitutes a cornerstone of pediatric cancer therapy; however, its clinical utility is frequently constrained by dose-limiting toxicities. Objectives: This study investigates the impact of genetic polymorphisms in genes involved in nucleotide metabolism, as well as methotrexate and folate metabolic pathways, on treatment-related toxicity in childhood cancer. Methods: Using real-time polymerase chain reaction, 14 polymorphisms across 12 genes were analyzed in a cohort of 107 patients. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v. 5.0. Results: Multivariate logistic regression analysis revealed that the male sex (p = 0.3) and the AA genotype of MTHFD1 rs2236225 were associated with grade III-IV gastrointestinal toxicity (p = 0.03), while the A allele of MTHFR rs1801133 and the AA genotype of GSTP1 rs1695 were associated with grade I-IV hematologic toxicity (p < 0.01 and p = 0.02, respectively). Conclusions: High-dose methotrexate (HDMTX) is a critical agent in the treatment of childhood cancers. Our findings suggest that genetic polymorphisms within methotrexate and folate metabolic pathways may serve as potential predictive biomarkers of treatment-related toxicity.

Individual variations in the response to thiopurine-based anticancer drugs are influenced by genetic and environmental factors, making it challenging to optimize dosing and minimize toxicity. Among the key genes involved, genetic variations in the nudix hydrolase 15 (NUDT15) gene affect on thiopurine metabolism, thus influencing drug efficacy and the risk of severe adverse effects, such as myelosuppression, These variations also contribute to inter-individual differences in drug tolerance and clinical outcomes. Despite the recognized impact of NUDT15 variations, there has been limited comprehensive exploration of these variants and their clinical significance in thiopurine therapy. This review provides a thorough analysis of NUDT15 genetic variants by synthesizing findings from prior clinical studies and employing in silico analyses to predict the functional effects of variants with uncertain significance. Comprehensive analysis of NUDT15 variants and their interactions with other metabolic pathways could offer valuable insights for advancing personalized medicine in cancer treatment. This review aims to establish a foundation for integrating NUDT15 genetic information into the clinical practice, reducing toxicity, and improved therapeutic outcomes in patients undergoing thiopurine-based chemotherapy.

Chemotherapy-induced toxicities remain challenging in pediatric oncology, affecting patient outcomes, hospital stays, and quality of life. Genetic variation can partly explain these toxicities, and pharmacogenomics could potentially optimize treatment. This review provides an overview of pharmacogenomic studies in relation to chemotherapy-induced toxicity in children with solid tumors. A systematic literature search was performed in PubMed, Embase, and Web of Science following PRISMA guidelines. Two independent reviewers assessed eligibility, risk of bias using ROBINS-I, and extracted data. Out of 9000 articles screened, 279 were deemed relevant, and 59 met the inclusion criteria by focusing on children with solid tumors and pharmacogenomics in relation to chemotherapy-induced toxicity. Following risk of bias assessment, 24 articles with low to moderate risk of bias were summarized. Identifying specific SNPs associated with toxicities proved challenging due to variability across studies. For methotrexate, the genes ABCC2, MTHFR, and SXR were associated with myelosuppression and hepatotoxicity. The genes ABCC3, COMT, ERCC2, GSTP1, GSTT1, LRP2, SLC22A2, and TPMT showed associations with ototoxicity due to platinum-based drugs. Anthracycline-induced cardiotoxicity was associated with CBR2, CELF4, GSTM1, HAS3, RARG, and SLC28A3, and further with HNMT and SLC22A2 in younger children, with ABCB4 in females, and with SULT2B1 in males. A dose-dependent effect of CELF4 on cardiotoxicity was noted with anthracycline doses over 300 mg/m². This review highlights the complexity and variability of pharmacogenomic associations with chemotherapy-induced toxicities in pediatric oncology. While certain genetic variants show associations with specific toxicities, larger multinational/center studies are needed to strengthen the associations and improve clinical guidelines.

This study aimed to evaluate the impact of Nudix hydrolase 15 (NUDT15) variants on thiopurine metabolites, DNA-incorporated thioguanine nucleotides (DNA-TG), erythrocyte thioguanine nucleotides (Ery-TGNs) and methyl mercaptopurine nucleotide (Ery-MMPN) levels, and the association among the levels of these 6-MP metabolites in Japanese children with acute lymphoblastic leukemia (ALL).

DNA-TG, Ery-TGNs, and Ery-MMPN levels were measured in 20 Japanese patients with childhood ALL (171 sampling points) on consecutive clinical visits, using liquid chromatography with tandem mass spectrometry. NUDT15 was genotyped using Sanger sequencing.

Three NUDT15 intermediate metabolizers (IM, *1/*2 or *1/*3) and two poor metabolizers (PM, *3/*3) were identified. DNA-TG/dose was significantly higher in PM than in normal metabolizers (NM). Intra-patient coefficients of variation (CV) of DNA-TG levels were similar in NUDT15 genotypes, and inter-patient CV was higher in IM and PM than in NM. The DNA-TG/Ery-TGNs ratio was higher in IM and PM than in NM (p < 0.01). The ranges of DNA-TG/dose and DNA-TG/Ery-TGNs ratio were not different within NUDT15 phenotypes. In NUDT15 NM, patients with high Ery-TGNs/dose showed high DNA-TG/dose. Absolute lymphocyte count was significantly correlated with DNA-TG, Ery-TGNs, and Ery-MMPN levels (p < 0.001). White blood cell counts were significantly correlated with Ery-TGNs levels (p < 0.02), and the levels of aspartate and alanine aminotransferases were significantly correlated with Ery-MMPN levels (p < 0.001).

NUDT15 phenotype is a strong factor for thiopurine trialability in Japanese children with ALL. Ery-TGNs levels may associate with difference of individual response.

Despite the emergence of numerous innovative targeted therapies for the management of pediatric inflammatory bowel disease (IBD), azathioprine continues to be a pivotal first-line therapeutic agent. Nonetheless, the considerable frequency of myelosuppression associated with its use warrants careful consideration and further investigation. This study aims to investigate the application of pharmacogenomics in Chinese pediatric IBD treated with azathioprine, and to elucidate its association with the occurrence of myelosuppression.

We conducted a retrospective analysis to determine the prevalence of pharmacogenetic abnormalities and thiopurine-induced myelosuppression in Chinese pediatric patients with IBD.

Among the 227 patients underwent pharmacogenetic testing, abnormal genetypes occurred in 66 patients, among which 7 patients exhibited aberrant TPMT and 59 had aberrant NUDT15. Of the 58 patients who were treated with azathioprine, 23 cases experienced myelosuppression. All three children with heterozygous mutations in NUDT15 developed leukopenia following azathioprine treatment. Among patients with normal pharmacogenetic results, 20 cases (36.4%) developed myelosuppression, while 35 cases (63.6%) did not. The dose of azathioprine was below the recommended level in guidelines. The mean dose of azathioprine (mg/kg/day) in the myelosuppression group was 1.22 ± 0.32, compared to 1.42 ± 0.42 in the non-myelosuppression group, which represented a statistically significant difference (p < 0.05). Age, gender, and the use of concomitant biologics, mesalazine, or glucocorticoids did not show significant differences between the groups (p > 0.05).

NUDT15 C415T is prevalent in China and is associated with an increased risk of azathioprine-induced myelosuppression. A reduced dose of azathioprine should be considered for Chinese pediatric patients with IBD, even in those with normal pharmacogenetic profiles.

Pharmacogenomics, the study of how genetic variations influence drug response, has become integral to cancer treatment as personalized medicine evolves. This review aims to explore key pharmacogenomic biomarkers relevant to cancer therapy and their clinical implications, providing an updated and comprehensive perspective on how genetic variations impact drug metabolism, efficacy, and toxicity in oncology. Genetic heterogeneity among oncology patients significantly impacts drug efficacy and toxicity, emphasizing the importance of incorporating pharmacogenomic testing into clinical practice. Genes such as CYP2D6, DPYD, UGT1A1, TPMT, EGFR, KRAS, and BRCA1/2 play pivotal roles in influencing the metabolism, efficacy, and adverse effects of various chemotherapeutic agents, targeted therapies, and immunotherapies. For example, CYP2D6 polymorphisms affect tamoxifen metabolism in breast cancer, while DPYD variants can result in severe toxicities in patients receiving fluoropyrimidines. Mutations in EGFR and KRAS have significant implications for the use of targeted therapies in lung and colorectal cancers, respectively. Additionally, BRCA1/2 mutations predict the efficacy of PARP inhibitors in breast and ovarian cancer. Ongoing research in polygenic risk scores, liquid biopsies, gene-drug interaction networks, and immunogenomics promises to further refine pharmacogenomic applications, improving patient outcomes and reducing treatment-related adverse events. This review also discusses the challenges and future directions in pharmacogenomics, including the integration of computational models and CRISPR-based gene editing to better understand gene-drug interactions and resistance mechanisms. The clinical implementation of pharmacogenomics has the potential to optimize cancer treatment by tailoring therapies to an individual's genetic profile, ultimately enhancing therapeutic efficacy and minimizing toxicity.

Pharmacogenomics has demonstrated benefits for clinical care, including a reduction in adverse events and cost savings. However, barriers in expanded implementation of pharmacogenomics testing include prolonged turnaround times and integration of results into the electronic health record with clinical decision support. A clinical workflow was developed and implemented to facilitate in-house result generation and incorporation into the electronic health record at a large academic medical center.

An 11-gene actionable pharmacogenomics panel was developed and validated using a QuantStudio 12K Flex platform. Allelic results were exported to a custom driver and rules engine, and result messages, which included a diplotype and predicted metabolic phenotype, were sent to the electronic health record; an electronic consultation (eConsult) service was integrated into the workflow. Postimplementation monitoring was performed to evaluate the frequency of actionable results and turnaround times.

The actionable pharmacogenomics panel covered 39 alleles across 11 genes. Metabolic phenotypes were resulted alongside gene diplotypes, and clinician-facing phenotype summaries (Genomic Indicators) were presented in the electronic health record. Postimplementation, 8 clinical areas have utilized pharmacogenomics testing, with 56% of orders occurring in the outpatient setting; 22.1% of requests included at least one actionable pharmacogene, and 67% of orders were associated with a pre- or postresult electronic consultation. Mean turnaround time from sample collection to result was 4.6 days.

A pharmacogenomics pipeline was successfully operationalized at a quaternary academic medical center, with direct integration of results into the electronic health record, clinical decision support, and eConsult services.

Nudix hydrolase 15 (NUDT15) deficiency is strongly associated with thiopurine-induced myelosuppression. Currently, testing for NUDT15 deficiency is based on the genotyping of the most frequent and clinically characterized no-function variants, that is, *2, *3 and *9. The Hispanic/Latino-predominant variant NUDT15 *4 (p.R139H) is classified as "uncertain function" by the Clinical Pharmacogenetics Implementation Consortium, because of insufficient data to ascertain its clinical actionability. In this study, we evaluated the association of NUDT15 *4 with mercaptopurine (6-MP) tolerance in a retrospective cohort of 1,399 patients with acute lymphoblastic leukemia (ALL) of diverse ancestries. All patients were wildtype for thiopurine methyltransferase gene. Patients were treated with 6-MP in the context of ALL frontline clinical trials. The tolerated dose of 6-MP was used to assess drug toxicity during the maintenance phase of ALL therapy. Patients with NUDT15 *1/*4 (n = 16, all of whom self-identified as Hispanic/Latino) tolerated a significantly lower dose of 6-MP than did those with NUDT15 *1/*1: median [interquartile range] of 39.0 [21.2-52.8] mg/m2, vs. 62.2 [47.9-71.6] mg/m2, P value < 0.001. No patient homozygous for *4 was detected. In a separate retrospective validation study, six patients were identified as having NUDT15 *1/*4 by routine clinical pharmacogenetics testing and tolerated a 6-MP median dose of 38.7 mg/m2 (IQR, 33.7-54.0), confirming the need for dose reduction attributed to the NUDT15 *4 variant. These results point to the need to include NUDT15 *4 in pharmacogenetics-guided thiopurine dosing algorithms.

In the era of precision medicine, pharmacogenetics has substantial potential for addressing inter-individual variability in drug responses. Although pharmacogenetics has been a research focus for many years, resulting in the establishment of several formal guidelines, its clinical implementation remains limited to several gene-drug combinations in most countries, including Korea. The main causes of delayed implementation are technical challenges in genotyping and knowledge gaps among healthcare providers; therefore, clinical laboratories play a critical role in the timely implementation of pharmacogenetics. This paper presents an update of the Clinical Pharmacogenetic Testing and Application guidelines issued by the Korean Society for Laboratory Medicine and aims to provide the necessary information for clinical laboratories planning to implement or expand their pharmacogenetic testing. Current knowledge regarding nomenclature, gene-drug relationships, genotyping technologies, testing strategies, methods for clinically relevant information delivery, QC, and reimbursements has been curated and described in this guideline.

Mesalazine and thiopurines are important therapeutic agents for pediatric patients with ulcerative colitis (UC). Mesalazine, which may be administered in different forms depending on delivery mechanisms, can affect thiopurine metabolism, leading to increased 6-thioguanine nucleotides (6-TGN) levels. Therefore, when using these two drugs simultaneously, their interactions must be considered. This study aimed to analyze 6-TGN according to mesalazine formulation in pediatric patients with UC.

We retrospectively reviewed the data of 236 pediatric patients with UC who visited a single health center between January 2021 and December 2023. Among the enrolled patients, 198 were administered thiopurines, and of these, 136 underwent testing for 6-TGN.

The mean dose of azathioprine (AZA) was 0.66 mg/kg, and the mean 6-TGN level was 211.64 pmol/8 × 10^8 red blood cells (RBCs). The mean 6-TGN level for the group concurrently using time-dependent mesalazine and AZA was 245.00 pmol/8 × 10^8 RBCs, while that for the group concurrently using multimatrix mesalazine (MMX) and AZA was 141.97 pmol/8 × 10^8 RBCs (P < 0.001). In the same patients, the mean 6-TGN level during time-dependent mesalazine treatment was 290.34 pmol/8 × 108 RBCs, whereas the mean 6-TGN level measured after switching to MMX was 148.54 pmol/8 × 108 RBCs (P = 0.016).

The group treated with MMX and AZA had a lower mean 6-TGN level than the group treated with time-dependent mesalazine and AZA. The mean 6-TGN level significantly decreased after switching from time-dependent mesalazine to MMX in the same patients. Therefore, when administering MMX, a higher dose of AZA is necessary to reach the target 6-TGN level, compared to the dose required when using time-dependent mesalazine.

Understanding the molecular mechanisms of medicines is crucial for developing novel drugs, for repurposing existing medicines, and for predicting toxicities. Thiopurine S-methyltransferase (TPMT) serves as an exemplary case in personalized medicine, as its activity is influenced by genetic variants, co-factors, substrates, and inhibitors, which lead to diverse outcomes in thiopurine therapy. This comprehensive review explores the role of TPMT in drug-drug interactions by investigating its interactions with co-factors, substrates, and inhibitors. We focus on the principal interactions of TPMT with clinically relevant inhibitors, and add to this information with molecular docking analyses for the substrate and co-factor binding sites of TPMT. Notably, methotrexate and sulfasalazine emerged as the top-ranked compounds with favorable docking scores for the co-factor binding site, while furosemide is presented as the highest ranked inhibitor for the substrate binding site. Furthermore, we highlight the chemical and structural properties governing ligand binding to TPMT. We support the molecular characteristics by using a summary of clinical implications. Examining the molecular interactions between substrates or inhibitors and TPMT not only addresses therapeutic consequences, but also reveals potential novel indications of interacting compounds. These insights are also invaluable for identifying endogenous ligands and enhancing our understanding of TPMT's biological function.

Pediatric solid organ transplantation is a complex process including a tightly orchestrated medication regimen, essential for prevention of infection, rejection, graft failure, and mortality. Pharmacogenomic (PGx) testing tailors medication therapy to the individual patient, focusing on safety, efficacy, and avoidance of adverse effects. Implementation of PGx panel results into clinical practice for pediatric transplant patients has not been evaluated.

Pediatric patients evaluated for heart, kidney, or combined heart-kidney transplant at a tertiary children's hospital from October 2021 to October 2023 received PGx panel testing.

Report the prevalence of actionable PGx variants for key genes impacting pharmacotherapy in pre- and post-heart and kidney transplant populations.

A total of 73 patients were included, predominately white (84.9%) and male (64.4%), with a mean age of 8.8 ± 6.4 years. Indications for PGx testing included evaluation for heart transplant (38.4%), kidney transplant (38.4%), combined heart-kidney transplant (4.1%), or to inform posttransplant care (19.2%). All patients had at least one actionable phenotype identified. 37 of 73 patients (50.7%) had at least one actionable phenotype for the transplant-specific genes captured including CYP3A5, SLCO1B1, G6PD, TPMT, prothrombin (Factor 2), and Factor V Leiden. 16 of 73 patients (21.9%) had actionable CYP3A5 phenotypes. 15 of 73 (20.5%) had actionable SLCO1B1 phenotypes. 9 of 73 patients (12.3%) had actionable TPMT phenotypes. 5 of 73 (6.8%) had Prothrombin or Factor V Leiden variants.

Routine pretransplant PGx testing provided information that was actionable and could be utilized to optimize posttransplant medications for all patients.

Thiopurine S-methyltransferase (TPMT) and Nudix hydrolase (NUDT15) polymorphisms predispose to thiopurine-related leukopenia.

Retrospective evaluation of inflammatory bowel disease (IBD) patients harboring NUDT15 polymorphisms and exposed to thiopurines. We report the frequency of NUDT15 polymorphism, frequency of leukopenia, the tolerated dose of azathioprine, and the clinical efficacy of thiopurines.

Of 1440 patients, 118 (8.2%) had NUDT15 polymorphism. Among 51 with complete details, 46 were heterozygous (90.2%), and 5 homozygous (9.2%) for NUDT15. Twenty (43.5%) heterozygous and all homozygous patients developed leukopenia. Leukopenia was significantly more in NUDT15 heterozygous group compared to controls (43.45% vs 7.8%, Odds ratio: 9, 95% CI 3.57-22.9). The maximum tolerated dose of azathioprine was lower in NUDT15 heterozygous group (1.1 ± 0.4 mg per kg vs 1.7 ± 0.7 mg per kg, p = 0.002). The mean time to leukopenia was earlier in the heterozygous group vs controls (19 ± 56 weeks vs 70 ± 53 weeks, p-value 0.002). Seven (35%) of 20 heterozygous patients who developed leukopenia, could be maintained at a lower dose of thiopurine. Twenty-five maintained clinical remission while on thiopurines.

Thiopurines should be avoided in NUDT15 homozygous but can be used cautiously at lower dosages with frequent monitoring among heterozygous patients.

Anaemia is a frequent consequence of many gastrointestinal (GI) diseases in children and it can even be the initial presenting symptom of underlying chronic GI disease. The definition of anaemia is age and gender-dependent and it can be classified based on pathophysiology, red cell morphology, and clinical presentation. Although nutritional deficiencies, including GI malabsorption of nutrients and GI bleeding, play a major role, other pathophysiologic mechanisms seen in chronic GI diseases, whether inflammatory (e.g., inflammatory bowel disease) or not (e.g., coeliac disease and dysmotility), are causing anaemia. Drugs, such as proton pump inhibitors, mesalamine, methotrexate and sulfasalazine, are also a potential cause of anaemia. Not uncommonly, due to a combination of factors, such as iron deficiency and a chronic inflammatory state, the underlying pathophysiology may be difficult to decipher and a broad diagnostic work-up is required. The goal of treatment is correction of anaemia by supplementation of iron and vitamins. The first therapeutic step is to treat the underlying cause of anaemia including bleeding control, restoration of intestinal integrity and reduction of inflammatory burden. The route of iron and vitamin supplementation is guided by the severity of anaemia.

Therapeutic drug monitoring (TDM) is important to optimize drug exposure and minimize toxicity for the individual patient.

This narrative review covers the pharmacokinetics (PK), -dynamics (PD) and -genetics of classic chemotherapeutic drugs used in frontline therapy for acute lymphoblastic leukemia (ALL), including anthracyclines, asparaginase, busulfan, cyclophosphamide, cytarabine, glucocorticoids, methotrexate, nelarabine, thiopurines, tyrosine kinase inhibitors, and vincristine. Furthermore, novel immunotherapies including blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor T-cells that are rapidly moving into frontline therapy are addressed. This review focuses on TDM already used in clinical practice as well as the unused potential and feasibility of TDM. Finally, important factors affecting PK/PD such as obesity and transition to adolescence and young adulthood are discussed.

Investigation of TDM as standard of care for antileukemic agents is highly warranted to personalize curative yet toxic anticancer regimens within frontline ALL treatment. Some of the drugs have been used in ALL treatment regimens for decades, but a wide range of new compounds are being introduced, some like blinatumomab reaching standard-of-care designation. Not least, optimized drug efficacy and reduction of the risk of serious toxicities may render TDM implementation cost-effective.

Maintenance of remission is essential in inflammatory bowel disease (IBD) in terms of disease course and long-term prognosis. The thiopurines azathioprine and 6-mercaptopurine have longstanding merit in ulcerative colitis, but more therapeutic options have been developed. This review is an update and extension of a review last published in 2016.

To assess the effectiveness and safety of azathioprine and 6-mercaptopurine in monotherapy or combined therapy regimens compared to placebo or active controls for the maintenance of remission in ulcerative colitis.

We searched Cochrane Central Register of Controlled Trials (until May 2023), ClinicalTrials.gov (until May 2023), Embase (until August 2022), MEDLINE (until May 2023), and WHO ICTRP (until May 2023). We checked reference lists of the included studies and, if needed, contacted the authors to request more data or information.

Randomized controlled trials (RCTs) of at least 24 weeks' duration comparing azathioprine or 6-mercaptopurine with placebo or any other medication, or comparing different treatment modalities of azathioprine or 6-mercaptopurine, in persons of any age with quiescent ulcerative colitis were eligible. We only considered studies with mixed IBD populations or with a preceding induction period if separate results on participants with ulcerative colitis in remission were available or could be calculated. The primary outcome was failure to maintain clinical or endoscopic remission (relapse). Secondary outcomes included change in disease activity, quality of life, hospitalization, need for surgery, days off work, adverse events, and withdrawal due to adverse events.

Two authors independently extracted data using standard forms, resolved any disagreements by consensus, and assessed study quality using the Cochrane risk of bias tool (RoB 2). We conducted separate analyses by type of control, calculated pooled risk ratios (RRs) or risk differences (RDs) using the fixed-effect model unless heterogeneity was likely, and assessed the certainty of evidence using the GRADE approach.

We included 10 studies in the review, including 468 adult participants with ulcerative colitis. The risk of bias across these was low for most outcomes, but we considered some outcomes to have some concerns or high risk of bias due to insufficient information on concealment of allocation and outcome measurement. Based on five placebo-controlled studies, azathioprine or 6-mercaptopurine may reduce the risk of failing to maintain remission. In the thiopurine group, 45% (64/143) of participants failed to maintain remission compared to 67% (96/143) of participants receiving placebo (RR 0.66, 95% confidence interval (CI) 0.54 to 0.82; 5 studies, 286 participants; low-certainty evidence). Three studies reported withdrawals due to adverse events. Among participants on azathioprine, 4% (3/80) withdrew due to adverse events compared to 0% (0/82) of placebo participants (RD 0.04, 95% CI -0.02 to 0.09; 3 studies, 162 participants; low-certainty evidence). The evidence is of low certainty when comparing 6-mercaptopurine to 5-aminosalicylate. Based on one three-armed trial, 27% (3/11) of 6-mercaptopurine participants failed to maintain remission compared to 100% (2/2) of 5-aminosalicylate participants (RR 0.35, 95% CI 0.13 to 0.97; 1 study, 13 participants; low-certainty evidence). This trial also involved an induction phase; we only included the results for participants in remission. The single trial comparing 6-mercaptopurine to 5-aminosalicylate did not report separate data on adverse events and withdrawals due to adverse events for the subgroup with successful induction of remission, so we could not analyze these outcomes for this comparison.

Low-certainty evidence suggests that azathioprine or 6-mercaptopurine therapy may be more effective than placebo for the maintenance of remission in ulcerative colitis. More research is needed to evaluate the value of therapeutic drug monitoring and the effects of various treatment modalities on long-term safety.

Kidney transplantation is currently the treatment of choice for patients with end-stage kidney diseases. Although significant advancements in kidney transplantation have been achieved over the past decades, the host's immune response remains the primary challenge, often leading to potential graft rejection. Effective management of the immune response is essential to ensure the long-term success of kidney transplantation. To address this issue, immunosuppressives have been developed and are now fully integrated into the clinical management of transplant recipients. However, the considerable inter- and intra-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs represents the primary cause of graft rejection. This variability is primarily attributed to the polymorphic nature (genetic heterogeneity) of genes encoding xenobiotic-metabolizing enzymes, transport proteins, and, in some cases, drug targets. These genetic differences can influence drug metabolism and distribution, leading to either toxicity or reduced efficacy. The main objective of the present review is to report an historical overview of the pharmacogenetics of immunosuppressants, shedding light on the most recent findings and also suggesting how relevant is the research and investment in developing validated NGS-based commercial panels for pharmacogenetic profiling in kidney transplant recipients. These advancements will enable the implementation of precision medicine, optimizing immunosuppressive therapies to improve graft survival and kidney transplanted patient outcomes.

As part of the 100,000 Genomes Project, we set out to assess the potential viability and clinical impact of reporting genetic variants associated with drug-induced toxicity for patients with cancer recruited for whole-genome sequencing (WGS) as part of a genomic medicine service.

Germline WGS from 76,805 participants was analyzed for pharmacogenetic (PGx) variants in four genes (DPYD, NUDT15, TPMT, UGT1A1) associated with toxicity induced by five drugs used in cancer treatment (capecitabine, fluorouracil, mercaptopurine, thioguanine, irinotecan). Linking genomic data with prescribing and hospital incidence records, a phenome-wide association study (PheWAS) was performed to identify whether phenotypes indicative of adverse drug reactions (ADRs) were enriched in drug-exposed individuals with the relevant PGx variants. In a subset of 7,081 patients with cancer, DPYD variants were reported back to clinicians and outcomes were collected.

We identified clinically relevant PGx variants across the four genes in 62.7% of participants in our cohort. Extending this to annual prescription numbers in England for the drugs affected by these PGx variants, approximately 14,540 patients per year could potentially benefit from a reduced dose or alternative drug to reduce the risk of ADRs. Validating PGx associations in a real-world data set, we found a significant association between PGx variants in DPYD and toxicity-related phenotypes in patients treated with capecitabine or fluorouracil. Reported DPYD variants were deemed informative for clinical decision making in a majority of cases.

Reporting PGx variants from germline WGS relevant to patients with cancer alongside primary findings related to their cancer can be clinically informative, informing prescribing to reduce the risk of ADRs. Extending the range of actionable variants to those found in patients of non-European ancestry is important and will extend the potential clinical impact.

To share the experience of a US national reference laboratory, offering genotyping for TPMT and NUDT15, TPMT enzyme phenotyping and detection of thiopurine metabolites.

Retrospective review of archived datasets related to thiopurines drug therapy including patients' data that underwent TPMT and NUDT15 genotyping, and smaller data sets where genotyping was performed with TPMT enzyme levels (phenotyping) +/- therapeutic drug monitoring (TDM).

Thirteen percent of patients had variants in one or both genes tested. Testing for NUDT15 revealed 3.9% additional patients requiring thiopurines dosing recommendations. A correlation between TPMT enzyme activity and TPMT polymorphisms (odds ratio OD = 71.41, p-value <0.001) and between older age and higher enzyme levels (OD = 0.98, p-value = 0.002) was identified. No correlation between sex and TPMT enzyme levels, nor between TPMT genotyping and the level of thiopurine metabolites was found.

Adding NUDT15 to TPMT genotyping, identified additional 3.9% patients to benefit from thiopurine dose modifications. A significant correlation between genetic variants in TPMT and TPMT enzyme levels and between age and enzyme levels was established, while no correlation was identified between sex and enzyme levels nor between TPMT variation and thiopurine metabolites. Providers rely more significantly on genotyping only approach, rather than genotyping and phenotyping.

Thiopurine drugs are effective treatment options in inflammatory bowel disease and other conditions but discontinued in some patients due to toxicity.

We investigated thiopurine-induced toxicity in a pediatric inflammatory bowel disease cohort by utilizing exome sequencing data across a panel of 46 genes, including TPMT and NUDT15.

The cohort included 487 patients with a median age of 13.1 years. Of the 396 patients exposed to thiopurines, myelosuppression was observed in 11%, gastroenterological intolerance in 11%, hepatotoxicity in 4.5%, pancreatitis in 1.8%, and "other" adverse effects in 2.8%. TPMT (thiopurine S-methyltransferase) enzyme activity was normal in 87.4%, intermediate 12.3%, and deficient in 0.2%; 26% of patients with intermediate activity developed toxicity to thiopurines. Routinely genotyped TPMT alleles associated with defective enzyme activity were identified in 28 (7%) patients: TPMT*3A in 4.5%, *3B in 1%, and *3C in 1.5%. Of these, only 6 (21%) patients developed toxic responses. Three rare TPMT alleles (*3D, *39, and *40) not assessed on routine genotyping were identified in 3 patients, who all developed toxic responses. The missense variant p.R139C (NUDT15*3 allele) was identified in 4 patients (azathioprine 1.6 mg/kg/d), but only 1 developed toxicity. One patient with an in-frame deletion variant p.G13del in NUDT15 developed myelosuppression at low doses. Per-gene deleteriousness score GenePy identified a significant association for toxicity in the AOX1 and DHFR genes.

A significant association for toxicity was observed in the AOX1 and DHFR genes in individuals negative for the TPMT and NUDT15 variants. Patients harboring the NUDT15*3 allele, which is associated with myelosuppression, did not show an increased risk of toxicity.

Autoimmune blistering diseases (AIBDs), classified into pemphigus and pemphigoid, consist of relatively rare skin disorders caused by autoantibodies that target desmosomal and hemidesmosomal proteins, respectively. Although systemic corticosteroids are used as a first-line treatment for AIBDs, azathioprine is frequently co-administered as a steroid-sparing agent. Azathioprine is metabolized into thioguanine nucleotides (TGNs) which are its major active metabolites. The enzyme nudix hydrolase 15 (NUDT15) plays a key role in regulating TGNs. Serious side effects of azathioprine, including leukopenia and alopecia, are known to be particularly problematic in individuals with NUDT15 variants. The single-nucleotide polymorphism c.415C >T (p.Arg139Cys) is one of the most frequent NUDT15 variants associated with severe thiopurine toxicity. Recently, we treated a case of pemphigus vulgaris in a patient with NUDT15 variants in which the patient developed rapidly progressive diffuse hair loss and myelosuppression while receiving azathioprine. Previous reports on NUDT15 polymorphisms mainly focused on patients with inflammatory bowel disease or hematological malignancies, and the prevalence of NUDT15 polymorphisms remains unknown in AIBDs. This highlights the urgent need for research on NUDT15 polymorphisms in AIBDs to achieve a better understanding of the genetic factors influencing adverse reactions to azathioprine. To clarify the prevalence of NUDT15 variants in Japanese patients with AIBDs, we retrospectively reviewed the medical records of 78 patients with AIBDs (26 with bullous pemphigoid, 26 with pemphigus vulgaris, 17 with pemphigus foliaceus, and nine with other AIBDs) who had come to Hokkaido University Hospital between 2018 and 2023. The frequencies of NUDT15 variants of Arg/Arg, Arg/Cys, and Cys/Cys in these patients were approximately 72%, 23%, and 5%, respectively. Our findings indicate a prevalence of NUDT15 variants in AIBD patients that is similar to the prevalences of previous studies on patients with other diseases. These results emphasize the importance of screening for NUDT15 variants prior to initiating azathioprine treatment in Japanese patients with AIBDs.

Pharmacogenomic testing identifies gene polymorphisms impacting drug metabolism, aiding in optimizing treatment efficacy and minimizing toxicity, thus potentially reducing healthcare utilization. 6-Mercaptopurine metabolism is affected by thiopurine methyltransferase ( TPMT ) and nudix hydrolase 15 ( NUDT15 ) polymorphisms. We sought to estimate the budget impact of preemptive pharmacogenomic testing for these genes in pediatric acute lymphoblastic leukemia (ALL) patients from an institutional perspective.

A Markov model was constructed to model the first cycle of the maintenance phase of chemotherapy for pediatric ALL patients transitioning between one of three health states: stable, moderately myelosuppressed, and severely myelosuppressed over 16 weeks, with each health state's associated costs derived from the literature. The patient's likelihood to experience moderate or severe myelosuppression based on metabolism phenotype was calculated from the literature and applied on a weekly basis, and the marginal budget impact of preemptive pharmacogenomic testing vs. no pharmacogenomic testing was calculated. One-way sensitivity analysis was conducted to assess parameter influence on results.

Preemptive pharmacogenomic testing of TPMT and NUDT15 provided savings of up to $26 028 per patient during the maintenance phase. In the sensitivity analysis, the cost of outpatient management of moderate myelosuppression had the greatest impact on the budget, resulting in cost savings ranging from $8592 to $30 129 when the minimum and maximum costs of management were used in the model.

Preemptive pharmacogenomic testing for TPMT and NUDT15 polymorphisms before initiation of maintenance therapy for pediatric ALL patients yielded considerable cost savings.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease requiring immunosuppressive medications to control symptoms and prevent organ damage. This review explores the influence of genetic polymorphisms on the pharmacokinetics and therapeutic responses of immunosuppressants in SLE. A total of 37 studies were reviewed, focusing on mycophenolic acid, tacrolimus, azathioprine, glucocorticoids, and cyclophosphamide. Genetic variants in UGT1A9, UGT2B7, CYP3A5, ABCB1,ABCC2 and TPMT significantly affect drug metabolism, efficacy, and toxicity. For instance, ABCB1 polymorphisms influence drug transport and bioavailability, impacting tacrolimus and glucocorticoid response, while ABCC2 variants alter MPA clearance, potentially affecting therapeutic outcomes, UGT1A9 and UGT2B7 variants influence mycophenolic acid metabolism, CYP3A5 impacts tacrolimus dosing, TPMT determines azathioprine metabolism, and CYP2C19 and CYP2B6 affect cyclophosphamide processing. These genetic differences can alter treatment effectiveness and risk of adverse effects. However, most pharmacogenetic studies focus on organ transplantation, leaving a critical gap in SLE-specific research, particularly among diverse populations. Addressing this gap is essential to optimizing personalized treatment for SLE. Integrating pharmacogenetics into clinical practice holds great potential to enhance the safety, efficacy, and outcomes of immunosuppressive therapy in SLE. This review highlights the urgent need for further studies to advance precision medicine for SLE patients.

Adverse drug reactions (ADRs) account for a large proportion of hospitalizations among adults and are more common in multimorbid patients, worsening clinical outcomes and burdening healthcare resources. Over the past decade, pharmacogenomics has been developed as a practical tool for optimizing treatment outcomes by mitigating the risk of ADRs. Some single-gene reactive tests are already used in clinical practice, including the DPYD test for fluoropyrimidines, which demonstrates how integrating pharmacogenomic data into routine care can improve patient safety in a cost-effective manner. The evolution from reactive single-gene testing to comprehensive pre-emptive genotyping panels holds great potential for refining drug prescribing practices. Several implementation projects have been conducted to test the feasibility of applying different genetic panels in clinical practice. Recently, the results of a large prospective randomized trial in Europe (the PREPARE study by Ubiquitous Pharmacogenomics consortium) have provided the first evidence that prospective application of a pre-emptive pharmacogenomic test panel in clinical practice, in seven European healthcare systems, is feasible and yielded a 30% reduction in the risk of developing clinically relevant toxicities. Nevertheless, some important questions remain unanswered and will hopefully be addressed by future dedicated studies. These issues include the cost-effectiveness of applying a pre-emptive genotyping panel, the role of multiple co-medications, the transferability of currently tested pharmacogenetic guidelines among patients of non-European origin and the impact of rare pharmacogenetic variants that are not detected by currently used genotyping approaches.

Genetic screening analyzes an individual's genetic information to assess disease risk and provide personalized health recommendations. This article introduces the public to genetic screening, explaining its definition, principles, history, and common types, including prenatal, newborn, adult disease risk, cancer, and pharmacogenetic screening. It elaborates on the benefits of genetic screening, such as early risk detection, personalized prevention, family risk assessment, and reproductive decision-making. The article also notes limitations, including result interpretation uncertainty, psychological and ethical issues, and privacy and discrimination risks. It provides advice on selecting suitable screening, consulting professionals, choosing reliable institutions, and understanding screening purposes and limitations. Finally, it discusses applying screening results through lifestyle adjustments, regular check-ups, and preventive treatments. By comprehensively introducing genetic screening, the article aims to raise public awareness and encourage utilizing this technology to prevent disease and maintain health.

Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or are in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, for example, somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for >5 decades, considering individual patients' genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient's tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information, which derives from both the tumor and the germline genome, and taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to integrate PGx data in cancer therapy with a special meaning for interdisciplinary molecular tumor boards, in which cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. SIGNIFICANCE STATEMENT: The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, the full potential of targeted therapy remains untapped owing to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.

Implementation of pharmacogenetic testing in clinical care has been slow and with few exceptions is hindered by the lack of real-world evidence on how to best target testing. In this retrospective register-based study, we analyzed a nationwide cohort of 1,425,000 patients discharged from internal medicine or surgical wards and a cohort of 2,178 university hospital patients for purchases and prescriptions of pharmacogenetically actionable drugs. Pharmacogenetic variants were obtained from whole genome genotype data for a subset (n = 930) of the university hospital patients. We investigated factors associated with receiving pharmacogenetically actionable drugs and developed a literature-based cost-benefit model for pre-emptive pharmacogenetic panel testing. In a 2-year follow-up, 60.4% of the patients in the nationwide cohort purchased at least one pharmacogenetically actionable drug, most commonly ibuprofen (25.0%) and codeine (19.4%). Of the genotyped subset, 98.8% carried at least one actionable pharmacogenetic genotype and 23.3% had at least one actionable gene-drug pair. Patients suffering from musculoskeletal or cardiovascular diseases were more prone to receive pharmacogenetically actionable drugs during inpatient episode. The cost-benefit model included frequently dispensed drugs in the university hospital cohort, comprising ondansetron (19.4%), simvastatin (7.4%), clopidogrel (5.0%), warfarin (5.1%), (es)citalopram (5.3%), and azathioprine (0.5%). For untargeted pre-emptive pharmacogenetic testing of all university hospital patients, the model indicated saving €17.49 in direct healthcare system costs per patient in 2 years without accounting for the cost of the test itself. Therefore, it might be reasonable to target pre-emptive pharmacogenetic testing to patient groups most likely to receive pharmacogenetically actionable drugs.