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Background: Evidence from clinical trials suggests a differential effect of sex on the effectiveness and safety of direct oral anticoagulants (DOACs) for stroke prophylaxis in atrial fibrillation (AF). Methods: This population-based cohort study examined the independent effect of sex on hemorrhage and ischemic stroke in 23,884 patients (55% females; age ≥ 66 years) with AF starting apixaban or rivaroxaban treatment in Ontario, Canada. Patients were followed for 90 days after their DOAC prescription. Using female sex as the exposure of interest, differences in baseline characteristics were balanced between sexes using inverse probability weights based on propensity scores. Applying weighted modified Poisson regression, risk ratios (RRs) were estimated for major hemorrhage, ischemic stroke/systemic embolism/transient ischemic attack (hereafter stroke), myocardial infarction, and all-cause mortality, with males as a reference. Results: Females were older, had higher predicted stroke risk (based on CHADS2 score), and had fewer comorbidities than did males. Males had a higher prevalence of coronary artery disease, diabetes, and cancer, and similar predicted bleeding risk (based on HAS-BLED score). After weighting, baseline characteristics were well balanced. The 90-day risks for hemorrhage (RR 0.96; 95% confidence interval [CI] 0.80-1.15; P = 0.69) and stroke (RR 1.01; 95% CI 0.86-1.19; P = 0.94) were similar between sexes, which remained true when assessing each DOAC separately by dosing regimen. Compared to males, females had a lower risk for myocardial infarction (RR 0.66; 95% CI 0.52-0.84; P = 0.0008), and for all-cause mortality (RR 0.76; 95% CI 0.67-0.87; P < 0.0001). Conclusions: Our findings do not suggest an association of sex with the 90-day risk of hemorrhage or ischemic stroke in older AF patients prescribed apixaban or rivaroxaban. Résumé: Contexte: Les données probantes issues des essais cliniques donnent à penser que l’efficacité et l’innocuité des anticoagulants oraux directs (AOD) utilisés pour la prophylaxie des accidents vasculaires cérébraux (AVC) dans un contexte de fibrillation auriculaire (FA) varient selon le sexe du patient. Méthodologie: Cette étude de cohorte populationnelle a examiné l’effet indépendant du sexe sur l’hémorragie et l’AVC ischémique chez 23 884 patients (55 % de femmes; âge ≥ 66 ans) atteints de FA ayant amorcé un traitement par l’apixaban ou le rivaroxaban en Ontario (Canada). Les patients ont été suivis pendant 90 jours après avoir reçu une ordonnance d’AOD. Le sexe féminin constituant l’exposition d’intérêt, les différences quant aux caractéristiques initiales ont été réparties de façon équilibrée entre les sexes au moyen d’une pondération par probabilité inverse reposant sur le score de propension. La régression de Poisson modifiée avec pondération a servi à estimer les rapports de risques (RR) d’hémorragie majeure, d’AVC ischémique/d’embolie systémique/d’accident ischémique transitoire (ci-après AVC), d’infarctus du myocarde et de mortalité toutes causes confondues, les hommes formant la population de référence. Résultats: Les femmes étaient plus âgées, présentaient un risque prévu d’AVC plus élevé (d’après le score CHADS2) et présentaient moins de maladies concomitantes que les hommes. Les hommes présentaient une prévalence plus élevée de coronaropathie, de diabète et de cancer, et un risque prévu d’hémorragie similaire (compte tenu du score HAS-BLED). Après la pondération, la répartition des caractéristiques initiales des patients était bien équilibrée. Le risque d’hémorragie (RR : 0,96; intervalle de confiance [IC] à 95 % : 0,80-1,15; P = 0,69) et d’AVC (RR : 1,01; IC à 95 % : 0,86-1,19; P = 0,94) sur 90 jours était similaire pour les deux sexes, et il en était de même lorsque chaque AOD a été évalué séparément en fonction du schéma posologique. Par rapport aux hommes, les femmes présentaient un risque plus faible d’infarctus du myocarde (RR : 0,66; IC à 95 % : 0,52-0,84; P = 0,0008) et de mortalité toutes causes confondues (RR : 0,76; IC à 95 % : 0,67-0,87; P < 0,0001). Conclusions: Nos résultats ne laissent présumer aucune association entre le sexe et le risque d’hémorragie ou d’AVC ischémique sur une période de 90 jours chez les patients âgés atteints de FA à qui l’apixaban ou le rivaroxaban sont prescrits.

5-fluorouracil (5-FU) and its pro-drug capecitabine are widely used anticancer agents. Most 5-FU catabolism is dependent on dihydropyrimidine dehydrogenase (DPD) encoded by the DPYD gene, and DPYD variants that reduce DPD function increase 5-FU toxicity. Most DPD deficient patients are heterozygous and can be treated with reduced 5-FU dosing. We describe a patient with a genotype associated with near complete absence of DPD function, and severe and likely fatal toxicity with 5-FU treatment. The patient was treated effectively with alternative systemic therapy. Routine pretreatment DPYD genotyping is recommended by the European Medicines Agency, and guidelines for use of 5-FU in DPD deficient patients are available. However, outside the province of Quebec, routine pretreatment screening for DPD deficiency remains unavailable in Canada. It is likely our patient would have died from 5-FU toxicity under the current standard of care, but instead provides an example of the potential benefit of DPYD screening on patient outcomes.

Patient ethnicity may influence the pharmacokinetics (PK) of tacrolimus. Because the Canadian First Nations (FN) constitute a large and increasing segment of the liver transplant population, we undertook to determine whether PK differences exist for a once-daily, extended release formulation of tacrolimus (Advagraf) in FN compared to Caucasian (CAUC) liver transplant recipients. Following achievement of a steady state with Advagraf, blood samples were drawn at 0, 1, 2, 4, 6, 8 and 24 hours for whole blood tacrolimus levels by commercial immunoassay and CYP3A4 and CYP3A5 allele analyses were performed by polymerase chain reactions. Nineteen subjects participated in the study (7 FN and 12 CAUC). The FN cohort had significantly higher AUC (214 ± 48 versus 168 ± 25, P

Sex and gender refer to biological and social differences between men and women. While well-evaluated in other disciplines, their roles in inflammatory bowel disease (IBD) are not well-defined. This study aimed to characterize differences in healthcare outcomes in men and women with IBD. A retrospective single-centre cohort study was conducted to evaluate differences between men and women receiving care for Crohn’s disease (CD) and ulcerative colitis (UC) at the Western University Personalized Medicine Clinic from March 2012 to September 2019. The primary endpoint was the proportion of IBD drugs used for all drug classes. Additional outcomes in healthcare utilization and disease phenotype were assessed. Student's t test and Fisher's exact test were used to assess differences A total of 1015 participants were included (CD = 656; UC = 359). In UC and CD, 47.9% and 59.0% were women, respectively. Overall, women were more likely prescribed budesonide than men (23.6% vs. 13.4%; p 55 being less likely to receive biologics. These findings highlight differences in disease course and treatment approaches between men and women with IBD and support the consideration of sex and gender when researching disease outcomes.

Consensus guidelines exist for genotype‐guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Patients referred for DPYD genotyping prior to fluoropyrimidine treatment were enrolled from December 2013 through November 2019 and followed until completion of fluoropyrimidine treatment. Patients were genotyped for DPYD c.1905+1G>A, c.2846A>T, c.1679T>G, and c.1236G>A. Genotype‐guided dosing recommendations were informed by Clinical Pharmacogenetics Implementation Consortium guidelines. The primary outcome was the proportion of patients who experienced a severe fluoropyrimidine‐related AE (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Secondary outcomes included early severe AEs, severe AEs by toxicity category, discontinuation of fluoropyrimidine treatment due to AEs, and fluoropyrimidine‐related death. Among 1394 patients, mean (SD) age was 64 (12) years, 764 (54.8%) were men, and 47 (3.4%) were DPYD variant carriers treated with dose reduction. Eleven variant carriers (23%) and 418 (31.0%) noncarriers experienced a severe fluoropyrimidine‐related AE (p = 0.265). Six carriers (15%) and 284 noncarriers (21.1%) experienced early severe fluoropyrimidine‐related AEs (p = 0.167). DPYD variant carriers treated with genotype‐guided dosing did not experience an increased risk for severe AEs. Our data support a role for DPYD genotyping in the use of fluoropyrimidines in North America.

At least 23 case reports link the muscle relaxant baclofen to encephalopathy in patients receiving dialysis. To explore this issue, we conducted a study to quantify the risk of encephalopathy from baclofen in patients receiving dialysis. Linked healthcare databases were used to conduct a population-based cohort study of older adults receiving maintenance dialysis in Ontario, Canada (1997-2018) to compare new users of baclofen to non-users. The primary outcome was the 30-day risk of hospitalization with encephalopathy, defined as a main diagnosis of delirium, disorientation, transient alteration of awareness, or transient cerebral ischemic attack. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. We studied 360 new baclofen users and 6109 non-users (2638 [41%] women; median age 75). The median baclofen dose was 20 mg/day. Hospitalization with encephalopathy occurred in 26 of 360 baclofen users (7.2%) and in under six of 6109 non-users (under 0.1%); weighted risk ratios, 78.3 (95% confidence interval 27.9 to 219.2); weighted risk differences, 7.1% (4.5% to 9.8%). The median time from baclofen dispensing to hospitalization with encephalopathy was three days. Among patients receiving dialysis, approximately one in 14 were hospitalized with encephalopathy shortly after starting baclofen. Thus, baclofen should be avoided in older adults receiving dialysis, and other muscle relaxants considered in its place. Hence, if baclofen must be used, a low dose should be prescribed, and older adults should be carefully monitored for signs of encephalopathy.

Female patients with breast cancer frequently develop arthralgia when treated with aromatase inhibitors (AI). Although the mechanism of AI-induced arthralgia is unknown, potential biomarkers have been identified. The purpose of this study was to investigate the clinical and genetic predictors of AI-induced arthralgia in a prospective cohort of patients with estrogen receptor-positive breast cancer. One hundred and ninety-six patients were enrolled at initiation of AI therapy with either letrozole or anastrozole. Patients completed two validated self-report questionnaires assessing pain, stiffness, and physical function at baseline, and repeated the questionnaires at two and at six months after the initiation of treatment with an AI. Germline DNA of all patients was genotyped for seven single-nucleotide polymorphisms (SNPs) previously identified by genetic screens and genome-wide association studies as associated with AI-induced arthralgia. More than 50% of the study group experienced arthralgia symptoms. Genetic analysis revealed that four SNPs, in CYP19A1 (rs4775936) and ESR1 (rs9322336, rs2234693, rs9340799), were associated with the development of arthralgia (adjusted P = 0.016, 0.018, 0.017, 0.047). High body mass index (BMI) was also associated with the development of arthralgia symptoms (adjusted P = 0.001). Patients prescribed letrozole were significantly more likely to develop arthralgia than patients on anastrozole (P = 0.018), and also more likely to discontinue AI therapy due to arthralgia. The CYP19A1 (rs4775936) SNP was significantly associated with discontinuation of therapy due to intolerable arthralgia. Our results suggested that BMI and AI drug (letrozole versus anastrozole) were clinical predictors of arthralgia, while genetic variants rs4775936, rs9322336, rs2234693, and rs9340799 were genetic predictors of AI-induced arthralgia. Significantly, rs4775936 was also a predictor of discontinuation of therapy.

A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10-4). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10-5). We observed significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1-5.0, P = 5.4 × 10-3). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1-1.2, P = 8.8 × 10-5). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.

Visual Abstract, Highlights • Combining CHD phenotype–driven gene set enrichment and CRISPR knockdown screening in zebrafish is an effective approach to identifying novel CHD genes. • Mutations affecting genes coding for the WAVE2 protein complex and small GTPase-mediated signaling are associated with LVOTO lesions. • WAVE2 complex genes brk1, nckap1, and wasf2 and regulators of small GTPase signaling cul3a and racgap1 are critical to zebrafish heart development., Summary Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development.

Na+-taurocholate cotransporting polypeptide (NTCP, SLC10A1) is a key hepatic uptake transporter for bile acids and drugs and is the main functional receptor for hepatitis B and D viruses. Next-generation sequencing has revealed that a large number of rare SLC10A1 variants exist in the population. Little data exist regarding head-to-head comparison of in silico algorithms to predict functional effects of pharmacogenetic variants when compared to direct in vitro functional assessment. This study aimed at characterizing rare SLC10A1 variants in vitro and to assess the performance of seven in silico algorithms to predict the observed functional impacts. Thirty-five previously uncharacterized, rare, missense SLC10A1 variants were transiently expressed in human embryonic kidney 293 type T (HEK293T) cells. NCTP protein expression as well as uptake of substrates taurocholic acid (TCA) and rosuvastatin were assessed. Substrate-specific effects were observed for NTCP G191R, with TCA and rosuvastatin transport observed at 89 and 8% of wild-type (WT) uptake, respectively. Significantly reduced transport of TCA and rosuvastatin was observed for 19 variants (p < 0.05), with seven variants displaying decreased protein expression and marked reduction in transport of both substrates (0-13% of WT uptake, p < 0.0001). Performance of in silico algorithms to predict in vitro uptake, assessed using the area under the receiver operating characteristic curves (AUCROC), ranged from 0.69 to 0.97 and 0.72 to 0.84 for TCA and rosuvastatin uptake, respectively. In conclusion, we identified rare variants with significantly reduced NTCP expression and function. We demonstrated that no algorithm performed robustly enough to replace functional study in vitro, particularly given the broad substrate specificity of many pharmacogenes.

Background: Tamoxifen is widely used in patients with hormone sensitive breast cancer in the adjuvant setting to decrease risk of recurrence and metastasis. 5-10 years of tamoxifen has demonstrated a near 50% reduction in recurrence risk. Despite marked interpatient variation in the metabolism of tamoxifen to its active metabolite endoxifen, all patients are prescribed 20 mg daily dose of tamoxifen. Current evidence suggests that patients are at risk for suboptimal benefit if measured endoxifen concentration is below 5.9 ng/ml (~15nM). However, there have been conflicting data on the clinical utility of CYP2D6 genotype testing, and measuring endoxifen plasma concentration as a predictor of breast cancer recurrence. The goal of this prospective study was to determine the impact of endoxifen levels and CYP2D6 genetic variations to clinical outcome among patients with early breast cancer. Methods: Since 2010, as part of Personalized Medicine Program in Oncology, our team has been prospectively enrolling patients on tamoxifen therapy. To date 950 patients have been enrolled and preliminary analysis has been completed in 429. After initial CYP2D6 genotype testing, plasma concentration of tamoxifen and its metabolites were quantified using liquid chromatography-tandem mass spectrometry during each clinic visit. Baseline characteristic are outlined in table 1. Primary outcome assessed was invasive disease-free survival (IDFS) defined as time since start of tamoxifen therapy till an event of interest such as loco-regional recurrence, distant metastasis, new contralateral primary breast cancer, death due to breast cancer and other causes. Patients were censored at their last encounter at our institution (London Health Sciences Centre). Results: IDFS data for 426 patients were obtained. Outcome was stratified by CYP2D6 phenotypes (ultra-rapid, extensive, intermediate and poor metabolizers) and endoxifen levels (>5.9ng/ml or vs< 5.9 ng/ml showed a clear trend towards lower IDFS (hazard ratio = 2.4, (95%CI,1.26-4.77) P=0.0002) among those with endoxifen < 5.9 ng/ml. We note this preliminary data analysis was unadjusted and will undergo further in-depth statistical analysis. Conclusion: Preliminary finding suggests endoxifen concentration, but not CYP2D6 phenotype, may be a predictor of risk for suboptimal benefit during tamoxifen therapy. Detailed statistical analysis is planned for the full cohort, including adjustment for covariates including tumor stage, menopausal status, drug interactions, and use of aromatase inhibitors. To our knowledge, this is the first study of its type to prospectively collect multiple plasma samples for tamoxifen and endoxifen level in real-world patients during tamoxifen therapy, with sufficient sample size and follow-up period for primary clinical outcome. Table 1: Baseline Characteristics of PatientsCharacteristicsCYP2D6-Phenotypes, n=429 (%)Endoxifen concentration, n=429 (%)UM/EMIMPM>5.9ng/ml(~15nm) Citation Format: Veera Durga Sravanthi Panuganty, Denise Keller, Wendy A Teft, John Gordon Lenehan, Kylea Raijann Potvin, Jawaid Younus, Theodorus Anthony Vandenberg, Diane Mary Logan, Karin Hahn, Muriel Brackstone, Phillip Stanley Blanchette, Francisco Perera, Yun-Hee Choi, Richard Brian Kim. Clinical outcomes in early breast cancer patients on adjuvant tamoxifen: Impact of CYP2D6 genotype and observed endoxifen concentrations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-05.

Background The current use of ribavirin in difficult-to-cure chronic hepatitis C patients (HCV) and patients with severe respiratory infections is constrained by the issue of ribavirin-induced hemolytic anemia that affects 30% of treated patients, requiring dosage modification or discontinuation. Though some genetic variants have been identified predicting this adverse effect, known clinical and genetic factors do not entirely explain the risk of ribavirin-induced anemia. Methods We assessed the associations of previously identified variants in inosine triphosphatase (ITPA), solute carrier 28A2 (SLC28A2) and vitamin D receptor (VDR) genes with ribavirin-induced anemia defined as hemoglobin decline of ≥30 g/L on treatment, followed by a staged discovery (n = 114), replication (n = 74), and combined (n = 188) genome-wide association study to uncover potential new predictive variants. Results We identified a novel association in the gene coding glycophorin C (rs6741425; OR:0.12, 95%CI:0.04–0.34, P = 2.94 × 10-6) that predicts protection against ribavirin-induced anemia. We also replicated the associations of ITPA and VDR genetic variants with the development of ribavirin-induced anemia (rs1127354; OR:0.13, 95%CI:0.04–0.41, P = 8.66 ×10-5; and rs1544410; OR:1.65, 95%CI:1.01–2.70, P = 0.0437). Conclusions GYPC variation affecting erythrocyte membrane strength is important in predicting risk for developing ribavirin-induced anemia. ITPA and VDR genetic variants are also important predictors of this adverse reaction.

Organic anion transporting polypeptide 2B1 (OATP2B1, gene SLCO2B1) is an uptake transporter that is thought to determine drug disposition and in particular, the oral absorption of medications. At present, the clinical relevance of SLCO2B1 genetic variation on pharmacokinetics is poorly understood. We sought to determine the functional activity of 5 of the most common missense OATP2B1 variants (c.76_84del, c.601G>A, c.917G>A, c.935G>A, and c.1457C>T) and a predicted dysfunctional variant (c.332G>A) in vitro. Furthermore, we measured the basal plasma concentrations of endogenous OATP2B1 substrates, namely estrone sulfate, dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate, coproporphyrin I (CPI), and CPIII, and assessed their relationships with SLCO2B1 genotypes in 93 healthy participants. Compared to reference OATP2B1, the transport activities of the c.332G>A, c.601G>A and c.1457C>T variants were reduced among the substrates examined (estrone sulfate, DHEAS, CPI, CPIII and rosuvastatin), although there were substrate-dependent effects. Lower transport function of OATP2B1 variants could be explained by diminished cell surface expression. Other OATP2B1 variants (c.76-84del, c.917G>A and c.935G>A) had similar activity to the reference transporter. In the clinical cohort, the SLCO2B1 c.935G>A allele was associated with both higher plasma CPI (42%) and CPIII (31%) concentrations, while SLCO2B1 c.917G>A was linked to lower plasma CPIII by 28% after accounting for the effects of age, sex, and SLCO1B1 genotypes. No association was observed between SLCO2B1 variant alleles and estrone sulfate or DHEAS plasma concentrations, however 45% higher plasma pregnenolone sulfate level was associated with SLCO2B1 c.1457C>T. Taken together, we found that the impacts of OATP2B1 variants on transport activities in vitro were not fully aligned with their associations to plasma concentrations of endogenous substrates in vivo. Additional studies are required to determine whether circulating endogenous substrates reflect OATP2B1 activity.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with an overall median 5-year survival rate of 8%. This poor prognosis is because of the development of resistance to chemotherapy and radiation therapy and lack of effective targeted therapies. IκB kinase enhancer (IKBKE) overexpression was previously implicated in chemoresistance. Because IKBKE is frequently elevated in PDAC and IKBKE inhibitors are currently in clinical trials, we evaluated IKBKE as a therapeutic target in this disease. Depletion of IKBKE was found to significantly reduce PDAC cell survival, growth, cancer stem cell renewal, and cell migration and invasion. Notably, IKBKE inhibitor CYT387 and IKBKE knockdown dramatically activated the MAPK pathway. Phospho-RTK array analyses showed that IKBKE inhibition leads to rapid upregulation of ErbB3 and IGF-1R expression, which results in MAPK-ERK pathway activation-thereby limiting the efficacy of IKBKE inhibitors. Furthermore, IKBKE inhibition leads to stabilization of FOXO3a, which is required for RTK upregulation on IKBKE inhibition. Finally, we demonstrated that the IKBKE inhibitors synergize with the MEK inhibitor trametinib to significantly induce cell death and inhibit tumor growth and liver metastasis in an orthotopic PDAC mouse model.

BACKGROUND Anti-drug antibodies (ADAs) are a leading contributor to infliximab loss of response and adverse drug events. It is not feasible to identify patients at risk of antibody formation before initiating infliximab. The genetic variation HLADQA1*05 (rs2097432) has been linked to infliximab antibody formation in Crohn's disease (CD). AIMS To evaluate the association between HLADQA1*05 and infliximab antibody formation, infliximab loss of response, treatment discontinuation and adverse drug events in patients with inflammatory bowel disease (IBD) METHODS: In a retrospective cohort study, infliximab-exposed patients with IBD (n = 262) were screened for the genetic variation, HLADQA1*05A>G (rs2097432). Risk of infliximab ADA formation, infliximab loss of response, adverse events and discontinuation were assessed in wild-type (GG) and variant-carrying (AG or AA) individuals. RESULTS Forty per cent of all participants were HLADQA1*05A>G variant carriers, with 79% of participants with infliximab antibodies carrying at least one variant allele. The risk of infliximab antibody formation was higher in HLADQA1*05A>G variant carriers (adjusted HR = 7.29, 95% confidence interval (CI) = 2.97-17.191, P = 1.46 × 10-5 ) independent of age, sex, weight, dose and co-immunosuppression with an immunomodulator. Variant carrier status was associated with an increased risk of infliximab loss of response (adjusted HR = 2.34, 95% CI = 1.41-3.88, P = .001) and discontinuation (adjusted HR = 2.27, 95% CI = 1.46-3.43, P = 2.53 × 10-4 ) although not with infliximab-associated adverse drug events. CONCLUSIONS HLADQA1*05 is independently associated with a high risk of infliximab antibody formation in addition to infliximab loss of response and treatment discontinuation. There may be a role for genotype-guided application of combination therapy in IBD.

The CYP4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at individual patients' level to capture the possible effect of ethnicity, gene-gene interaction or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95%CI 7-10%), with a higher effect in females, in patients taking acenocoumarol and in Whites. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived. This article is protected by copyright. All rights reserved.

Author(s): Sukumar, Smrithi; Gulilat, Markus; Linton, Bradley; Gryn, Steven E; Dresser, George K; Alfonsi, Jeffrey E; Schwarz, Ute I; Kim, Richard B; Schwartz, Janice B | Abstract: ObjectivesLower than recommended doses of direct-acting oral anticoagulants are often prescribed to older adults with nonvalvular atrial fibrillation (NVAF). Our goal was to determine the consequences of lower than recommended dosing on plasma apixaban concentrations during the clinical care of older adults with NVAF.DesignConvenience sample of patients receiving anticoagulation during 2017.SettingAcademic medical center.ParticipantsStable adults older than 65 years with NVAF receiving apixaban on a chronic basis.MeasurementsPatient age, weight, creatinine, co-medications, and apixaban concentrations.ResultsA total of 110 older adults with NVAF (mean age = 80.4 y; range = 66-100 y with 45% women) were studied. Overall, 48 patients received recommended dosing of 5 mg twice/day, and 42 received lower than recommended dosing. One patient in each category had concentrations below the expected 5% to 95% range at time of peak concentrations. Differences in proportion of apixaban concentrations within or outside expected ranges were not significant between patients receiving lower than recommended doses and those dosed as recommended at 5 mg twice/day (P = .35). However, in patients dosed as recommended with 5 mg twice/day, four had concentrations above the 5% to 95% range for peak levels expected at 3 to 4 hours after dosing; in two, this occurred around the midpoint of the dosing interval. Twenty patients received 2.5 mg twice/day as recommended. One-third had apixaban concentrations higher than expected peak concentrations compared with the clinical trials, and more than two-thirds had levels above the reported median for peak concentrations.ConclusionsApixaban concentrations in older adults with NVAF seen clinically were higher than expected based on clinical trial data. The findings raise questions about the optimal dosing of apixaban in older adults with NVAF encountered outside of clinical trials and suggest a role for the monitoring of apixaban concentrations during care of patients that differ from those in randomized trials or when considering dosing outside of published guidelines. J Am Geriatr Soc 67:1902-1906, 2019.

An increasing number of patients with metastatic colorectal cancer (mCRC) are able to receive 3 or more lines of therapy. Treatments in this setting can include regorafenib (an oral multikinase inhibitor), trifluridine/tipiracil hydrochloride (TAS-102), antibodies that target epidermal growth factor receptor for patients with RAS wild-type tumors (if no prior exposure), and, where approved, anti-programmed cell death protein 1 inhibitors for patients with microsatellite instability-high mCRC. Although guidelines describe the available treatment options, few insights are provided to guide selection and sequencing. In this article, we share expert opinion from diverse geographic regions, to offer guidance for best practice when selecting and managing third-line treatment for mCRC. Various factors, including performance status, age, and tumor sidedness, can be used to guide treatment selection. Biomarkers, such as RAS, BRAF, and microsatellite instability, can be useful for treatment stratification. Management of adverse events, to maintain quality of life, is a key consideration and is crucial to best practice in this setting. Common toxicities associated with third-line treatments are hand-foot skin reaction, fatigue, diarrhea, and cytopenias. Patients who receive third-line and later-line treatments should be monitored for these events, especially during the first 2 cycles. Dose modifications can also be used to manage toxicities and to minimize the effect on quality of life, while maximizing treatment benefit. Clinical trials of emerging agents, new treatment combinations, and novel therapies continue the efforts to improve outcomes for patients with mCRC. Sharing expert opinions on best practice for treatment selection and management can ultimately improve outcomes for patients with mCRC.

Population differences in warfarin dosing requirement have been reported; however, unlike the pharmacokinetics (PK) of warfarin, the quantitative influences of pharmacodynamic (PD) factors on the anticoagulation response to warfarin in different ethnic populations are totally unknown. Using population PK/PD analysis, we attempted to identify predictors of S-warfarin clearance [CL(S)] and half maximal effective concentration (EC50) to quantify racial differences in both PK and PD parameters, and to assess the contribution of these parameters to the international normalized ratio (INR) and over-anticoagulation response (INR ≥ 4) in a cohort of 309 White, Asian and African American patients. Similar to our previous findings, the median CL(S) was 30% lower in African American patients than Asian and White patients (169 vs. 243 and 234 mL/h, p A) factors, as well as African American ethnicity. In all three racial groups, genetic predictors of INR appeared to have greater influence than demographic/clinical predictors. Both CL(S) and EC50 contributed to the over-anticoagulation response to warfarin. Patients having VKORC1 −1639 G>A and/or factors associated with reduced CYP2C9 activity were more likely to have an INR ≥ 4. Although there were contrasting racial differences in CL(S) and EC50 that impacted on the INR, the racial difference in EC50 was greater than that for CL(S), thus explaining the higher warfarin requirement for African American patients.

Bile acids are endogenous ligands of nuclear receptors pregnane X (PXR) and farnesoid X (FXR). PXR and FXR regulate pathways that are impaired in inflammatory bowel disease (IBD). Decreases in PXR and FXR activity are documented in IBD; however reasons for this are unknown. We aimed to assess the effect of Crohn’s disease (CD) on the plasma bile acid composition in vivo and the resultant impact on PXR and FXR activation. A cross-sectional study evaluated the plasma concentrations of 12 bile acids in addition to 4β-hydroxycholesterol (4βOHC), an in vivo probe of the PXR target-gene cytochrome 3A4 (CYP3A4) and the FXR target-gene, fibroblast growth factor (FGF) 19 in individuals with (n = 74) and without (n = 71) CD. An in vitro model was used to assess the impact of CD-specific changes in the plasma bile acid composition on PXR and FXR activation. Decreases in glycochenodeoxycholic acid, taurocholic acid and lithocholic acid were seen in CD with increases in glycodeoxycholic acid and glycocholic acid relative to the total plasma bile acid profile. In vitro, increasing concentrations of bile acids applied in the same ratio as seen in the study cohorts resulted in decreased activation of both PXR and FXR in the CD model. In vivo, plasma 4βOHC (CD = 18.68 ng/ml ± 13.02 ng/ml, non-CD = 46.38 ng/ml ± 40.70 ng/ml, p ≤ 0.0001) and FGF19 (CD = 0.276 pg/L ± 0.189 pg/L, non-CD = 0.485 pg/L ± 0.42 pg/L, p = 0.0002) concentrations were lower in CD versus controls. Ultimately, CD-specific changes in the plasma bile acid composition lead to reduced activation of FXR and PXR target genes in vitro and in vivo.

Background The threshold concentration of infliximab during maintenance therapy has not been well-defined in relation to histologic remission. The aim of the study is to dentify the maintenance-phase infliximab concentration associated with histologic remission in inflammatory bowel disease patients (IBD). Methods A prospective cohort study was carried out in 104 IBD patients seen at a tertiary care centre in London, Canada. Infliximab trough concentrations were collected during the maintenance phase of treatment and compared between participants with and without evidence of histologic remission. Participants were additionally evaluated for sustained histologic remission, and relapse to active disease. Results Participants in histologic remission attained higher mean concentrations of infliximab during the maintenance phase (10.34 ± 0.69 μg/ml) compared to those with persistent disease activity (6.23 ± 0.67 μg/ml, p-value Conclusion Maintenance-phase infliximab trough concentrations greater than 8 μg/ml, which is higher than the currently recommended target concentration, are highly associated with histologic remission and sustained histologic remission.

The farnesoid X receptor (FXR) is implicated in Crohn's disease (CD) pathogenesis. It is unclear how genetic variation in FXR impacts CD severity versus genetic variation in nuclear receptors such as pregnane X receptor (PXR) and the multi-drug resistance protein 1 (MDR1, ABCB1). To evaluate FXR-1G > T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism. A retrospective study (n = 542) was conducted in a Canadian cohort of CD patients. Genotypic analysis (FXR-1G > T, MDR1 3435C > T and PXR -25385C > T) as well as determination of the FXR downstream product, fibroblast growth factor (FGF) 19 was performed. Primary outcomes included risk and time to first CD-related surgery. The effect of estrogen on wild type and variant FXR activity was assessed in HepG2 cells. The FXR-1GT genotype was associated with the risk of (odds ratio, OR = 3.34, 95% CI = 1.58–7.05, p = 0.002) and earlier progression to surgery (hazard ratio, HR = 3.00, 95% CI = 1.86–4.83, p FXR-1GT genotype had the greatest risk of surgery (OR = 14.87 95% CI = 4.22–52.38, p p FXR-1GT polymorphism had a three-fold lower FGF19 plasma concentration versus women with FXR-1GG genotype (p MDR1 and PXR, FXR-1GT genetic variation is associated with earlier and more frequent surgery in women with CD. This may be through ER-mediated attenuation of FXR activation.

We completed a phase 1 dose-escalation trial to evaluate the safety of a dopamine receptor D2 (DRD2) antagonist thioridazine (TDZ), in combination with cytarabine. Thirteen patients 55 years and older with relapsed or refractory acute myeloid leukemia (AML) were enrolled. Oral TDZ was administered at 3 dose levels: 25 mg (n = 6), 50 mg (n = 4), or 100 mg (n = 3) every 6 hours for 21 days. Intermediate-dose cytarabine was administered on days 6 to 10. Dose-limiting toxicities (DLTs) included grade 3 QTc interval prolongation in 1 patient at 25 mg TDZ and neurological events in 2 patients at 100 mg TDZ (gait disturbance, depressed consciousness, and dizziness). At the 50-mg TDZ dose, the sum of circulating DRD2 antagonist levels approached a concentration of 10 μM, a level noted to be selectively active against human AML in vitro. Eleven of 13 patients completed a 5-day lead-in with TDZ, of which 6 received TDZ with hydroxyurea and 5 received TDZ alone. During this period, 8 patients demonstrated a 19% to 55% reduction in blast levels, whereas 3 patients displayed progressive disease. The extent of blast reduction during this 5-day interval was associated with the expression of the putative TDZ target receptor DRD2 on leukemic cells. These preliminary results suggest that DRD2 represents a potential therapeutic target for AML disease. Future studies are required to corroborate these observations, including the use of modified DRD2 antagonists with improved tolerability in AML patients. This trial was registered at www.clinicaltrials.gov as #NCT02096289.

Rosuvastatin is commonly prescribed for the treatment of hypercholesterolemia and hepatic transporter-mediated accumulation in the liver enhances its efficacy. Current guidelines indicate no preference for fed or fasted rosuvastatin administration. We investigated the association between food intake and rosuvastatin disposition in healthy subjects and low-density lipoprotein cholesterol (LDL-C)-lowering effects among patients taking rosuvastatin. We demonstrate that administration with food resulted in a near 40% reduction of rosuvastatin exposure in healthy Asian (n = 12) and Caucasian (n = 11) subjects. Higher rosuvastatin concentrations in Asian subjects also correlated with higher allele frequency of ABCG2 c.421C>A. In mice, a greater rosuvastatin liver:plasma ratio was noted when administered with food. Among rosuvastatin patients (n = 156), there was no difference in dose needed to reach target LDL-C, measured LDL-C, or lathosterol concentrations, when administered in a fed or fasting state. Therefore, taking rosuvastatin with food could reduce systemic concentrations, and subsequent myopathy risk, without compromising LDL-C-lowering benefit.

Background The effect of the timing of stage-2-palliation (S2P) on survival through single ventricle palliation remains unknown. This study investigated the optimal timing of S2P that minimizes pre-S2P attrition and maximizes post-S2P survival. Methods The Congenital Heart Surgeons' Society's critical left ventricular outflow tract obstruction cohort was used. Survival analysis was performed using multiphase parametric hazard analysis. Separate risk factors for death after the Norwood and after S2P were identified. Based on the multivariable models, infants were stratified as low, intermediate, or high risk. Cumulative 2-year, post-Norwood survival was predicted. Optimal timing was determined using conditional survival analysis and plotted as 2-year, post-Norwood survival versus age at S2P. Results A Norwood operation was performed in 534 neonates from 21 institutions. The S2P was performed in 71%, at a median age of 5.1 months (IQR: 4.3 to 6.0), and 22% died after Norwood. By 5 years after S2P, 10% of infants had died. For low- and intermediate-risk infants, performing S2P after age 3 months was associated with 89% ± 3% and 82% ± 3% 2-year survival, respectively. Undergoing an interval cardiac reoperation or moderate-severe right ventricular dysfunction before S2P were high-risk features. Among high-risk infants, 2-year survival was 63% ± 5%, and even lower when S2P was performed before age 6 months. Conclusions Performing S2P after age 3 months may optimize survival of low- and intermediate-risk infants. High-risk infants are unlikely to complete three-stage palliation, and early S2P may increase their risk of mortality. We infer that early referral for cardiac transplantation may increase their chance of survival.

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

Introduction: Statins are beneficial for both primary and secondary prevention of cardiovascular disease in many patients at elevated risk. However, selection of patients most likely to respond and least likely to have adverse effects can benefit from refinement. While pharmacogenomic aspects of statins have been thoroughly evaluated, as yet there has been no major impact on patient care, although there is great potential that a precision medicine approach might one day enhance patient care.Areas covered: This paper provides a brief overview of genetic variants that influence statin responsiveness, together with newer information on genetic risk scores that combine numerous common DNA variants into a stronger prediction of cardiovascular risk reduction from statins. We also discuss a pharmacokinetic-based approach to aid in prediction and prevention of statin adverse effects.Expert commentary: While individual genetic variants appear to have statistically significant effects on lipid lowering by s...

Organic anion-transporting polypeptides (OATPs) are membrane proteins that mediate cellular uptake of structurally diverse endogenous and exogenous compounds, including bile salts, thyroid and sex hormones, pharmacological agents, and toxins. Roles of OATPs in human liver are well established. Our recent report suggested the presence of the hepatic transporter OATP1B3 in human β cells. The aim of this study was to better characterize cellular localization and interindividual variation in OATP1B3 expression in human adult islets as a function of age, sex, and pancreatic disease, and to assess the expression of other OATPs. High transcript levels of OATP1B3, OATP2B1, OATP1A2, but not OATP1B1 were observed in isolated human adult islets. While OATP1B3 protein expression was variable, the carrier co-localized more frequently with glucagon-positive α cells than insulin-positive β cells in islets of normal pancreatic tissues from ten subjects using dual immunostaining. Moreover, OATP1B3 co-staining with endocrine cells was two- to three-fold higher in older (≥60 years) than younger (years) subjects. In comparison, in a subset of three individuals, OATP2B1 was primarily found in β cells, suggesting a distinct expression pattern for OATP1B3 and OATP2B1 in islets. Abundant OATP1B3 staining was also observed in islet as well as ductal cells of diseased tissues of patients with pancreatitis or pancreatic adenocarcinoma. Considering the abundance of key OATP carriers in β and α cells, potential implications of OATP transport in islet cell function may be suggested. Future studies are needed to gain insights into their specific endocrine roles as well as pharmacological relevance.

Background Crohn’s disease (CD) is an immune-mediated inflammatory bowel disease defined by episodes of intestinal inflammation. There is now an increasing appreciation of the bile acid-sensing nuclear receptor, FXR, as an important regulator of intestinal inflammation, intestinal permeability and response to bacterial overgrowth. Many of these processes are dysregulated in CD. It is unclear how genetic variation in FXR impacts on CD severity. FXR deficiency is rare. Loss of function mutations in FXR as contributors to CD are unlikely; however, partial loss of function of FXR may contribute to CD progression or severity. Our group demonstrated that FXR-1G>T, a SNV adjacent to the ATG start codon, is linked to reduced transactivation of FXR gene targets. We hypothesized that changes in the intestinal barrier as a result of reduced FXR expression among those who harbor the FXR-1T allele are more likely to exhibit a severe CD phenotype compared to G (reference) allele carriers, and thereby experience a more rapid progression to surgery. Alterations in FXR activity may in part be secondary to genetic variation in the FXR gene. Aims To evaluate FXR-1G>T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism. Methods A retrospective study (n=542) was conducted in a Canadian cohort of CD patients. Blood samples were obtained for genotypic analysis (FXR-1G>T), as well as determination of the FXR downstream product, fibroblast growth factor (FGF) 19. Primary outcomes included risk and time to first CD-related surgery. To better elucidate a potential molecular basis for the observed effect of FXR-1G>T genotype on CD prognosis (more frequent and early surgery) in female CD patients, we explored a connection between the estrogen receptor (ER)-mediated pathway and genetic variation in FXR using a cell-based model. . Results The FXR-1GT genotype was associated with the risk of (odds ratio, OR=3.34, 95%CI=1.58–7.05, p=0.002) and early progression to surgery (hazard ratio, HR=3.00, 95%CI=1.86–4.83, p Conclusions FXR-1GT is deleterious to women with CD through ER-mediated attenuation of FXR activation. Female CD FXR-1GT carriers should be considered for more aggressive medical management. Funding Agencies CAG, CCC, CIHR

Cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) have broad substrate overlap and are involved in the metabolism and transport of nearly 50% of currently prescribed medications. In the intestine, CYP3A4 and P-gp are coexpressed in the enterocytes at the intestinal villous tip and act in a coordinated manner to limit drug and xenobiotic oral bioavailability prior to further metabolism and disposition in the liver. Crohn's disease (CD), a form of inflammatory bowel disease, introduces a transmural intestinal insult that disrupts the intestinal barrier function; it therefore has the potential to affect intestinal drug metabolism and transport. We hypothesized that individuals with CD have reduced intestinal expression of CYP3A4 and P-gp. We obtained intestinal biopsy samples from individuals with and without CD and quantified the expression of CYP3A4 and P-gp. When we carried out Western analysis for protein expression, we observed a significant reduction in ileal (45% decrease) and colonic (78% decrease) CYP3A4 protein expression in subjects with CD compared with those without. Similarly, an 85% reduction in colonic P-gp protein expression was seen in the CD patients. Our data highlight important and novel findings pertaining to CD-associated changes to the intestinal expression of CYP3A4 and P-gp that are of relevance to better predict substrate drug dosing for patients with CD.

5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas.

Background The interleukin-6 family cytokine, oncostatin-M (OSM) has been associated with a lack of remission to tumor necrosis factor-α antagonists (anti-TNFs) in small cohorts of patients with inflammatory bowel disease (IBD). We aimed to further evaluate the association between plasma OSM concentrations and response to anti-TNFs (infliximab and adalimumab) in addition to other clinical outcomes in both ulcerative colitis (UC) and Crohn’s disease (CD). Methods A retrospective cohort study was carried out in patients with IBD with a history of anti-TNF exposure. Blood samples, collected prior to anti-TNF exposure, were analyzed by enzyme-linked immunosorbent assay for the presence and quantity of OSM. The primary outcome evaluated was clinical remission at 1-year based on the Harvey Bradshaw Index (HBI, remission, HBI Results One hundred and fourteen patients with IBD (CD, n=73; UC, n=40) seen at a tertiary care centre in London, Ontario Canada, were included in the analyses. Patients received one of infliximab (n=61) or adalimumab (n=53). For those with UC achieving clinical remission at 1-year (n=24), the mean OSM concentration was 84.5±119.7pg/ml versus those not achieving clinical remission (n=16) where the mean OSM concentration was 1064.0±958.8pg/ml (p A threshold OSM concentration of 168.7pg/ml in CD and 233.6pg/ml in UC separated those who achieved clinical remission at 1-year on an anti-TNF from those who did not (CD: area under the receiver operator characteristic curve, AUROC=0.880, 95%CI=0.79-0.96, p In CD, participants with a plasma OSM concentration above the threshold concentration of 168.7pg/ml, were more likely to discontinue their anti-TNF at 1-year (p Conclusion OSM plasma concentrations were associated with response to anti-TNFs at 1-year in IBD. A threshold OSM concentration of 168.7pg/ml distinguished patients with CD at-risk of poor clinical outcomes.

The organic anion-transporting polypeptides represent an important family of drug uptake transporters that mediate the cellular uptake of a broad range of substrates including numerous drugs. Doxorubicin is a highly efficacious and well-established anthracycline chemotherapeutic agent commonly used in the treatment of a wide range of cancers. Although doxorubicin is a known substrate for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), significantly less is known regarding its interactions with drug uptake transporters. Here, we investigated the role of organic anion transporting polypeptide (OATP) transporters to the disposition of doxorubicin. A recombinant vaccinia-based method for expressing uptake transporters in HeLa cells revealed that OATP1A2, but not OATP1B1 or OATP1B3, and the rat ortholog Oatp1a4 were capable of significant doxorubicin uptake. Interestingly, transwell assays using Madin-Darby canine kidney II cell line cells stably expressing specific uptake and/or efflux transporters revealed that OATP1B1, OATP1B3, and OATP1A2, either alone or in combination with MDR1, significantly transported doxorubicin. An assessment of polymorphisms in SLCO1A2 revealed that four variants were associated with significantly impaired doxorubicin transport in vitro. In vivo doxorubicin disposition studies revealed that doxorubicin plasma area under the curve was significantly higher (1.7-fold) in Slco1a/1b-/- versus wild-type mice. The liver-to-plasma ratio of doxorubicin was significantly decreased (2.3-fold) in Slco1a/1b2-/- mice and clearance was reduced by 40% compared with wild-type mice, suggesting Oatp1b transporters are important for doxorubicin hepatic uptake. In conclusion, we demonstrate important roles for OATP1A/1B in transporter mediated uptake and disposition of doxorubicin.

Aromatase inhibitors (AIs) are routinely used for the adjuvant treatment of women with hormone receptor-positive early breast cancer. AIs are widely prescribed in the postmenopausal setting, as they are effective at preventing recurrence. However, their use is complicated by significant adverse effects, particularly arthralgia, noted in up to 50% of treated patients, and thereby affects quality of life and AI compliance. The mechanism by which AIs cause arthralgia is largely unknown, although there is a growing body of literature which suggests that there may be multiple intersecting mechanisms. Areas covered: This review describes the evidence for the mechanistic basis of AI arthralgia as well as potential pathways that could contribute to the development of AI associated arthralgia. Expert opinion: Interplay of multiple factors, such as interpatient variability in AI metabolism, possibly related to pharmacogenetic factors, the sudden decline of estrogen synthesis, vitamin D status, as well as upregulation of cytokines and inflammation pathways may precipitate or exacerbate muscle and joint pain are linked during AI therapy. However, much more research is needed in this area given the frequency and severity of AI-associated arthralgia.

Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 μM; interquartile range [IQR]: 12.82–32.70 μM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06–1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04–2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12–1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.

Purpose of review This article evaluates the link between trimethylamine-N-oxide (TMAO) and bile acids and the consequent impact on the development of atherosclerosis. Recent findings Elevation in plasma TMAO concentrations is associated with an increased risk of cardiovascular disease in many different patient cohorts. In addition to the recently identified direct effects of TMAO on the development of atherosclerosis, other components involved in TMAO metabolism may also have an impact. Furthermore, the relationship between TMAO and bile acid regulation is emerging as a possible mediator of atherosclerosis. Summary Studies that are emerging highlight the mechanistic relationship of TMAO to the development atherosclerosis in addition to its role as disease biomarker. The interplay between TMAO and bile acid metabolism mediated through multiple factors, such as the gut microbiome, farnesoid X receptor signaling, and flavin monooxygenase 3 activity may help identify another pathway by which atherosclerosis occurs. In this review, we discuss the most recent data regarding atherosclerosis, TMAO, and bile acid metabolism.

Ticagrelor has shown superiority compared with clopidogrel in reducing cardiovascular events [(1)][1]. Although some of the clinical benefits of ticagrelor may simply reflect its potency in inhibiting platelet aggregation, the action of this drug on blood vessels may also play a role. Ticagrelor

Organic anion transporting polypeptide 2B1 (OATP2B1) is a widely expressed membrane transporter with diverse substrate specificity. In vitro and clinical studies suggest a role for intestinal OATP2B1 in the oral absorption of medications. Moreover, OATP2B1 is highly expressed in hepatocytes where it is thought to promote liver drug clearance. But until now, a shortcoming of studies implicating OATP2B1 in drug disposition has been a lack of in vivo models. Here, we report the development of a mouse model with targeted, global disruption of the Slco2b1 gene (KO) for examining the disposition of two confirmed mOATP2B1 substrates, namely fexofenadine and rosuvastatin. The plasma pharmacokinetics of intravenously administered fexofenadine was not different between KO and wildtype (WT) mice. However, after oral fexofenadine administration, KO mice had 70% and 41% lower maximal plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-last) than WT mice, respectively. In WT mice, co-administration of fexofenadine with grapefruit juice (GFJ) or apple juice (AJ) was associated with reduced Cmax by 80% and 88%, respectively, while the AUC0-last was lower by 35% and 70%, respectively. In KO mice, AJ co-administration reduced oral fexofenadine Cmax and AUC0-last by 67% and 59%, respectively, while GFJ had no effects. Intravenous and oral rosuvastatin pharmacokinetics were similar among WT and KO mice. We conclude that intestinal OATP2B1 is a determinant of oral fexofenadine absorption, as well as a target for fruit juice interactions. OATP2B1 does not significantly influence rosuvastatin disposition in mice. SIGNIFICANCE STATEMENT A novel mouse model with targeted disruption of the Slco2b1 gene revealed that OATP2B1 is a determinant of the oral absorption but not systemic disposition of fexofenadine, as well as a target of fruit juice interactions. Rosuvastatin oral and intravenous pharmacokinetics were not dependent on OATP2B1. These findings support the utility of the Slco2b1 knockout mice model for defining mechanisms of drug disposition at the intersection of in vitro and clinical pharmacology.

In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than SLC6A3 wildtype. Whether SLC6A3 genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number innervated by the SNc. We found that dopaminergic therapy worsened encoding of abstract images in 9R carriers only. In contrast, dopaminergic therapy improved recall of abstract images in all PD patients, irrespective of SLC6A3 genotype. Our findings suggest that 9R-carrier PD patients are more predisposed to dopamine overdose and medication-induced impairment of cognitive functions mediated by VTA-innervated brain regions. Interestingly, PD patients without the 9R polymorphism did not show such an impairment. SLC6A3 genotype does not modulate the dopaminergic therapy-induced improvement of functions mediated by SNc-innervated regions in PD patients.

The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia. We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms. More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P