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Background and aims: A number of case reports have documented the occurrence of acute hepatic and renal toxicity during treatment with deferasirox (DFX). The precise mechanisms underlying these adverse events remain unclear, with the time to toxicity varying considerably between patients—some experiencing it within weeks of treatment initiation, while others after several years. Recent studies have underscored the association of pharmacogenetic variants in genes responsible for the metabolism and clearance of DFX (ABCC2 , ABCG2 , and UGT1A1) in the development of toxicity. We present the case of an 8-year-old patient with beta thalassemia major who developed acute hepatic failure years after the initiation of DFX therapy. After ruling out the most likely causes, we performed a pharmacogenetic analysis, which suggested a possible link between the patient's genotype and the development of toxicity. Methods: Sanger sequencing was performed for the most extensively studied single nucleotide polymorphisms (SNPs) studied associated with changes in transporter/enzyme function: ABCC2 rs717620 (c.-24C>T), rs2273697 (c.1249G>A), rs8187710 (c.4544G>A), rs369192412 (g.99781071delG); ABCG2 rs2231142 (c.421C>A); UGT1A1 *6 rs4148323 (c.211G>A), *28 rs3064744 (g.233760235TA[8]), *36 rs3064744 (g.233760235TA[6]) and *37 rs3064744 (g.233760235TA[9]). Results: The patient is heterozygous for two ABCC2 variants, namely rs717620 (c.-24C>T) and rs2273697 (c.1249G>A). These variants have the potential to cause a reduction in transporter function, which could in turn result in decreased drug clearance and increased toxicity. Discussion: The precise mechanism by which toxicity developed in this case remains unclear and is likely multifactorial. However, it is probable that the presence of SNPs in the gene ABCC2 played a substantial role. Our findings align with those of previously published reports of remarkably similar cases, where patients also exhibited genetic variants in the gene ABCC2. [ABSTRACT FROM AUTHOR]

Introduction: The Cuban population is genetically diverse, and information on the prevalence of genetic variants is still limited. As complex admixture processes have occurred, we hypothesized that the frequency of pharmacogenetic variants and drug responses may vary within the country. The aims of the study were to describe the frequency distribution of 43 single-nucleotide variants (SNVs) from 25 genes of pharmacogenetic interest within the Cuba population and in relation to other populations, while taking into consideration some descriptive variables such as place of birth and skin color. Materials and Methods: SNVs were analyzed in 357 unrelated healthy Cuban volunteers. Genotype, allele frequencies, and ancestry proportions were determined, and the pairwise fixation index (FST) was evaluated. Results: Hardy–Weinberg equilibrium (HWE) deviations in six loci (rs11572103, rs2740574, rs776746, rs3025039, rs861539, and rs1762429) were identified. Minor allele frequencies (MAFs) ranged from 0.00 to 0.15 for variants in genes encoding xenobiotic metabolizing enzymes. They also ranged from 0.01 to 0.21 for variants in DNA repair, growth factors, methyltransferase, and methyl-binding proteins, while they ranged from 0.04 to 0.27 for variants in the O-6-methylguanine-DNA methyltransferase enzyme. Moderate genetic divergence was observed upon comparison to Africans (FST = 0.071 and SD 0.079), with 19 markers exhibiting moderate-to-large genetic differentiation. The average European, African, and Amerindian ancestry proportions were 67.8%, 27.2%, and 5.3%, respectively. Ancestry proportions differed by skin color and birthplace for both African and European components, with the exception of the European component, which showed no significant difference between individuals from Western and Eastern regions. Meanwhile, the statistical significance varied in comparisons by skin color and birthplace within the Amerindian component. Low genetic divergence was observed across geographical regions. We identified 12 variants showing moderate-to-large differentiation between White/Black individuals. Conclusion: Altogether, our results may support national strategies for the introduction of pharmacogenetic tools in clinical practice, contributing to the development of precision medicine in Cuba. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the utilization of drugs with pharmacogenomic guidelines (PGx-drugs) for personalized dosing in pediatric leukemia. A retrospective observational study of pediatric leukemia patients admitted between 2009–2019 at a single-center academic children's hospital was conducted to determine PGx-drug exposure within 3 years of diagnosis. Along with baseline demographic and clinical characteristics of these patients, data regarding dates of diagnosis, relapse, death were collected. During the study period, inclusion criteria were met by 714 patients. The most frequently given medications were ondansetron (96.1%), morphine (92.2%), and allopurinol (85.3%) during the study period. In this cohort, 82% of patients received five or more PGx-drugs. Patients diagnosed with acute myeloid leukemia and leukemia unspecified were prescribed more PGx-drugs than other types of leukemia. There was a significant relationship between age at diagnosis and the number of PGx-drugs prescribed. Adolescents and adults both received a median of 10 PGx-drugs, children received a median of 6 PGx-drugs, and infants received a median of 7 PGx-drugs (p < 0.001). Patients with recurrent leukemia had significantly more PGx-drugs prescribed compared to those without recurrent disease, 10 drugs and 6 drugs, respectively (p < 0.001). Patients diagnosed with childhood leukemia are high utilizers of PGx-drugs. There is a vital need to understand how PGx testing may be utilized to optimize treatment and enhance quality of life. Preemptive PGx testing is a tool that aids in optimization of drug therapy and decreases the need for later treatment modifications. This can result in financial savings from decreased health-care encounters. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease is a neurodegenerative disorder with polygenic etiology. Genetic risk variants for Alzheimer’s disease differ among populations. Thus, discovering them in each population is clinically important. A total of 118 patients and 97 controls for VDR rs11568820 and 88 patients and 100 healthy controls for MTHFR C677T polymorphism were genotyped to evaluate the association of these polymorphisms with late-onset Alzheimer’s disease in the Iranian population, along with their impacts on the response to Rivastigmine treatment. The VDR C allele was significantly associated with Alzheimer’s disease and provided protection against it (P = 0.003, RR = 1.14, 95% CI 1.04–1.24), while the T allele increased susceptibility (P = 0.003, RR = 1.93, 95% CI 1.23–3.02). These results were also considerable upon excluding the effect of APOE ε4 allele. The Prevalence-corrected Positive Predictive Value was 1.71% for the VDR CC genotype and 4% for the VDR CT genotype, indicating lower and almost twofold higher chances of developing Alzheimer’s disease, respectively. No significant correlation was observed between MTHFR C677T and Alzheimer’s disease. Based on our pharmacogenetic study, MTHFR T allele carriers lacking APOE ε4 allele showed a better response to Rivastigmine treatment after a 2-year follow-up. Moreover, patients with VDR CC genotype displayed milder Alzheimer’s disease, particularly when coincided with the APOE ε4 allele. The VDR rs11568820 polymorphism affects both Alzheimer’s disease risk and the response to Rivastigmine in Iranian patients. Also, MTHFR C677T polymorphism may play a role in the response to Rivastigmine, through a pathway that needs to be elucidated in future studies. [ABSTRACT FROM AUTHOR]

Abstract Bictegravir, a key second-generation integrase strand transfer inhibitor in the treatment of HIV, is subject to active efflux transport mediated by ABCB1 (P-glycoprotein). Several coding variants of ABCB1 have been described and associated with variable effects on substrate drugs pharmacokinetics. Here, we investigated the effect of the four most common coding ABCB1 single nucleotide polymorphisms (i.e., c.1199G > A, c.1236C > T, c.2677G > T and c.3435C > T) on the intracellular accumulation of bictegravir. Using a previously validated HEK293 recombinant cell line model, we found decreased bictegravir intracellular concentrations in cell lines overexpressing ABCB1 as compared to control cell lines, in line with the known role of ABCB1 in bictegravir transport. However, we were unable to demonstrate any significant difference in bictegravir intracellular accumulation when comparing HEK293 cells overexpressing the wild type (1236C-2677G-3435C, 1199G) or the variant (1236C-2677G-3435T, 1236T-2677T-3435T or 1199A) proteins. These findings suggest that the ABCB1 c.1199G > A and c.1236C > T-c.2677G > T-c.3435C > T variants have no or at least limited impact on the active transport of bictegravir by ABCB1.

Abstract Analyze the relationship between genetic variations in the MTHFR gene at SNPs (rs1801131 and rs1801133) and the therapy outcomes for Iraqi patients with rheumatoid arthritis (RA). The study was conducted on a cohort of 95 RA Iraqi patients. Based on their treatment response, the cohort was divided into two groups: the responder (47 patients) and the nonresponder (48 patients), identified after at least three months of methotrexate (MTX) treatment. A polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) technique was employed to analyze the MTHFR variations, specifically at rs1801133 and rs1801131. Overall, rs1801131 followed both codominant and dominate models, in which in the codominant model, GG [OR (95% CI) 0.11 (0.022–0.553)] and TG [OR (95% CI) 0.106 (0.021–0.528)] predict responders compared to the TT genotype; meanwhile, for the dominate model, the presence of both GG and TG genotypes [OR (95% CI) 0.108 (0.023–0.507)] together predict responders compared to the TT genotype. The Ars1801133Grs1801131 haplotype was significantly associated with responders [OR (95% CI): 0.388 (0.208–0.723)], while the Grs1801133Trs1801131 haplotype was associated marginally with nonresponders [OR (95% CI) 1.980 (0.965–4.064)]. In the final multivariate analysis, GG/TGrs1801131 genotypes were independently related to responders after adjustment for patients, disease, and treatment characteristics, while TTrs1801131 genotypes were associated with nonresponders. The Iraqi RA patients showed genetic polymorphism in MTHFR gene rs1801131 with T carrier allele associated with nonresponders to MTX therapy. The rs1801131 followed both codominant and dominant models. The G-carried allele for rs1801131 showed an independent association with responder to MTX therapy after adjustment for patients, disease, and treatment characteristics.

Background: Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing challenge is the variable occurrence of adverse drug reactions in some TB patients. Previous studies have indicated that genetic variations in the N-acetyltransferase 2 (NAT2) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) genes can impact the blood concentrations of the first-line anti-TB drugs isoniazid (INH) and rifampicin (RIF), respectively. This study aimed to investigate the influence of pharmacogenetic markers in the NAT2 and SLCO1B1 genes on TB treatment outcomes using whole-exome sequencing (WES) analysis. Methods: DNA samples were collected from 30 healthy Iranian adults aged 18–40 years. The allelic frequencies of single-nucleotide polymorphisms (SNPs) in the NAT2 and SLCO1B1 genes were determined through WES. Results: Seven frequent SNPs were identified in the NAT2 gene (rs1041983, rs1801280, rs1799929, rs1799930, rs1208, rs1799931, rs2552), along with 16 frequent SNPs in the SLCO1B1 gene (rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs2291075, rs201722521, rs11045852, rs11045854, rs756393362, rs11045859, rs74064211, rs201556175, rs34671512, rs71581985, rs4149085). Conclusion: Genetic variations in NAT2 and SLCO1B1 can affect the metabolism of INH and RIF, respectively. A better understanding of the pharmacogenetic profile in the study population may facilitate the design of more personalized and effective TB treatment strategies. Further research is needed to directly correlate these genetic markers with clinical outcomes in TB patients.

Bictegravir, a key second-generation integrase strand transfer inhibitor in the treatment of HIV, is subject to active efflux transport mediated by ABCB1 (P-glycoprotein). Several coding variants of ABCB1 have been described and associated with variable effects on substrate drugs pharmacokinetics. Here, we investigated the effect of the four most common coding ABCB1 single nucleotide polymorphisms (i.e., c.1199G > A, c.1236C > T, c.2677G > T and c.3435C > T) on the intracellular accumulation of bictegravir. Using a previously validated HEK293 recombinant cell line model, we found decreased bictegravir intracellular concentrations in cell lines overexpressing ABCB1 as compared to control cell lines, in line with the known role of ABCB1 in bictegravir transport. However, we were unable to demonstrate any significant difference in bictegravir intracellular accumulation when comparing HEK293 cells overexpressing the wild type (1236C-2677G-3435C, 1199G) or the variant (1236C-2677G-3435T, 1236T-2677T-3435T or 1199A) proteins. These findings suggest that the ABCB1 c.1199G > A and c.1236C > T-c.2677G > T-c.3435C > T variants have no or at least limited impact on the active transport of bictegravir by ABCB1. [ABSTRACT FROM AUTHOR]

Analyze the relationship between genetic variations in the MTHFR gene at SNPs (rs1801131 and rs1801133) and the therapy outcomes for Iraqi patients with rheumatoid arthritis (RA). The study was conducted on a cohort of 95 RA Iraqi patients. Based on their treatment response, the cohort was divided into two groups: the responder (47 patients) and the nonresponder (48 patients), identified after at least three months of methotrexate (MTX) treatment. A polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) technique was employed to analyze the MTHFR variations, specifically at rs1801133 and rs1801131. Overall, rs1801131 followed both codominant and dominate models, in which in the codominant model, GG [OR (95% CI) 0.11 (0.022–0.553)] and TG [OR (95% CI) 0.106 (0.021–0.528)] predict responders compared to the TT genotype; meanwhile, for the dominate model, the presence of both GG and TG genotypes [OR (95% CI) 0.108 (0.023–0.507)] together predict responders compared to the TT genotype. The Ars1801133Grs1801131 haplotype was significantly associated with responders [OR (95% CI): 0.388 (0.208–0.723)], while the Grs1801133Trs1801131 haplotype was associated marginally with nonresponders [OR (95% CI) 1.980 (0.965–4.064)]. In the final multivariate analysis, GG/TGrs1801131 genotypes were independently related to responders after adjustment for patients, disease, and treatment characteristics, while TTrs1801131 genotypes were associated with nonresponders. The Iraqi RA patients showed genetic polymorphism in MTHFR gene rs1801131 with T carrier allele associated with nonresponders to MTX therapy. The rs1801131 followed both codominant and dominant models. The G-carried allele for rs1801131 showed an independent association with responder to MTX therapy after adjustment for patients, disease, and treatment characteristics. [ABSTRACT FROM AUTHOR]

Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients' response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = −2.21% ± 2.56; p = 0.026) and TH (CC = −2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis. [ABSTRACT FROM AUTHOR]

In Peru, 29 292 people were diagnosed with tuberculosis in 2022. Although tuberculosis treatments are effective, 3.4%–13% are associated with significant adverse drug reactions, with drug‐induced liver injury (DILI) considered the most predominant. Among the first‐line antituberculosis drugs, isoniazid is the main drug responsible for the appearance of DILI. In liver, isoniazid (INH) is metabolized by N‐acetyltransferase‐2 (NAT2) and cytochrome P450 2E1 (CYP2E1). Limited information exists on genetic risk factors associated with the presence of DILI to antituberculosis drugs in Latin America, and even less is known about these factors in the native and mestizo Peruvian population. The aim of this study was to determine the prevalence of NAT2 and CYP2E1 genotypes in native and mestizo population. An analytical cross‐sectional analysis was performed using genetic data from mestizo population in Lima and native participants from south of Peru. NAT2 metabolizer was determined as fast, intermediate and slow, and CYP2E1 genotypes were classified as c1/c1, c1/c2 and c2/c2, from molecular tests and bioinformatic analyses. Of the 472 participants, 36 and 6 NAT2 haplotypes were identified in the mestizo and native population, respectively. In mestizo population, the most frequent NAT2*5B and NAT2*7B haplotypes were associated with DILI risk; while in natives, NAT2*5G and NAT2*13A haplotypes were associated with decreased risk of DILI. For CYP2E1, c1/c1 and c1/c2 genotypes are the most frequent in natives and mestizos, respectively. The linkage disequilibrium of NAT2 single nucleotide polymorphisms (SNPs) was estimated, detecting a block between all SNPs natives. In addition, a block between rs1801280 and rs1799929 for NAT2 was detected in mestizos. Despite the limitations of a secondary study, it was possible to report associations between NAT2 and CYP2E alleles with Peruvian native and mestizo by prevalence ratios. The results of this study will help the development of new therapeutic strategies for a Tuberculosis efficient control between populations. [ABSTRACT FROM AUTHOR]

IntroductionThe Cuban population is genetically diverse, and information on the prevalence of genetic variants is still limited. As complex admixture processes have occurred, we hypothesized that the frequency of pharmacogenetic variants and drug responses may vary within the country. The aims of the study were to describe the frequency distribution of 43 single-nucleotide variants (SNVs) from 25 genes of pharmacogenetic interest within the Cuba population and in relation to other populations, while taking into consideration some descriptive variables such as place of birth and skin color.Materials and MethodsSNVs were analyzed in 357 unrelated healthy Cuban volunteers. Genotype, allele frequencies, and ancestry proportions were determined, and the pairwise fixation index (FST ) was evaluated.ResultsHardy–Weinberg equilibrium (HWE) deviations in six loci (rs11572103, rs2740574, rs776746, rs3025039, rs861539, and rs1762429) were identified. Minor allele frequencies (MAFs) ranged from 0.00 to 0.15 for variants in genes encoding xenobiotic metabolizing enzymes. They also ranged from 0.01 to 0.21 for variants in DNA repair, growth factors, methyltransferase, and methyl-binding proteins, while they ranged from 0.04 to 0.27 for variants in the O-6-methylguanine-DNA methyltransferase enzyme. Moderate genetic divergence was observed upon comparison to Africans (FST = 0.071 and SD 0.079), with 19 markers exhibiting moderate-to-large genetic differentiation. The average European, African, and Amerindian ancestry proportions were 67.8%, 27.2%, and 5.3%, respectively. Ancestry proportions differed by skin color and birthplace for both African and European components, with the exception of the European component, which showed no significant difference between individuals from Western and Eastern regions. Meanwhile, the statistical significance varied in comparisons by skin color and birthplace within the Amerindian component. Low genetic divergence was observed across geographical regions. We identified 12 variants showing moderate-to-large differentiation between White/Black individuals.ConclusionAltogether, our results may support national strategies for the introduction of pharmacogenetic tools in clinical practice, contributing to the development of precision medicine in Cuba.

Suspected adverse drug reactions (ADRs) during treatment with clozapine often prompt therapeutic drug monitoring (TDM) in clinical practice. Currently, there is no official recommendation for pharmacogenetic (PGx) testing in the context of clozapine therapy. In this case report, we demonstrate and discuss the challenges of interpreting PGx and TDM results highlighting the possibilities and limitations of both analytical methods. A 36-year-old male patient with catatonic schizophrenia was treated with clozapine. He experienced multiple hospitalizations due to elevated creatine kinase (CK) levels (up to 9000 U/L, reference range: 30-200 U/L). With no other medical explanation found, physicians suspected clozapine-induced ADRs. However, plasma levels of clozapine were consistently low or subtherapeutic upon admission, prompting us to conduct a PGx analysis and retrospectively review the patient's TDM data, progress notes, and discharge reports. We investigated two possible hypotheses to explain the symptoms despite low clozapine plasma levels: Hypothesis i. suggested the formation and accumulation of a reactive intermediate metabolite due to increased activity in cytochrome P450 3A5 and reduced activity in glutathione S-transferases 1, leading to myotoxicity. Hypothesis ii. proposed under-treatment with clozapine, resulting in ineffective clozapine levels, leading to a rebound effect with increased catatonic symptoms and CK levels. After considering both data sources (PGx and TDM), hypothesis ii. appeared more plausible. By comprehensively assessing all available TDM measurements and examining them in temporal correlation with the drug dose and clinical symptoms, we observed that CK levels normalized when clozapine plasma levels were raised to the therapeutic range. This was achieved through hospitalization and closely monitored clozapine intake. Therefore, we concluded that the symptoms were not an ADR due to altered clozapine metabolism but rather the result of under-treatment. Interpreting TDM and PGx results requires caution. Relying solely on isolated PGx or single TDM values can result in misinterpretation of drug reactions. We recommend considering the comprehensive patient history, including treatment, dosages, laboratory values, clinic visits, and medication adherence. [ABSTRACT FROM AUTHOR]

Background: The implementation of pharmacogenetic (PGx) testing may contribute to health disparities if access to testing is inequitable, as medically underserved patients are prescribed higher rates of drugs with PGx guidelines and often experience the benefits of emerging health technologies last. Limited research has evaluated potential implementation of PGx testing in populations who are medically underserved and none have evaluated their preferences regarding PGx test characteristics and cost. Our study endeavored to assess the willingness to pay for PGx testing and key PGx test preferences in a nationwide cohort of medically underserved respondents. Methods: A survey was developed to assess willingness to pay and preferences for PGx testing through a discrete choice experiment (DCE). Five attributes of PGx tests were included in the DCE: doctor recommendation, wait time, number of actionable results, benefit of the test (avoid a side effect or address a health problem), and out-of-pocket cost. A convenience sample of U.S. adults with an average yearly household income of $42,000 or less was collected utilizing an online survey fielded by Qualtrics Research Services (Provo, UT). For the DCE analysis, conditional logit and mixed-logit regression models were utilized to determine relative utility of attributes and levels, conditional relative importance for each attribute, and marginal willingness to pay. Results: Respondents completed the survey with an 83.1% response completion rate. Following quality control procedures, 1,060 respondents were included in the final nationwide cohort. Approximately, 82% of respondents were willing to pay less than $100 for PGx testing, and a strong price ceiling was identified at $200. Out-of-pocket cost was the attribute identified as having the greatest relative importance on choice, while wait time had the lowest importance. Greater utility was observed if the PGx test was doctor recommended, had a higher number of actionable results, and resolved major or minor health problems compared with avoiding side effects. Conclusion: This first-of-its-kind study provides important insights into the willingness to pay for PGx testing and PGx test preferences of a large medically underserved population. Applying these findings can potentially lead to improvements in the successful implementation of PGx testing in this population. [ABSTRACT FROM AUTHOR]

Background: Pharmacogenomic knowledge as a biomarker for cancer care has transformed clinical practice, however, as current guidelines are primarily derived from Eurocentric populations, this limits their application in Latin America, particularly among Hispanic or Latino groups. Despite advancements, systemic chemotherapy still poses challenges in drug toxicity and suboptimal response. This study explores pharmacogenetic markers related to anticancer drugs in a Chilean cohort, filling a gap in Latin American research. Notably, the influence of native South American Mapuche-Huilliche ancestry. Methods: To explore pharmacogenetic markers related to anticancer drugs, we utilized an ethnically Admixed Chilean genome-wide association studies (GWAS) dataset of 1095 unrelated individuals. Pharmacogenomic markers were selected from PharmGKB, totaling 36 level 1 and 2 evidence single nucleotide polymorphisms (SNPs) and 571 level 3 SNPs. Comparative analyses involved assessing SNP frequencies across diverse populations from the 1000 Genomes Project. Haplotypes were estimated, and linkage disequilibrium was examined. Ancestry-based association analyses explored relationships between SNPs and Mapuche-Huilliche and European ancestries. Chi-square distribution with p ≤ 0.05 and Bonferroni's multiple adjustment tests determined statistical differences between allele frequencies. Results: Our study reveals significant disparities in SNP frequency within the Chilean population. Notably, dihydropyrimidine dehydrogenase (DPYD) variants (rs75017182 and rs67376798), linked to an increased risk of severe fluoropyrimidine toxicity, exhibit an exceptionally low frequency (minor allele frequency (MAF) < 0.005). Nudix hydrolase 15 (NUDT15) rs116855232, associated with hematological mercaptopurine toxicity, is relatively common (MAF = 0.062), and is further linked to Mapuche-Huilliche ancestry. Thiopurine methyltransferase enzyme (TPMT), implicated in severe toxicity to mercaptopurines, SNPs rs1142345 and rs1800460 of TMPT gene demonstrate higher MAFs in Admixed Americans and the Chilean population (MAF range 0.031–0.057). Finally, the variant in the UDP-glucuronosyltransferase 1 gene (UGT1A1) rs4148323, correlated with irinotecan neutropenia, exhibits the highest MAF in East Asian (MAF = 0.136) and Chilean (MAF = 0.025) populations, distinguishing them from other investigated populations. Conclusions: This study provides the first comprehensive pharmacogenetic characterization of cancer therapy-related SNPs and highlights significant disparities in SNP frequencies within the Chilean population. Our findings underscore the necessity for inclusive research and personalized therapeutic strategies to ensure the equitable and effective application of precision medicine across diverse global communities. [ABSTRACT FROM AUTHOR]

Arterial hypertension is characterized by systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg and its treatment consists of the use of antihypertensive drugs, as losartan and hydrochlorothiazide. Blood pressure is regulated by angiotensin-converting enzyme (ACE) and polymorphisms in the ACE gene are associated to a greater predisposition to hypertension and response to treatment. The aim of this study was to evaluate the association of genetic polymorphisms of ACE rs4363, rs4291 and rs4335 and the response to antihypertensive drugs in hypertensive patients from Ouro Preto/MG, Brazil. A case-control study was carried out with 87 hypertensive patients being treated with losartan and 75 with hydrochlorothiazide, who answered a questionnaire and had blood samples collected. Biochemical analyzes were performed on serum using UV/Vis spectrophotometry and identification of ACE variants rs4363, rs4291 and rs4335 was performed by real-time PCR using the TaqMan® system. Univariate logistic regression test was performed to compare categorical data in STATA 13.0 software. The results showed that there was an influence of ACE polymorphisms on the response to losartan, demonstrating that AT or TT genotypes of rs4291 were more frequent in the group of controlled AH (54.9%), indicating that these individuals are 2.8 times more likely to of being controlled AH (95% CI 1.12–6.80, p. =0.026) compared to those with AA genotype. In contrast, no influence of ACE polymorphisms on the response to hydrochlorothiazide was observed. In conclusion, the presence of the T allele of the rs4291 variant was associated to controled blood pressure when losartan was used as an antihypertensive agent. These results show the importance of pharmacogenetic studies to detect genetic characteristics, enabling therapeutic individuality and reducing costs for the healthcare system. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab. Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models. Results and discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p<0.01) higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD. [ABSTRACT FROM AUTHOR]

Abstract In Peru, 29 292 people were diagnosed with tuberculosis in 2022. Although tuberculosis treatments are effective, 3.4%–13% are associated with significant adverse drug reactions, with drug‐induced liver injury (DILI) considered the most predominant. Among the first‐line antituberculosis drugs, isoniazid is the main drug responsible for the appearance of DILI. In liver, isoniazid (INH) is metabolized by N‐acetyltransferase‐2 (NAT2) and cytochrome P450 2E1 (CYP2E1). Limited information exists on genetic risk factors associated with the presence of DILI to antituberculosis drugs in Latin America, and even less is known about these factors in the native and mestizo Peruvian population. The aim of this study was to determine the prevalence of NAT2 and CYP2E1 genotypes in native and mestizo population. An analytical cross‐sectional analysis was performed using genetic data from mestizo population in Lima and native participants from south of Peru. NAT2 metabolizer was determined as fast, intermediate and slow, and CYP2E1 genotypes were classified as c1/c1, c1/c2 and c2/c2, from molecular tests and bioinformatic analyses. Of the 472 participants, 36 and 6 NAT2 haplotypes were identified in the mestizo and native population, respectively. In mestizo population, the most frequent NAT2*5B and NAT2*7B haplotypes were associated with DILI risk; while in natives, NAT2*5G and NAT2*13A haplotypes were associated with decreased risk of DILI. For CYP2E1, c1/c1 and c1/c2 genotypes are the most frequent in natives and mestizos, respectively. The linkage disequilibrium of NAT2 single nucleotide polymorphisms (SNPs) was estimated, detecting a block between all SNPs natives. In addition, a block between rs1801280 and rs1799929 for NAT2 was detected in mestizos. Despite the limitations of a secondary study, it was possible to report associations between NAT2 and CYP2E alleles with Peruvian native and mestizo by prevalence ratios. The results of this study will help the development of new therapeutic strategies for a Tuberculosis efficient control between populations.

Abstract Here we describe a new public pharmacogenetic (PGx) annotation database of a large (n = 3,202) and diverse biospecimen collection of 1000 Genomes Project cell lines and DNAs. The database is searchable with a user friendly, web-based tool ( www.coriell.org/StarAllele/Search ). This resource leverages existing whole genome sequencing data and PharmVar annotations to characterize *alleles for each biospecimen in the collection. This new tool is designed to facilitate in vitro functional characterization of *allele haplotypes and diplotypes as well as support clinical PGx assay development, validation, and implementation.

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab. Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models. Results and discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.2, 95%CI: 1.7-2.8; p<0.11) higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD. [ABSTRACT FROM AUTHOR]

Here we describe a new public pharmacogenetic (PGx) annotation database of a large (n = 3,202) and diverse biospecimen collection of 1000 Genomes Project cell lines and DNAs. The database is searchable with a user friendly, web-based tool (www.coriell.org/StarAllele/Search). This resource leverages existing whole genome sequencing data and PharmVar annotations to characterize *alleles for each biospecimen in the collection. This new tool is designed to facilitate in vitro functional characterization of *allele haplotypes and diplotypes as well as support clinical PGx assay development, validation, and implementation. [ABSTRACT FROM AUTHOR]

Suspected adverse drug reactions (ADRs) during treatment with clozapine often prompt therapeutic drug monitoring (TDM) in clinical practice. Currently, there is no official recommendation for pharmacogenetic (PGx) testing in the context of clozapine therapy. In this case report, we demonstrate and discuss the challenges of interpreting PGx and TDM results highlighting the possibilities and limitations of both analytical methods. A 36-year-old male patient with catatonic schizophrenia was treated with clozapine. He experienced multiple hospitalizations due to elevated creatine kinase (CK) levels (up to 9000 U/L, reference range: 30-200 U/L). With no other medical explanation found, physicians suspected clozapine-induced ADRs. However, plasma levels of clozapine were consistently low or subtherapeutic upon admission, prompting us to conduct a PGx analysis and retrospectively review the patient’s TDM data, progress notes, and discharge reports. We investigated two possible hypotheses to explain the symptoms despite low clozapine plasma levels: Hypothesis i. suggested the formation and accumulation of a reactive intermediate metabolite due to increased activity in cytochrome P450 3A5 and reduced activity in glutathione S-transferases 1, leading to myotoxicity. Hypothesis ii. proposed under-treatment with clozapine, resulting in ineffective clozapine levels, leading to a rebound effect with increased catatonic symptoms and CK levels. After considering both data sources (PGx and TDM), hypothesis ii. appeared more plausible. By comprehensively assessing all available TDM measurements and examining them in temporal correlation with the drug dose and clinical symptoms, we observed that CK levels normalized when clozapine plasma levels were raised to the therapeutic range. This was achieved through hospitalization and closely monitored clozapine intake. Therefore, we concluded that the symptoms were not an ADR due to altered clozapine metabolism but rather the result of under-treatment. Interpreting TDM and PGx results requires caution. Relying solely on isolated PGx or single TDM values can result in misinterpretation of drug reactions. We recommend considering the comprehensive patient history, including treatment, dosages, laboratory values, clinic visits, and medication adherence.

Background: Single nucleotide polymorphisms in the gene encoding proteins involved in mercaptopurine metabolism can influence drug efficacy and safety. This study aims to assess clinical pharmacists’ knowledge about mercaptopurine-related genes and their polymorphisms and investigate their attitudes, perceptions, and beliefs about the need for and importance of pharmacogenetic testing for mercaptopurine. Methods: A cross-sectional descriptive study was conducted among oncology/hematology clinical pharmacists in Saudi Arabia using an online-questionnaire developed by experts in the field. The questionnaire consists of four-sections exploring clinical pharmacists’ knowledge, attitudes, perceptions, and beliefs about the importance of gene testing and genes polymorphism when prescribing mercaptopurine. Descriptive statistics were used to analyze the data in the study. Results: A total of 41 oncology/hematology clinical pharmacists responded to the survey invitation. Almost half of them had more than 10 years of work experience, but only 17 % of them received formal training in pharmacogenetics. The overall level of knowledge about pharmacogenetics among participants was low, with a mean score of 2.8 points (1.7) out of 8 items. However, around 76 % agreed that it is important to perform pharmacogenetic screening prior to prescribing mercaptopurine, and almost 93 % state that it will influence their dosage recommendation. Most of the participants had a good perception (95.1 %) of their role in genetic testing for medication selection, dosing, and monitoring; however, about 10 % of surveyed pharmacists reported not being completely responsible about recommending pharmacogenetic testing. The surveyed pharmacists had a good belief in the importance of pharmacogenetic testing and their overall attitude was positive toward the use of pharmacogenetic testing, with emphasis on the importance of training on the proper assessment and interpretation of pharmacogenetic tests. Conclusions: Pharmacists demonstrated good perception and positive attitude toward pharmacogenetic testing, despite the low level of knowledge and limited formal training. Thus, more attention to developing national guidelines on pharmacogenetic testing is warranted to ensure successful pharmacogenetic testing implementation.

Background: The implementation of pharmacogenetic (PGx) testing may contribute to health disparities if access to testing is inequitable, as medically underserved patients are prescribed higher rates of drugs with PGx guidelines and often experience the benefits of emerging health technologies last. Limited research has evaluated potential implementation of PGx testing in populations who are medically underserved and none have evaluated their preferences regarding PGx test characteristics and cost. Our study endeavored to assess the willingness to pay for PGx testing and key PGx test preferences in a nationwide cohort of medically underserved respondents.Methods: A survey was developed to assess willingness to pay and preferences for PGx testing through a discrete choice experiment (DCE). Five attributes of PGx tests were included in the DCE: doctor recommendation, wait time, number of actionable results, benefit of the test (avoid a side effect or address a health problem), and out-of-pocket cost. A convenience sample of U.S. adults with an average yearly household income of $42,000 or less was collected utilizing an online survey fielded by Qualtrics Research Services (Provo, UT). For the DCE analysis, conditional logit and mixed-logit regression models were utilized to determine relative utility of attributes and levels, conditional relative importance for each attribute, and marginal willingness to pay.Results: Respondents completed the survey with an 83.1% response completion rate. Following quality control procedures, 1,060 respondents were included in the final nationwide cohort. Approximately, 82% of respondents were willing to pay less than $100 for PGx testing, and a strong price ceiling was identified at $200. Out-of-pocket cost was the attribute identified as having the greatest relative importance on choice, while wait time had the lowest importance. Greater utility was observed if the PGx test was doctor recommended, had a higher number of actionable results, and resolved major or minor health problems compared with avoiding side effects.Conclusion: This first-of-its-kind study provides important insights into the willingness to pay for PGx testing and PGx test preferences of a large medically underserved population. Applying these findings can potentially lead to improvements in the successful implementation of PGx testing in this population.

Long-read sequencing technologies offer new opportunities to generate high-confidence phased whole-genome sequencing data for robust pharmacogenetic annotation. Here, we describe a new user-friendly R package, ursaPGx, designed to accept multi-sample phased whole-genome sequencing data VCF input files and output star allele annotations for pharmacogenes annotated in PharmVar.

IntroductionWe evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab.MethodsBaseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p

Core clinical pharmacology principles must be considered when designing and executing neonatal clinical trials. In this review, the authors discuss important aspects of drug dose selection, pharmacokinetics, pharmacogenetics and pharmacodynamics that stakeholders may consider when undertaking a neonatal or infant clinical trial.

Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients’ response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = −2.21% ± 2.56; p = 0.026) and TH (CC = −2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis.

Background: Pharmacogenomic knowledge as a biomarker for cancer care has transformed clinical practice, however, as current guidelines are primarily derived from Eurocentric populations, this limits their application in Latin America, particularly among Hispanic or Latino groups. Despite advancements, systemic chemotherapy still poses challenges in drug toxicity and suboptimal response. This study explores pharmacogenetic markers related to anticancer drugs in a Chilean cohort, filling a gap in Latin American research. Notably, the influence of native South American Mapuche-Huilliche ancestry. Methods: To explore pharmacogenetic markers related to anticancer drugs, we utilized an ethnically Admixed Chilean genome-wide association studies (GWAS) dataset of 1095 unrelated individuals. Pharmacogenomic markers were selected from PharmGKB, totaling 36 level 1 and 2 evidence single nucleotide polymorphisms (SNPs) and 571 level 3 SNPs. Comparative analyses involved assessing SNP frequencies across diverse populations from the 1000 Genomes Project. Haplotypes were estimated, and linkage disequilibrium was examined. Ancestry-based association analyses explored relationships between SNPs and Mapuche-Huilliche and European ancestries. Chi-square distribution with p ≤ 0.05 and Bonferroni’s multiple adjustment tests determined statistical differences between allele frequencies. Results: Our study reveals significant disparities in SNP frequency within the Chilean population. Notably, dihydropyrimidine dehydrogenase (DPYD) variants (rs75017182 and rs67376798), linked to an increased risk of severe fluoropyrimidine toxicity, exhibit an exceptionally low frequency (minor allele frequency (MAF) < 0.005). Nudix hydrolase 15 (NUDT15) rs116855232, associated with hematological mercaptopurine toxicity, is relatively common (MAF = 0.062), and is further linked to Mapuche-Huilliche ancestry. Thiopurine methyltransferase enzyme (TPMT), implicated in severe toxicity to mercaptopurines, SNPs rs1142345 and rs1800460 of TMPT gene demonstrate higher MAFs in Admixed Americans and the Chilean population (MAF range 0.031–0.057). Finally, the variant in the UDP-glucuronosyltransferase 1 gene (UGT1A1) rs4148323, correlated with irinotecan neutropenia, exhibits the highest MAF in East Asian (MAF = 0.136) and Chilean (MAF = 0.025) populations, distinguishing them from other investigated populations. Conclusions: This study provides the first comprehensive pharmacogenetic characterization of cancer therapy-related SNPs and highlights significant disparities in SNP frequencies within the Chilean population. Our findings underscore the necessity for inclusive research and personalized therapeutic strategies to ensure the equitable and effective application of precision medicine across diverse global communities.

Introduction and Objectives: Despite tacrolimus (TAC) or mycophenolate mofetil (MMF) for alternate approaches, a proportion of patients still required further exploration of other therapeutic options due to uncontrolled autoimmune hepatitis(AIH). The role of cyclophosphamide (CYC) for AIH has been explored in isolated case reports and small series. We present a review of CYC therapy in AIH patients., Materials and Methods: A search for studies with keywords 'autoimmune hepatitis' and 'cyclophosphamide' was performed. Data recorded included gender, age, laboratory parameters and histological findings at the time of AIH diagnosis and before initiation of CYC therapy., Results: We identified 13 patients across 7 studies who met criteria for study inclusion, of whom around 69.2% (9/13) were primary refractory; 30.8% (4/13) patients used CYC as rescue therapy due to their coexisting autoimmune complications. The main findings of the study were that CYC appears to have an acceptable safety profile in difficult-to-treat AIH patients, with an overall remission rate of 88.9% (8/9). The other four patients with AIH accompanied by extrahepatic autoimmune disorders also achieved remission of transaminase levels and stability of liver function after the addition of CYC. A positive response to CYC treatment was seen in 12(92.3%) patients and none of them relapsed during the follow-up., Conclusions: We cautiously recommend that CYC could be a conditioning alternative to starting second-line therapy after unsuccessful intensification of first-line treatment. Pharmacogenetic methods may play a role in guiding cyclophosphamide therapy. Given our small sample size, results should be considered preliminary., Competing Interests: Declaration of competing interest Disclosure statement: The authors have declared no conflicts of interest., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Cytochrome P450 3A4 (CYP3A4) enzyme is involved in the metabolism of about 30 % of clinically used drugs, including the antimalarials artemether and lumefantrine. CYP3A4 polymorphisms yield enzymatic variants that contribute to inter-individual variation in drug metabolism. Here, we examined CYP3A4 polymorphisms in populations from malaria-endemic islands in Lake Victoria, Kenya, and Vanuatu, to expand on the limited data sets. We used archived dried blood spots collected from 142 Kenyan and 263 ni-Vanuatu adults during cross-sectional malaria surveys in 2013 and 2005-13, respectively, to detect CYP3A4 variation by polymerase chain reaction (PCR) and sequencing. In Kenya, we identified 14 CYP3A4 single nucleotide polymorphisms (SNPs), including the 4713G (CYP3A4∗1B; allele frequency 83.9 %) and 19382A (CYP3A4∗15; 0.7 %) variants that were previously linked to altered metabolism of antimalarials. In Vanuatu, we detected 15 SNPs, including the 4713A (CYP3A4∗1A; 88.6 %) and 25183C (CYP3A4∗18; 0.6 %) variants. Additionally, we detected a rare and novel SNP C4614T (0.8 %) in the 5' untranslated region. A higher proportion of CYP3A4 genetic variance was found among ni-Vanuatu populations (16 %) than among Lake Victoria Kenyan populations (8 %). Our work augments the scarce data sets and contributes to improved precision medicine approaches, particularly to anti-malarial chemotherapy, in East African and Pacific Islander populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

The administration of aminoglycosides can induce nephrotoxicity or ototoxicity, which can be monitored through pharmacological therapeutic drug monitoring. However, there are cases of genetic predisposition to ototoxicity related to the MT-RNR1 gene, which may occur from the first administrations. Pharmacogenetic analysis recommendations have recently been proposed by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The Francophone Pharmacogenetics Network (RNPGx) provides a bibliographic synthesis of this genetic predisposition, as well as professional recommendations. The MT-RNR1 gene codes for mitochondrial 12S rRNA, which constitutes the small subunit of the mitochondrial ribosome. Three variants can be identified: the variants m.1555A>G and m.1494C>T of the MT-RNR1 gene have a 'high' level of evidence regarding the risk of ototoxicity. The variant m.1095T>C has a 'moderate' level of evidence. The search for these variants can be performed in the laboratory if the administration of aminoglycosides can be delayed after obtaining the result. However, if the treatment is urgent, there is currently no rapid test available in France (a 'point-of-care' test is authorized in Great Britain). RNPGx considers: (1) the search for the m.1555A>G, m.1494C>T variants as 'highly recommended' and the m.1095T>C variant as 'moderately recommended' before the administration of an aminoglycoside (if compatible with the medical context). It should be noted that the level of heteroplasmy detected does not modify the recommendation; (2) pharmacogenetic analysis is currently not feasible in situations of short-term aminoglycoside administration, in the absence of an available analytical solution (rapid test to be evaluated in France); (3) the retrospective analysis in case of aminoglycoside-induced ototoxicity is 'recommended'; (4) analysis of relatives is 'recommended'. Through this summary, RNPGx proposes an updated review of the MT-RNR1-aminoglycoside gene-drug pair to serve as a basis for adapting practices regarding pharmacogenetic analysis related to aminoglycoside treatment., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Single nucleotide polymorphisms in the gene encoding proteins involved in mercaptopurine metabolism can influence drug efficacy and safety. This study aims to assess clinical pharmacists' knowledge about mercaptopurine-related genes and their polymorphisms and investigate their attitudes, perceptions, and beliefs about the need for and importance of pharmacogenetic testing for mercaptopurine. A cross-sectional descriptive study was conducted among oncology/hematology clinical pharmacists in Saudi Arabia using an online-questionnaire developed by experts in the field. The questionnaire consists of four-sections exploring clinical pharmacists' knowledge, attitudes, perceptions, and beliefs about the importance of gene testing and genes polymorphism when prescribing mercaptopurine. Descriptive statistics were used to analyze the data in the study. A total of 41 oncology/hematology clinical pharmacists responded to the survey invitation. Almost half of them had more than 10 years of work experience, but only 17 % of them received formal training in pharmacogenetics. The overall level of knowledge about pharmacogenetics among participants was low, with a mean score of 2.8 points (1.7) out of 8 items. However, around 76 % agreed that it is important to perform pharmacogenetic screening prior to prescribing mercaptopurine, and almost 93 % state that it will influence their dosage recommendation. Most of the participants had a good perception (95.1 %) of their role in genetic testing for medication selection, dosing, and monitoring; however, about 10 % of surveyed pharmacists reported not being completely responsible about recommending pharmacogenetic testing. The surveyed pharmacists had a good belief in the importance of pharmacogenetic testing and their overall attitude was positive toward the use of pharmacogenetic testing, with emphasis on the importance of training on the proper assessment and interpretation of pharmacogenetic tests. Pharmacists demonstrated good perception and positive attitude toward pharmacogenetic testing, despite the low level of knowledge and limited formal training. Thus, more attention to developing national guidelines on pharmacogenetic testing is warranted to ensure successful pharmacogenetic testing implementation. [ABSTRACT FROM AUTHOR]

Long-read sequencing technologies offer new opportunities to generate high-confidence phased whole-genome sequencing data for robust pharmacogenetic annotation. Here, we describe a new user-friendly R package, ursaPGx, designed to accept multi-sample phased whole-genome sequencing data VCF input files and output star allele annotations for pharmacogenes annotated in PharmVar., Competing Interests: Author NG is employed by Gharani Consulting Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Calendo, Kusic, Madzo, Gharani and Scheinfeldt.)

Core clinical pharmacology principles must be considered when designing and executing neonatal clinical trials. In this review, the authors discuss important aspects of drug dose selection, pharmacokinetics, pharmacogenetics and pharmacodynamics that stakeholders may consider when undertaking a neonatal or infant clinical trial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Yeung, Verstegen, Greenberg and Lewis.)