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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]

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]

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.

AbstractThis 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]

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]

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]

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.

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]

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]

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.

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—Various antidepressant agents are metabolized by the CYP2C19 enzyme, including Citalopram and Escitalopram. Variation in CYP2C19 expression might give rise to different plasma concentrations of the active metabolites, potentially affecting both drugs' efficacy and tolerability. Aim—The aim of this study was to evaluate differences in the Escitalopram and Citalopram efficacy and tolerability between different CYP2C19 genotype-based metabolizing categories in outpatients suffering from major depressive disorder (MDD). Methods—In a retrospective, longitudinal cohort study of electronic medical-record data, 283 patients with MDD who were prescribed Escitalopram or Citalopram with the available CYP2C19-genotyping test were enrolled. The primary efficacy end point was adverse drug reactions recorded in the medical files. A proportional-odds, multilevel-regression model for longitudinal ordinal data was used to estimate the relation between the CYP2C19 genotype and adverse drug reactions, adjusting for potential confounding variables and other explanatory variables. Latent-class analysis (LCA) was utilized to detect the presence of clinically significant subgroups and their relation to an individual's metabolizing status for CYP2D6/CYP2C19. Results—With poor CYP2C19 metabolizers as a reference, for each unit difference in the activity score of the CYP2C19 phenotype, the odds ratio for drug intolerability was lowered by 0.73 (95% credible intervals: 0.56–0.89), adjusting for significant covariates. In addition, applying LCA, we identified two qualitatively different subgroups: the first group (61.85%) exhibited multiple side effects, low compliance, and frequent treatment changes, whereas the second group (38.15%) demonstrated fewer side effects, good adherence, and fewer treatment changes. The CYP2C19 phenotype was substantially associated with the group membership. Conclusions—We found a positive association between the CYP2C19 activity scores, as inferred from the genotype, and both the efficacy of and tolerability to both Es/Citalopram. LCA enabled valuable insights into the underlying structure of the population; the CYP2C19 phenotype has a predictive value that discriminates between low-adherence, low-drug-tolerance, and low-response patients and high-adherence, high-drug-tolerance, and high-response patients. Personalized medicine based on CYP2C19 genotyping could evolve as a promising new avenue towards mitigating Escitalopram and Citalopram therapy and the associated side effects and enhancing treatment success. [ABSTRACT FROM AUTHOR]

Pharmacological therapy represents one of the essential approaches to treatment of Major Depressive Disorder (MDD). However, currently available antidepressant medications show high rates of first-level treatment non-response, and several attempts are often required to find an effective molecule for a specific patient in clinical practice. In this context, pharmacogenetic analyses could represent a valuable tool to identify appropriate pharmacological treatment quickly and more effectively. However, the usefulness and the practical effectiveness of pharmacogenetic testing currently remains an object of scientific debate. The present narrative and critical review focuses on exploring the available evidence supporting the usefulness of pharmacogenetic testing for the treatment of MDD in clinical practice, highlighting both the points of strength and the limitations of the available studies and of currently used tests. Future research directions and suggestions to improve the quality of available evidence, as well as consideration on the potential use of pharmacogenetic tests in everyday clinical practice are also presented. [ABSTRACT FROM AUTHOR]

Background: Genetic testing may provide information for diagnostic, prognostic and pharmacogenetic purposes. The PREPARE study recently showed that the number of clinically relevant adverse drug reactions could be reduced via genotype-guided treatment. The aim of this work was to assess the relevance of genetic testing and its actual use in consecutive rheumatic outpatients. Methods: A retrospective cross-sectional analysis was performed with data from a prospectively designed observational project with outpatients consecutively recruited from a university clinic of rheumatology. Results: In this cohort of 2490 patients, the potential need for genetic testing is immense, with 57.3% of patients having the potential to benefit from genetic testing according to their diagnosis and treatment and 53.3% of patients with actually performed genetic testing for diagnostic, prognostic or pharmacogenetic purposes. In detail, patients would potentially benefit from genetic testing especially for therapeutic (28.0%) and diagnostic (26.9%) purposes. Genetic testing was performed for diagnostic purposes in 51.6% of subjects, for pharmacogenetic purposes in 3.7% and for prognostic purposes in 0.1%. The ratio between the number of patients who had had tests performed to those with a potential need for genetic testing decreased with age, from 127.1% for 20 to <30-year-old patients to 46.1% for 80 to <90-year-old patients. Pharmacogenetic testing was only performed for disease-related medications. Conclusions: Genetic testing is frequently needed in patients with rheumatic diseases. The value of pharmacogenetic testing is certainly underestimated, especially in case of medications for comorbidities. [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.

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.

Betablockers (BBs) are prescribed for ischaemia in patients with acute coronary syndrome (ACS). In Spain, bisoprolol and carvedilol are the most prescribed BBs, but patients often had to discontinue them due to adverse effects. Single nucleotide polymorphisms (SNPs) in ADRB1, ADRB2 and CYP2D6 genes have strong evidence of pharmacogenetic association with BBs in heart failure or hypertension, but the evidence in ACS is limited. Therefore, our study focuses on investigating how these genes influence the response to BBs in ACS patients. We analysed the association between SNPs in ADRB1 Gly389Arg (rs1801253) and Ser49Gly (rs1801252), ADRB2 Gly16Arg (rs1042713) and Glu27Gln (rs1042714), and CYP2D* 6 (*2– rs1080985, *4- rs3892097, *10 – rs1065852) and the occurrence of bradycardia/hypotension events during one year of follow-up. We performed an observational study and included 285 ACS-PCI-stent patients. A first analysis including patients treated with bisoprolol and a second analysis including patients treated with other BBs were performed. We found that the presence of the G allele (Glu) of the ADRB2 gene (rs1042714; Glu27Gln) conferred a protective effect against hypotension-induced by BBs; OR (CI 95%) = 0,14 (0,03−0,60), p

Pharmacological therapy represents one of the essential approaches to treatment of Major Depressive Disorder (MDD). However, currently available antidepressant medications show high rates of first-level treatment non-response, and several attempts are often required to find an effective molecule for a specific patient in clinical practice. In this context, pharmacogenetic analyses could represent a valuable tool to identify appropriate pharmacological treatment quickly and more effectively. However, the usefulness and the practical effectiveness of pharmacogenetic testing currently remains an object of scientific debate. The present narrative and critical review focuses on exploring the available evidence supporting the usefulness of pharmacogenetic testing for the treatment of MDD in clinical practice, highlighting both the points of strength and the limitations of the available studies and of currently used tests. Future research directions and suggestions to improve the quality of available evidence, as well as consideration on the potential use of pharmacogenetic tests in everyday clinical practice are also presented.

Schizophrenia spectrum disorders (SSD) are complex mental disorders, and while treatment with antipsychotics is important, many patients do not respond or develop serious side effects. Genetic variation has been shown to play a considerable role in determining an individual's response to antipsychotic medication. However, previous pharmacogenetic (PGx) studies have been limited by small sample sizes, lack of consensus regarding relevant genetic variants, and cross-sectional designs. The current study aimed to investigate the association between PGx variants and long-term clinical outcomes in 691 patients of European ancestry with SSD. Using evidence from the literature on candidate genes involved in antipsychotic pharmacodynamics, we created a polygenic risk score (PRS) to investigate its association with clinical outcomes. We also created PRS using core variants of psychotropic drug metabolism enzymes CYP2D6 and CYP2C19. Furthermore, the CYP2D6 and CYP2C19 functional activity scores were calculated to determine the relationship between metabolism and clinical outcomes. We found no association for PGx PRSs and clinical outcomes; however, an association was found with CYP2D6 activity scores by the traditional method. Higher CYP2D6 metabolism was associated with high positive and high cognitive impairment groups relative to low symptom severity groups. These findings highlight the need to test PGx efficacy with different symptom domains. More evidence is needed before pharmacogenetic variation can contribute to personalized treatment plans. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most common chronic neurodisorders in the pediatric age group. Despite the availability of over 20 anti-seizure medications (ASMs) on the market, drug-resistant epilepsy still affects one-third of individuals. Consequently, this research aimed to investigate the association between single-nucleotide polymorphisms (SNPs) of the ATP-binding cassette subfamily B member 1 (ABCB1) gene in epileptic pediatric patients and their response to ASMs. This multicentric, cross-sectional study was conducted among Saudi children with epilepsy in Jeddah, Saudi Arabia. The polymorphism variants of ABCB1 rs1128503 at exon 12, rs2032582 at exon 21, and rs1045642 at exon 26 were genotyped using the Sanger sequencing technique. The study included 85 children with epilepsy: 43 patients demonstrated a good response to ASMs, while 42 patients exhibited a poor response. The results revealed that good responders were significantly more likely to have the TT genotypes at rs1045642 and rs2032582 SNPs compared to poor responders. Additionally, haplotype analysis showed that the T-G-C haplotype at rs1128503, rs2032582, and rs1045642 was only present in poor responders. In conclusion, this study represents the first pharmacogenetic investigation of the ABCB1 gene in Saudi epileptic pediatric patients and demonstrates a significant association between rs1045642 and rs2032582 variants and patient responsiveness. Despite the small sample size, the results underscore the importance of personalized treatment for epileptic patients. [ABSTRACT FROM AUTHOR]

Tacrolimus is a calcineurin inhibitor with a narrow therapeutic range and is metabolized by cytochrome P450 (CYP) isoenzymes CYP3A4 and CYP3A5. The Clinical Pharmacogenetic Implementation Consortium published evidence‐based guidelines for CYP3A5 normal/intermediate metabolizers prescribed tacrolimus, yet few transplant centers have implemented routine testing. The objective of this study was to implement preemptive CYP3A genotyping into clinical practice in a large kidney transplant program and to evaluate workflow feasibility, potential clinical benefit, and reimbursement to identify barriers and determine sustainability. Preemptive pharmacogenetic testing for CYP3A5 and CYP3A4 was implemented in all patients listed for a kidney transplant as part of standard clinical care. Genotyping was performed at the listing appointment, results were reported as discrete data in the electronic medical record, and education and clinical decision support alerts were developed to provide pharmacogenetic‐recommended tacrolimus dosing. During this initial phase, all patients were administered standard tacrolimus dosing, and clinical and reimbursement outcomes were collected. Greater than 99.5% of genotyping claims were reimbursed by third‐party payers. CYP3A5 normal/intermediate metabolizers had significantly fewer tacrolimus trough concentrations within the target range and a significantly longer time to their first therapeutic trough compared to poor metabolizers. The challenge of tacrolimus dosing is magnified in the African American population. The US Food and Drug Administration drug label recommends increased starting doses in African ancestry, yet only ≈66% of African Americans in our cohort were normal/intermediate metabolizers who required higher doses. Routine CYP3A5 genotyping may overcome this issue by using genotype over race as a more accurate predictor of drug response. [ABSTRACT FROM AUTHOR]

The molecular mechanisms of susceptibility to malignant hyperthermia are complex. The malignant hyperthermia susceptibility phenotype should be reserved for patients who have a personal or family history consistent with malignant hyperthermia under anaesthesia and are subsequently demonstrated through diagnostic testing to be at risk. [ABSTRACT FROM AUTHOR]

Abstract Inflammatory bowel disease (IBD) involves a variety of conditions, particularly Crohn’s disease (CD) and ulcerative colitis (UC). IBD is characterized by chronic inflammatory process of patient’s gut. This review aims to summarize the pharmacogenetics of biologics approved for IBD and the correlation with azathioprine-metabolizing enzymes and adverse reactions, therefore highlighting a likely relationship between particular polymorphisms and therapeutic response. Therefore, we reviewed and discussed the activities of TDM protocols which use monoclonal antibodies (mABs) with a particular attention on the integration of other actions aimed to exploit the most effective and safest medications for IBD cases. The pharmacotherapy of IBD (CD and UC) has experienced a great advancement with the advent of mABs which have peculiar pharmacokinetic properties differentiating them from chemical agents, like aminosalicylates, antimetabolites (e.g., azathioprine (AZA), 6-mercaptopurine (6MP)), and methotrexate), and immunosuppressant agents (steroids and cyclosporine). But clinical studies showed that biologicals might have pharmacokinetic variability which can affect the anticipated clinical outcomes, beyond primary resistance phenomena. Thus, therapeutic drug monitoring (TDM) protocols are applied to the doses of medications according to the required serum mABs levels. This aims to maximize the favorable effects of mABs and minimizing the toxicity. But, the presence of particular genetic polymorphisms in patients might determine a different outcome in response to treatment, indicating the heterogeneity of the effectiveness among IBD cases. Indeed, many reports demonstrated significant associations between polymorphisms and response to biologics. In conclusion, the improvement of TNF-, TNFR and IL-1 pharmacogenetics could be the best approach toward a targeted treatment for IBD. Pre-therapy genotyping has to be integrated with IBD therapeutic guidelines, as it is the most suitable approach to choose the most appropriate biologicals for each case. Also, the addition of pharmacodynamic markers (including serum, cellular, or tissue concentrations of TNF-alpha and IL-8) might boost the predictive performance of models and, eventually, control the disease with a significant improvement in quality of life (QOL).

Abstract Background Pharmacogenetics could represent a further resource to understand the interindividual heterogeneity of response of the host to sepsis and to provide a personalized approach to the critical care patient. Methods Secondary analysis of data from the prospective observational study NCT02750163, in 50 adult septic and septic shock patients treated with Acetaminophen (ACT) for pyrexia. We investigated the presence of two polymorphisms, located respectively in the genes UGT1A1 and CYP3A5, that encode for proteins related to the hepatic metabolism of ACT. The main dependent variables explored were plasmatic concentration of ACT, body temperature and hepatic parameters. Results 8% of the patients carried CYP3A5 rs776746 A/G genotypes and showed significantly higher plasma levels of ACT than GG wild type patients, and than patients with UGT1A1 rs8330 C/G genotypes. Conclusions Identifying specific genotypes of response to ACT may be helpful to guide a more personalized titration of therapy in sepsis and septic shock. CYP3A5 might be a good biomarker for ACT metabolism; however further studies are needed to confirm this result. Trial registration NCT02750163.

Abstract Background Inflammatory Bowel disease (IBD) is a chronic progressive condition that prompts generous physical and mental morbidity. Choosing the best kind of management and medication dosage prevents new episodes of high disease activity during therapy because of adverse drug reactions (ADRs). This can lead to cessation or inefficacy of the treatment, or complete non-responsiveness to specific medications. Pharmacogenetics (PGx) is a well-established aspect in IBD. One of the exemplary instances of PGx is thiopurines, which are frequently utilized as IBD therapy. This study aimed to evaluate specific gene polymorphism involved in the toxicity and efficacy of Azathioprine (AZA) use in the management in Egyptian patients and to find the correlation between the polymorphism of Nudix Hydrolase15 (NUDT15) gene (rs116855232), The Thiopurine methyltransferase (TPMT) gene (rs1800460) and Inosine Triphosphatase (ITPA) gene (rs1127354) which are involved in the metabolism of the medications utilized in IBD management. Methods This prospective study was performed in 150 patients with IBD. All patients were treated with 2 mg/kg per day AZA (Imuran, GlaxoSmithKline®) for at least 3 months at therapeutic doses to induce remission. Subsequent treatment of AZA. The minimum follow-up period for those who did not experience ADR was one year. Among the studied patients, one hundred twenty-nine patients were treated with combination regimen of steroids (oral prednisone 1 mg/kg/day). Also, treatment failure was considered among the patients who could not tolerate AZA side effects, or there was no improvement after dose modification. Results The most identifiable adverse effect among the studied population was anemia followed by leukopenia and myelosuppression. SNPs genotype TPMT (rs1800460) and ITPA gene (rs1127354) were significantly related to adverse effects among IBD patients receiving Azathioprine treatment. There was a lack of any variants in the NUDT15 genotype among the Egyptian population. Conclusion Further research is required in to clarify the relationship between NUDT15 PGx and AZA-ADRs. The effect of NUDT15 PGx on toxicity and ADRs as yet necessitates to be elucidated. Studies with a larger sample size and involving different ethnicities are also necessary.

ObjectivesTo evaluate pharmacokinetics and pharmacogenetics of contraceptive implant progestin concentrations in HIV-positive women initiating efavirenz (EFV)-containing or nevirapine (NVP)-containing antiretroviral therapy (ART).DesignWe analyzed stored samples from women self-reporting implant use in the Partners PrEP Study.MethodsPlasma samples collected every 6 months were analyzed for levonorgestrel and etonogestrel concentrations. Progestin concentrations from samples collected after ART initiation were compared with pre-ART concentrations for intraindividual comparisons. We used adjusted linear mixed models to compare hormone concentrations between individuals on EFV and NVP to a no ART group. We then evaluated whether possessing certain alleles with known or possible influences on EFV, NVP, or progestin metabolism were associated with changes in progestin concentrations or modified the association between ART use and progestin concentrations.ResultsOur analysis included 11 women who initiated EFV, 13 who initiated NVP, and 36 who remained ART-naive. In the EFV group, the adjusted geometric mean ratio (aGMR) of levonorgestrel was 0.39 [90% confidence intervals (0.31, 0.49); P

Saowalak Turongkaravee,1 Naiyana Praditsitthikorn,2 Thundon Ngamprasertchai,3 Jiraphun Jittikoon,4 Surakameth Mahasirimongkol,5 Chonlaphat Sukasem,6– 9 Wanvisa Udomsinprasert,4 Olivia Wu,10 Usa Chaikledkaew11,12 1Social, Economic and Administrative Pharmacy (SEAP) Graduate Program, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 2Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand; 3Department of Clinical Tropical Medicine, Faculty of Tropical Medicine; Mahidol University, Bangkok, Thailand; 4Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 5Department of Medical Sciences, Medical Genetics Center, Medical Life Sciences Institute, Ministry of Public Health, Nonthaburi, Thailand; 6Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 7Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand; 8Pharmacogenomics and Precision Medicine, The Preventive Genomics & Family Check-Up Services Center, Bumrungrad International Hospital, Bangkok, Thailand; 9MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 3GL, UK; 10Health Economics and Health Technology Assessment (HEHTA), Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK; 11Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 12Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, ThailandCorrespondence: Usa Chaikledkaew, Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhaya Road, Rajathevi, Bangkok, 10400, Thailand, Tel +662-644-8679 ext 5317, Fax +662-644-8694, Email usa.chi@mahidol.ac.thPurpose: Pharmacogenetics (PGx) testing is one of the methods for determining whether individuals are at risk of adverse drug reactions (ADRs). It has been reported that multiple-PGx testing, a sequencing technology, has a higher predictive value than single-PGx testing. Therefore, this study aimed to determine the most cost-effective PGx testing strategies for preventing drug-induced serious ADRs in human immunodeficiency virus (HIV)-infected patients.Patients and Methods: Potential strategies, including 1) single-PGx esting (ie, HLA-B&ast;57:01 testing before prescribing abacavir, HLA-B&ast;13:01 testing before prescribing co-trimoxazole and dapsone, and NAT2 testing before prescribing isoniazid) and 2) multiple-PGx testing as a combination of four single-gene PGx tests in one panel, were all compared to no PGx testing (current practice). To evaluate total cost in Thai baht (THB) and quality-adjusted life years (QALYs) for each strategy-based approach to a societal perspective, a hybrid decision tree and Markov model was constructed. Incremental cost-effectiveness ratios (ICERs) were estimated. Uncertainty, threshold, and scenario analyses were all performed.Results: Before prescribing HIV therapy, providing single or multiple-PGx testing might save roughly 68 serious ADRs per year, and the number needed to screen (NNS) to avoid one serious ADR was 40. Consequently, approximately 35% and 40% of the cost of ADR treatment could be avoided by the implementation of single- and multiple-PGx testing, respectively. Compared with no PGx testing strategy, the ICERs were 146,319 THB/QALY gained for single-PGx testing and 152,014 THB/QALY gained for multiple-PGx testing. Moreover, the probability of multiple-PGx testing being cost-effective was 45% at the Thai willingness to pay threshold of 160,000 THB per QALY. Threshold analyses showed that multiple-PGx testing remained cost-effective under the range of cost, sensitivity at 0.95– 1.00 and specificity at 0.98– 1.00.Conclusion: Single and multiple-PGx testing might be cost-effective options for reducing the incidence of drug-induced serious ADRs in people living with HIV.Keywords: pharmacogenetic, adverse drug reactions, HIV, cost-utility analysis, economic evaluation

Background: Pharmacogenetics could represent a further resource to understand the interindividual heterogeneity of response of the host to sepsis and to provide a personalized approach to the critical care patient. Methods: Secondary analysis of data from the prospective observational study NCT02750163, in 50 adult septic and septic shock patients treated with Acetaminophen (ACT) for pyrexia. We investigated the presence of two polymorphisms, located respectively in the genes UGT1A1 and CYP3A5, that encode for proteins related to the hepatic metabolism of ACT. The main dependent variables explored were plasmatic concentration of ACT, body temperature and hepatic parameters. Results: 8% of the patients carried CYP3A5 rs776746 A/G genotypes and showed significantly higher plasma levels of ACT than GG wild type patients, and than patients with UGT1A1 rs8330 C/G genotypes. Conclusions: Identifying specific genotypes of response to ACT may be helpful to guide a more personalized titration of therapy in sepsis and septic shock. CYP3A5 might be a good biomarker for ACT metabolism; however further studies are needed to confirm this result. Trial registration: NCT02750163. [ABSTRACT FROM AUTHOR]

Non-vitamin K antagonist oral anticoagulants' interindividual trough concentration variability affects efficacy and safety, especially in bleeding events. Rivaroxaban is metabolised via CYP3A4/5-, CYP2J2-, and CYP-independent mechanisms and is a substrate of two transporter proteins: ABCB1 (MDR1, P-glycoprotein) and ABCG2 (BCRP; breast-cancer-resistance protein). The polymorphisms of these genes may possibly affect the pharmacokinetics of rivaroxaban and, consequently, its safety profile. Rivaroxaban variability may be associated with age, liver and kidney function, concomitant illness and therapy, and pharmacogenetic predisposition. This case series is the first, to our knowledge, that presents multiple risk factors for rivaroxaban-related bleeding (RRB) including age, renal function, concomitant diseases, concomitant treatment, and pharmacogenetic data. It presents patients with RRB, along with their complete clinical and pharmacogenetic data, as well as an evaluation of possible risk factors for RRB. Thirteen patients were carriers of ABCB1, ABCG2, CYP2J2, and/or CYP3A4/5 gene polymorphisms. Possible drug–drug interactions with increased bleeding risk were identified in nine patients. Six patients had eGFR <60 mL/min/1.73 m2. Our data suggest a possible role of multiple factors and their interactions in predicting RRB; however, they also indicate the need for further comprehensive multidisciplinary research to enable safer use of this product based on a personalised approach. [ABSTRACT FROM AUTHOR]

Flecainide is a class IC antiarrhythmic utilized in prophylaxis of refractory paroxysmal supraventricular tachycardias in pediatric populations. Despite being a highly effective agent, its narrow therapeutic index increases the risk of toxicity and proarrhythmic events, including wide-complex tachycardia. In the absence of direct plasma sampling in the fetus to quantitate flecainide systemic concentrations, clinicians typically make drug dosing decisions from maternal plasma concentrations and QRS duration on maternal ECGs. There remains a paucity of standard guidelines and data to inform the timing and frequency of the aforementioned test in pregnancy and timing of flecainide discontinuation prior to childbirth. Flecainide primarily undergoes metabolism via cytochrome P450 (CYP). Given the variance of CYP-mediated metabolism at the level of the individual patient, pharmacogenomics can be considered in patients who present with flecainide toxicity to determine the maternal vs. fetal factors as an etiology for the event. Finally, pharmacogenetic testing can be utilized as an adjunct to guide flecainide dosing decisions, but must be done with caution in neonates

Background—Various antidepressant agents are metabolized by the CYP2C19 enzyme, including Citalopram and Escitalopram. Variation in CYP2C19 expression might give rise to different plasma concentrations of the active metabolites, potentially affecting both drugs’ efficacy and tolerability. Aim—The aim of this study was to evaluate differences in the Escitalopram and Citalopram efficacy and tolerability between different CYP2C19 genotype-based metabolizing categories in outpatients suffering from major depressive disorder (MDD). Methods—In a retrospective, longitudinal cohort study of electronic medical-record data, 283 patients with MDD who were prescribed Escitalopram or Citalopram with the available CYP2C19-genotyping test were enrolled. The primary efficacy end point was adverse drug reactions recorded in the medical files. A proportional-odds, multilevel-regression model for longitudinal ordinal data was used to estimate the relation between the CYP2C19 genotype and adverse drug reactions, adjusting for potential confounding variables and other explanatory variables. Latent-class analysis (LCA) was utilized to detect the presence of clinically significant subgroups and their relation to an individual’s metabolizing status for CYP2D6/CYP2C19. Results—With poor CYP2C19 metabolizers as a reference, for each unit difference in the activity score of the CYP2C19 phenotype, the odds ratio for drug intolerability was lowered by 0.73 (95% credible intervals: 0.56–0.89), adjusting for significant covariates. In addition, applying LCA, we identified two qualitatively different subgroups: the first group (61.85%) exhibited multiple side effects, low compliance, and frequent treatment changes, whereas the second group (38.15%) demonstrated fewer side effects, good adherence, and fewer treatment changes. The CYP2C19 phenotype was substantially associated with the group membership. Conclusions—We found a positive association between the CYP2C19 activity scores, as inferred from the genotype, and both the efficacy of and tolerability to both Es/Citalopram. LCA enabled valuable insights into the underlying structure of the population; the CYP2C19 phenotype has a predictive value that discriminates between low-adherence, low-drug-tolerance, and low-response patients and high-adherence, high-drug-tolerance, and high-response patients. Personalized medicine based on CYP2C19 genotyping could evolve as a promising new avenue towards mitigating Escitalopram and Citalopram therapy and the associated side effects and enhancing treatment success.

Eloy A Zepeda-Carrillo,1,2,&ast; Omar Ramos-Lopez,3 Erika Martínez-López,4 Elisa Barrón-Cabrera,5 J Antonio Bernal-Pérez,6 Luisa E Velasco-González,6 Ernesto Rangel-Rios,6 J Fausto Bustamante Martínez,2 Rafael Torres-Valadez1,7,&ast; 1Specialized Unit in Research, Development and Innovation in Genomic Medicine, Nayarit Center for Innovation and Technology Transfer, Autonomous University of Nayarit, Tepic, Nayarit, Mexico; 2Civil Hospital “Dr. Antonio González Guevara”, Health Services in Nayarit, Tepic, Nayarit, Mexico; 3Medicine and Psychology School, Autonomous University of Baja California, Tijuana, B.C, Mexico; 4Institute of Translational Nutrigenetics and Nutrigenomics, Department of Molecular and Genomic Biology, University Center of Health Sciences, University of Guadalajara, Guadalajara, Jalisco, Mexico; 5Faculty of Nutrition and Gastronomy Sciences, Autonomous University of Sinaloa, Culiacan, Sinaloa, Mexico; 6Family Medicine Unit No. 24 “Ignacio García Téllez”, Mexican Social Security Institute, Tepic, Nayarit, Mexico; 7Integral Health Academic Unit, Autonomous University of Nayarit, Tepic, Nayarit, Mexico&ast;These authors contributed equally to this workCorrespondence: Rafael Torres-Valadez, Nayarit Center for Innovation and Technology Transfer, Autonomous University of Nayarit, Tepic, Nayarit, Mexico, Tel +52-3312523644, Email rafael.torres@uan.edu.mxPurpose: Differences in metformin effect on glycemic control in type 2 Diabetes (T2D) have been associated with diet, obesity, years since T2D diagnosis and genetic factors, such as the Met408Val (rs628031) SLC22A1/OCT1 gene polymorphism. This study aimed to analyze the effect of metformin and diet on glycemic control and its association with the Met408Val polymorphism in patients with T2D from western Mexico.Patients and Methods: A total of 240 T2D adult patients were enrolled in this cross-sectional study. Anti-hyperglycemic therapy, dietary intake, body composition and glycemic profile were recorded and the determination of genotypes of SLC22A1/OCT1 gene (rs628031) was performed using an allelic discrimination assay.Results: The type of metformin therapy was 47% monotherapy, 45% dual therapy (metformin+glibenclamide or metformin+insulin) and 8% triple therapy (metformin+glibenclamide+insulin). Individuals with metformin monotherapy had a higher glycemic control frequency (%HbA1c < 7.0) compared with the dual and triple treatment schemes (77% vs 35% and 15%, respectively; p< 0.001). Interestingly, a high potassium intake was documented in the three anti-hyperglycemic therapies and a lower intake of micronutrients, including calcium, magnesium, and zinc. An interaction was found between calcium intake and carriers of the risk allele A (408Val) with %HbA1c (P interaction=0.028), and potassium intake with the TyG index (P interaction=0.027). In addition, there was a positive correlation between calcium intake and %HbA1c (r=0.682; p=0.010), and potassium intake vs TyG index (r=0.593; p=0.033) in risk allele A (408Val) carriers with metformin monotherapy. Genotype frequencies were GG homozygotes (76.6%), GA heterozygotes (21.5%) and AA homozygotes (1.9%). The allele frequency was 87.4% for the ancestral allele G and 12.6% for the risk allele A.Conclusion: These findings suggest a differing effect of metformin on glycemic control regarding calcium and potassium intake and the Met408Val SLC22A1/OCT1 gene polymorphism in T2D patients.Keywords: nutrigenetic, pharmacogenetic, SLC22A1/OCT1 gene, gene-nutrient interactions, calcium intake, potassium intake

Introduction: Pharmacogenetic testing may hold promise in addressing health disparities, as medically underserved patients appear to be prescribed medications with pharmacogenetic guidelines at higher rates. While routine clinical implementation of testing in medically underserved populations has not yet been achieved, using patient perspectives to inform implementation should increase the likelihood of success. The aim of this study was to assess the perceptions, knowledge, and attitudes regarding pharmacogenetic testing in medically underserved patients.Methods: We developed a survey instrument to assess respondent views on pharmacogenetic testing. The survey instrument was developed through a process of literature review, expert input, iterative pilot testing, and final refinement. The survey instrument was fielded to US adults with an estimated household income of $42,000 per year or less.Results: During the survey instrument development, 59 pilot testers provided 133 comments which lead to 38 revisions to the survey instrument. The nationwide survey resulted in 1,060 respondents, of which half (49.8%) reported having no health insurance or being on Medicaid. Most patients (78.9%) had not previously heard of pharmacogenetic testing. After being provided an explanation of pharmacogenetic testing, 60.5% were very or moderately interested in receiving testing if there were no cost and 75.8% of respondents agreed or strongly agreed that pharmacogenetic testing should be available to help with medication selection regardless of cost. Respondents shared that their greatest concern with pharmacogenetic testing was that the test would cost them money, which was expressed by over half (52.7%). This was followed by concerns that the results could reveal a risk for a disease, could affect health insurance, and would not improve care.Discussion: Our results indicate a strong interest in pharmacogenetic testing and identify key perceptions, attitudes, concerns, and potential barriers that can be addressed as pharmacogenetic testing is clinically implemented in medically underserved patient populations.

Personalized medicine is a multidisciplinary area that contains several techniques to provide patients with more efficient, cheaper, and fewer side effects treatment strategies. In customized medicine, each patient is viewed individually in order to provide more specific and efficient treatment. Using liquid biopsy, pharmacogenetics, point-of-care-testing, multi-omicbased technologies, wearable technologies, organoids, and 3D printers are some of the strategies covered in this review. Omics technology is promising for data collection, and management is vital for health records to combine complete information in one single platform. 3D printer technologies give opportunities to produce multi-drug tablets with controlled and targeted drug release. Additionally, organoids are the other biomaterial approaches to mimic the tumoroid microenvironment to develop new treatment strategies. Increasing demand for personalized medicine affects the improvement scope of this technology; personalized medicine is a vital and urgent area to improve. [ABSTRACT FROM AUTHOR]

Polymorphisms in CYP2C9 can significantly interfere with the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen. The present research aimed to study the PK/PD parameters of naproxen and its metabolite, 6-O-desmethylnaproxen, associated with allelic variations of CYP2C9. In our study, a rapid, selective, and sensitive Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) method was developed and validated for the determination of naproxen and its main metabolite, 6-O-desmethylnaproxen, in oral fluid. Naproxen and its main metabolite were separated using a Shim-Pack XR-ODS 75L × 2.0 column and C18 pre-column at 40 °C using a mixture of methanol and 10 mM ammonium acetate (70:30, v/v), with an injection flow of 0.3 mL/min. The total analytical run time was 3 min. The volunteers, previously genotyped for CYP2C9 (16 ancestral—CYP2C9 *1 and 12 with the presence of polymorphism—CYP2C9 *2 or *3), had their oral fluids collected sequentially before and after taking a naproxen tablet (500 mg) at the following times: 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6 8, 11, 24, 48, 72 and 96 h. Significant differences in the PK parameters (* p < 0.05) of naproxen in the oral fluid were: Vd/F (L): 98.86 (55.58–322.07) and 380.22 (261.84–1097.99); Kel (1/h): 0.84 (0.69–1.34) and 1.86 (1.09–4.06), in ancestral and mutated CYP2C9 *2 and/or *3, respectively. For 6-O-desmethylnaproxen, no PK parameters were significantly different between groups. The analysis of prostaglandin E2 (PGE2) proved to be effective and sensitive for PD parameters analysis and showed higher levels in the mutated group (p < 0.05). Both naproxen and its main metabolite, 6-O-desmethylnaproxen, and PGE2 in oral fluid can be effectively quantified using LC-MS/MS after a 500 mg oral dose of naproxen. Our method proved to be effective and sensitive to determine the lower limit of quantification of naproxen and its metabolite, 6-O-desmethylnaproxen, in oral fluid (2.4 ng/mL). All validation data, such as accuracy, precision, and repeatability intra- and inter-assay, were less than 15%. Allelic variations of CYP2C9 may be considered relevant in the PK of naproxen and its main metabolite, 6-O-desmethylnaproxen. [ABSTRACT FROM AUTHOR]