How to handle a delayed or missed dose of edoxaban in patients with non-valvular atrial fibrillation? A model-informed remedial strategy.

AIMS: Edoxaban is a non-vitamin K antagonist oral anticoagulant (NOAC) widely used for the long-term prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). Adherence to NOAC therapy has been unsatisfactory and decreases over time. Remedial strategies are currently used to address the non-adherence events. Current recommendations, however, are generic and not well supported by evidence. The aim of this study was to explore appropriate remedial dosing regimens for non-adherent edoxaban-treated NVAF patients through Monte Carlo simulation. METHODS: Six regimens were compared with the current recommendations of the European Heart Rhythm Association (EHRA) guide based on total deviation time. Both edoxaban plasma concentration and intrinsic Factor Xa activity were considered. Monte Carlo simulations were performed using RxODE based on a published population pharmacokinetic/pharmacodynamic (PK/PD) model. RESULTS: The proposed remedial strategies were different than the EHRA recommendations and were related to the delay time. However, it was found that the missed dose can be administered immediately if the delay time is within 11 h. When the delay is between 12 and 19 h, a half dose followed by a regular dosing schedule is recommended. When the delay time exceeds 19 h, a full dose followed by a half dose is preferred. CONCLUSION: PK/PD modelling and simulation are effective in developing and evaluating the remedial strategies of edoxaban, which can help maximise its therapeutic effect.

Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial.

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.

Effect of ultrasound-assisted EDTA and citric acid washing on heavy metal removal, residual heavy metal mobility, and sewage sludge quality.

We investigated the effects of ultrasound-assisted ethylenediaminetetraacetic acid (EDTA) and citric acid (CA) washing on heavy metal (HM) removal, residual HM mobility, and sewage sludge quality. EDTA and CA washing of sewage sludge successfully reduced the total concentration of HMs after one round of washing, but the mobility of residual HMs increased significantly. The eluate had a high concentration of HMs and nutrients (nitrogen, phosphorus, potassium, and total organic carbon), although the nutritional content of the sludge remained high. The three-phase ratio of the sludge after six rounds of washing by CA was closest to the ideal three-phase ratio, and the degree of influence on the physical structure of the soil after a land application was reduced, according to the fluctuation of generalized soil structure index (GSSI) and soil three-phase structure distance (STPSD) values. The results indicate that CA as an environmental-friendly washing agent can be the superior choice for sludge HM washing; single washing of sewage sludge may increase the mobility of residual HMs, so multiple washings should be considered for land application of sludge.

Risk factors for high-dose methotrexate associated toxicities in patients with primary central nervous system lymphoma.

WHAT IS KNOWN AND OBJECTIVE: Methotrexate (MTX) is an antimetabolic antitumor drug with high individual differences and may lead to severe toxicities in a considerable number of patients. This study aimed to explore the factors influencing major adverse events in patients with primary central nervous system lymphoma treated with high-dose MTX (HD-MTX), which could be useful in clinical practice. METHODS: Fifty-four patients who received 175 courses of MTX at 3-8 g/m2 between January 2015 and December 2016 were enrolled in this study. We assessed the association between clinical characteristics, MTX pharmacokinetics, MTX delayed elimination, and adverse events, including hepatotoxicity, acute kidney injury (AKI), and myelosuppression. RESULTS AND DISCUSSION: A total of 124 adverse events occurred after MTX infusion. Using independent sample t-tests, we found that patients with myelosuppression had higher MTX area under the concentration-time curve up to 48 h after infusion (AUC0-48h ) (p = 0.001) and MTX peak concentration (Cmax ) (p = 0.002). MTX concentrations at 48 and 72 h were higher in patients with AKI than in those without (p = 0.034 and p = 0.041, respectively). Using chi-square tests, we found that AKI was correlated with MTX elimination at either 48 h or 72 h (22.1% vs. 8.2%, p = 0.010). By multivariate logistic regression model, our results showed that baseline level of ALT and WBC had a significant effect on hepatotoxicity (OR = 1.079, 95% CI 1.044-1.116, p = 6.9 × 10-6 ; OR = 0.808, 95% CI 0.711-0.917, p = 0.001, respectively). Patient's age, eGFR before MTX infusion, and co-administration of vindesine had a significant effect on AKI (OR = 0.960, 95% CI 0.935-0.986, p = 0.003; OR = 1.009, 95% CI 1.001-1.017, p = 0.034; OR = 5.463, 95% CI 1.793-16.646, p = 0.003, respectively). LDH and Co-administration of vindesine had a significant effect on myelosuppression (OR = 0.985, 95% CI 0.972-0.998, p = 0.025; OR = 3.070, 95% CI 1.032-9.133, p = 0.044). WHAT IS NEW AND CONCLUSION: Our study demonstrated that co-administration of VDS, eGFR before MTX infusion, and the baseline index of laboratory examinations including ALT, WBC, LDH may be useful biomarkers for predicting MTX-induced toxicities.

Deep Phenotyping on Electronic Health Records Facilitates Genetic Diagnosis by Clinical Exomes.

Integration of detailed phenotype information with genetic data is well established to facilitate accurate diagnosis of hereditary disorders. As a rich source of phenotype information, electronic health records (EHRs) promise to empower diagnostic variant interpretation. However, how to accurately and efficiently extract phenotypes from heterogeneous EHR narratives remains a challenge. Here, we present EHR-Phenolyzer, a high-throughput EHR framework for extracting and analyzing phenotypes. EHR-Phenolyzer extracts and normalizes Human Phenotype Ontology (HPO) concepts from EHR narratives and then prioritizes genes with causal variants on the basis of the HPO-coded phenotype manifestations. We assessed EHR-Phenolyzer on 28 pediatric individuals with confirmed diagnoses of monogenic diseases and found that the genes with causal variants were ranked among the top 100 genes selected by EHR-Phenolyzer for 16/28 individuals (p < 2.2 × 10-16), supporting the value of phenotype-driven gene prioritization in diagnostic sequence interpretation. To assess the generalizability, we replicated this finding on an independent EHR dataset of ten individuals with a positive diagnosis from a different institution. We then assessed the broader utility by examining two additional EHR datasets, including 31 individuals who were suspected of having a Mendelian disease and underwent different types of genetic testing and 20 individuals with positive diagnoses of specific Mendelian etiologies of chronic kidney disease from exome sequencing. Finally, through several retrospective case studies, we demonstrated how combined analyses of genotype data and deep phenotype data from EHRs can expedite genetic diagnoses. In summary, EHR-Phenolyzer leverages EHR narratives to automate phenotype-driven analysis of clinical exomes or genomes, facilitating the broader implementation of genomic medicine.

Population pharmacokinetics of unbound valproic acid in pediatric epilepsy patients in China: a protein binding model.

PURPOSE: The purpose of this study was to establish a protein binding model of unbound valproic acid (VPA) based on Chinese pediatric patients with epilepsy and provide a reference for clinical medication. METHODS: A total of 313 patients were included and both their total and unbound VPA concentrations (375 pairs of concentrations) were measured. NONMEM software was used for population pharmacokinetic modeling. The stepwise method was used to screen the potential covariates. Goodness-of-fit plot, bootstrap, and visual predictive check were used for model evaluation. In addition, dose recommendations for typical patients aged 0 to 16 years were proposed by Monte Carlo simulations. RESULTS: A one-compartment model of first-order absorption and first-order elimination was used to describe the pharmacokinetic characteristics of unbound VPA, and the linear non-saturable binding equation was introduced to describe the protein binding. Body weight, age-based maturation, and co-medicated with lamotrigine could affect the CL/F of unbound and bound VPA. Model evaluation showed satisfactory robustness of the final model. The dosing regimens for children aged 0 to 16 years were proposed based on the final established model. CONCLUSION: We developed a population pharmacokinetic model of unbound and bound VPA that took account of protein binding. The VPA dosing regimen in pediatric patients with epilepsy needs to be optimized by the body weight, age, and co-medications.

Doc2Hpo: a web application for efficient and accurate HPO concept curation.

We present Doc2Hpo, an interactive web application that enables interactive and efficient phenotype concept curation from clinical text with automated concept normalization using the Human Phenotype Ontology (HPO). Users can edit the HPO concepts automatically extracted by Doc2Hpo in real time, and export the extracted HPO concepts into gene prioritization tools. Our evaluation showed that Doc2Hpo significantly reduced manual effort while achieving high accuracy in HPO concept curation. Doc2Hpo is freely available at https://impact2.dbmi.columbia.edu/doc2hpo/. The source code is available at https://github.com/stormliucong/doc2hpo for local installation for protected health data.

Ensembles of natural language processing systems for portable phenotyping solutions.

BACKGROUND: Manually curating standardized phenotypic concepts such as Human Phenotype Ontology (HPO) terms from narrative text in electronic health records (EHRs) is time consuming and error prone. Natural language processing (NLP) techniques can facilitate automated phenotype extraction and thus improve the efficiency of curating clinical phenotypes from clinical texts. While individual NLP systems can perform well for a single cohort, an ensemble-based method might shed light on increasing the portability of NLP pipelines across different cohorts. METHODS: We compared four NLP systems, MetaMapLite, MedLEE, ClinPhen and cTAKES, and four ensemble techniques, including intersection, union, majority-voting and machine learning, for extracting generic phenotypic concepts. We addressed two important research questions regarding automated phenotype recognition. First, we evaluated the performance of different approaches in identifying generic phenotypic concepts. Second, we compared the performance of different methods to identify patient-specific phenotypic concepts. To better quantify the effects caused by concept granularity differences on performance, we developed a novel evaluation metric that considered concept hierarchies and frequencies. Each of the approaches was evaluated on a gold standard set of clinical documents annotated by clinical experts. One dataset containing 1,609 concepts derived from 50 clinical notes from two different institutions was used in both evaluations, and an additional dataset of 608 concepts derived from 50 case report abstracts obtained from PubMed was used for evaluation of identifying generic phenotypic concepts only. RESULTS: For generic phenotypic concept recognition, the top three performers in the NYP/CUIMC dataset are union ensemble (F1, 0.634), training-based ensemble (F1, 0.632), and majority vote-based ensemble (F1, 0.622). In the Mayo dataset, the top three are majority vote-based ensemble (F1, 0.642), cTAKES (F1, 0.615), and MedLEE (F1, 0.559). In the PubMed dataset, the top three are majority vote-based ensemble (F1, 0.719), training-based (F1, 0.696) and MetaMapLite (F1, 0.694). For identifying patient specific phenotypes, the top three performers in the NYP/CUIMC dataset are majority vote-based ensemble (F1, 0.610), MedLEE (F1, 0.609), and training-based ensemble (F1, 0.585). In the Mayo dataset, the top three are majority vote-based ensemble (F1, 0.604), cTAKES (F1, 0.531) and MedLEE (F1, 0.527). CONCLUSIONS: Our study demonstrates that ensembles of natural language processing can improve both generic phenotypic concept recognition and patient specific phenotypic concept identification over individual systems. Among the individual NLP systems, each individual system performed best when they were applied in the dataset that they were primary designed for. However, combining multiple NLP systems to create an ensemble can generally improve the performance. Specifically, the ensemble can increase the results reproducibility across different cohorts and tasks, and thus provide a more portable phenotyping solution compared to individual NLP systems.

Porphobilinogen deaminase HEMC interacts with the PPR-protein AtECB2 for chloroplast RNA editing.

The pentatricopeptide repeat-DYW protein AtECB2 affects plastid RNA editing at seven sites, including accD-794, accD-1568, ndhF-290, ndhG-50, petL-5, rpoA-200 and rpoC1-488. To understand the mechanism of its involvement in RNA editing, a transgenic line was constructed with AtECB2 fused to a 4xMYC tag that could complement the atecb2 phenotype. RNA immunoprecipitation analysis indicated that AtECB2 is associated with the transcripts of accD, ndhF, ndhG and petL. Co-immunoprecipitation and mass spectrometry experiments showed that multiple organelle RNA editing factor 2 (MORF2) and porphobilinogen deaminase HEMC are associated with AtECB2. Biochemical analysis showed that AtECB2 directly interacts with HEMC through its E domain, while HEMC interacts with MORF8/RIP1. Deletion analysis showed that the E domain is essential for RNA editing. The hemc-1 mutant showed an albino and seedling-lethal phenotype. Of the seven editing sites affected in atecb2, the editing of accD-794 and ndhF-290 was also reduced in hemc-1. RNA immunoprecipitation analysis suggested that HEMC is associated with the editing sites of ndhF transcripts. These results showed that both HEMC and multiple organellar RNA editing factor (MORF) proteins are associated with AtECB2 for RNA editing in plastids.

PPR protein PDM1/SEL1 is involved in RNA editing and splicing of plastid genes in Arabidopsis thaliana.

After transcription, most chloroplast precursor RNAs undergo further post-transcriptional processing including cleavage, editing, and splicing. Previous investigation has shown that the cleavage of the rpoA transcript and most editing sites, including accD-1, are defective in the knockout mutant of PDM1/SEL1, a PLS-type PPR protein, and that PDM1 is associated with the rpoA transcript. In this work, we found that the splicing of group II introns in trnK and ndhA is also affected in pdm1. Co-immunoprecipitation mass spectrometry experiments were performed to identify proteins that are associated with PDM1. We obtained 126 non-redundant proteins, of which MORF9 was reported to be involved in RNA editing in chloroplast. Yeast two-hybrid assays showed that PDM1 interacts directly with MORF9, MORF2, and MORF8. RNA immunoprecipitation showed that PDM1 associates with the transcripts of trnK and ndhA, as well as accD-1, suggesting that PDM1 is involved in RNA editing and splicing. Therefore, PDM1 is an important protein for post-transcriptional regulation in chloroplast.

Hyperthermic intraperitoneal chemotherapy plus simultaneous versus staged cytoreductive surgery for gastric cancer with occult peritoneal metastasis.

BACKGROUND: Our aim is to evaluate the safety and efficacy of two treatment strategies, hyperthermic intraperitoneal chemotherapy (HIPEC) plus simultaneous versus staged cytoreductive surgery (CRS) in patients with occult peritoneal metastasis of gastric cancer (GC). METHODS: We retrospectively reviewed 26 GC patients who were potential curatively resectable by pre-operative evaluation and found occult peritoneal metastasis by diagnostic laparoscopy. Patients were treated by HIPEC plus either simultaneous CRS (CRS+HIPEC group, n = 11) or staged CRS after systematic chemotherapy (HIPEC+Chemo+CRS group, n = 15). RESULTS: There is no mortality observed in both groups. The treatment complications in two group is comparable (P = 0.683), with 26.7% (4/15) in HIPEC+Chemo+CRS group, and 36.4% (4/11) in CRS+HIPEC group, respectively. The compliance of patients undergoing subsequent chemotherapy is higher in HIPEC+Chemo+CRS group (93.3%, 14/15) than that of CRS+HIPEC group (45.5%, 5/11) (P = 0.021). The mean interval time between CRS and first post-CRS systematic chemotherapy were 42.0 ± 12.0 days in HIPEC+Chemo+CRS group versus 69.8 ± 36.3 in CRS+HIPEC group (P = 0.163), respectively. The median OS in the HIPEC+Chemo+CRS group was 25.0 months, while 28.2 months in the CRS+HIPEC group (P = 0.738). CONCLUSION: For resectable GC patients with laparoscopic findings of occult peritoneal metastasis, HIPEC plus staged CRS is with better tolerance and compliance than simultaneous CRS.

Donor and recipient polymorphisms of MAPK signaling pathway genes influence post-transplant liver function in Chinese liver transplant patients taking tacrolimus.

Tacrolimus (TAC) is an immunosuppressive drug that is widely used for patients who underwent liver transplantation. In addition to inhibiting the action of calcineurin, TAC also exerts its immunosuppressive effects by interfering with mitogen activated protein kinase (MAPK) pathway. In this study, we investigated the impact of both recipient and donor genetic polymorphisms of MAPK kinase kinase (MAP3K) genes on clinical events in Han Chinese liver transplantation recipients taking TAC. Fifty-seven tag SNPs of 11 genes (MEKK1, MEKK2, MEKK4, MLK1, MLK3, ASK1, TAO1, TAO2, Tpl2, TAK1 and ZAK1) in the MAPK pathway were detected by MALDI-TOF MS assay in 175 TAC-treated liver transplant recipients. The associations of SNPs with incidence of acute rejection, TAC-induced acute nephrotoxicity, and post-transplantation liver and kidney function were explored using Kaplan-Meier survival analysis, Cox-proportional hazard model and linear mixed model, respectively. For the sites significantly associated with clinical events, the dual-luciferase reporter gene system was used to perform preliminary function verification. The results showed that (1) Donor-recipient combinational (D-R) MEKK1 rs62355944 and D-R MLK1 rs8006424 genotypes were significant influence factors of post-transplantation γ-glutamyl transpeptidase (GGT) level (P < 0.0001); (2) D-R MLK1 rs8006424 genotypes were found to significantly affect the alkaline phosphatase (ALP) level after transplantation (P < 0.0001). The results of the dual luciferase reporter gene system demonstrated that the luciferase activity of the pGL3-rs8006424A was significantly higher than that of pGL3-rs8006424G (3.47 ± 0.10 vs 2.97 ± 0.08, P = 0.002). Therefore, MEKK1 rs62355944 and MLK1 rs8006424 might serve as biomarkers to predict post-transplant liver function in liver transplant patients.

Germline genetic variations in methotrexate pathway are associated with pharmacokinetics, outcome, and toxicity in patients with primary central nervous system lymphoma.

BACKGROUND: High-dose methotrexate (HD-MTX)-based regimens are the standard treatment for patients with primary central nervous system lymphoma (PCNSL); however, MTX has extensive interpatient variability in pharmacokinetics and clinical outcomes, with genetic variation an important factor involved in the variability in drug response. METHODS: 123 PCNSL patients who received 524 courses of chemotherapy were genotyped for 42 single nucleotide polymorphisms in MTX pathway. The relationship between these polymorphisms and the pharmacokinetics, clinical outcomes, and toxicity of MTX was explored using both univariate and multivariate analyses. RESULTS: We found ABCB1 rs2032582 and GGH rs2305558 were substantially associated with the pharmacokinetics of MTX. Patients with GGH rs2305558 T and ABCB1 rs2032582 non-G allele had a higher Cmax increased by 20.5%, area under the concentration-time curve (AUC0-48h) increased by 19.6% and lower clearance decreased by 19.6%. ABCB1 rs1045642 and rs2032582 might be independent predictors of progression-free survival. Patients with ABCB1 rs1045642 non-A and rs2032582 G allele correlated with higher progression risk of the disease. Furthermore, ATIC rs3821353 was associated with MTX-induced hepatotoxicity (Grade ≥ 2). CONCLUSION: These variants may serve as biomarkers to predict the pharmacokinetics, clinical outcomes, and hepatotoxicity of MTX and contribute to personalized therapy for PCNSL patients.

Is a Lower Dose of Rivaroxaban Required for Asians? A Systematic Review of a Population Pharmacokinetics and Pharmacodynamics Analysis of Rivaroxaban.

Rivaroxaban has been widely used to prevent and treat various thromboembolic diseases for more than a decade. However, whether a lower dose of rivaroxaban is required for Asians is still debatable. This review aimed to explore the potential ethnic difference in pharmacokinetic/pharmacodynamic (PK/PD) characteristics between Asians and Caucasians. A systematic search was conducted and twenty-four studies were identified, of which 10 were conducted on Asian adults, 11 on predominantly Caucasian adults, and 3 on Caucasian pediatrics. The apparent clearance (CL/F) of rivaroxaban in Caucasian adults with non-valvular atrial fibrillation (6.45-7.64 L/h) was about 31-43% higher than that in Asians (4.46-5.98 L/h) taking 10~20 mg rivaroxaban every 24 h. Moreover, there was no obvious difference in CL/F among Japanese, Chinese, Thai, and Irani people. Regarding PK/PD relationship, prothrombin time was linked to rivaroxaban concentration in a linear or near-linear manner, and Factor Xa activity was linked with the Emax model. The exposure-response relationship was comparable between Asians and Caucasians. Renal function has a significant influence on CL/F, and no covariate was recognized for exposure-response relationship. In conclusion, a lower dose of rivaroxaban might be required for Asians, and further studies are warranted to verify this ethnic difference to facilitate optimal dosing regimens.

Sodium-glucose co-transporter-2 inhibitor (SGLT2i) treatment and risk of osteomyelitis: A pharmacovigilance study of the FAERS database.

Background and purpose: Several clinical trials have indicated that the use of canagliflozin increases the risk of lower extremity amputation. Although the US Food and Drug Administration (FDA) has withdrawn its black box warning about amputation risk for canagliflozin, the risk still exists. We sought to estimate the association between hypoglycemic medications, especially sodium-glucose co-transporter-2 inhibitors (SGLT2is), and adverse events (AEs) before the irreversible outcome of amputation as a promising early warning, based on the FDA Adverse Event Reporting System (FAERS) data. Methods: Publicly available FAERS data were analyzed using a reporting odds ratio (ROR) method and validated by a Bayesian confidence propagation neural network (BCPNN) method. The developing trend of the ROR was investigated by a series of calculations based on the accumulation of data in the FAERS database quarter by quarter. Results: Ketoacidosis, infection, peripheral ischemia, renal impairment, and inflammation including osteomyelitis might be more likely to occur among users of SGLT2is, especially canagliflozin. Osteomyelitis and cellulitis are AEs unique to canagliflozin. Among 2,888 osteomyelitis-related reports referring to hypoglycemic medications, 2,333 cases were associated with SGLT2is, with canagliflozin accounting for 2,283 of these cases and generating an ROR value of 360.89 and a lower limit of information component (IC025) of 7.79. No BCPNN-positive signal could be generated for drugs other than insulin and canagliflozin. Reports suggesting that insulin could generate BCPNN-positive signals span from 2004 to 2021, whereas reports with BCPNN-positive signals emerged only since the second quarter (Q2) of 2017, 4 years since the approval of SGLT2is in Q2 of 2013, for canagliflozin and drug groups containing canagliflozin. Conclusion: This data-mining investigation revealed a strong association between canagliflozin treatment and developing osteomyelitis that might be a crucial forewarning to lower extremity amputation. Further studies with updated data are needed to better characterize the risk of osteomyelitis associated with SGLT2is.

Major adverse cardiovascular events associated with testosterone treatment: a pharmacovigilance study of the FAERS database.

Background and purpose: Testosterone is an essential sex hormone in maintaining masculine characteristics, which is prescribed for male hypogonadism as testosterone replacement treatment (TRT). Herein, we investigated long-standing controversies about the association between TRT and major adverse cardiovascular events (MACEs), based on real world adverse event (AE) reports, registered in the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Publicly available FAERS data from 1 January 2004 to 31 December 2022 were retrieved from the Food and Drug Administration (FDA) website. The data mining protocol including the reporting odds ratio (ROR) and the Bayesian confidence propagation neural network (BCPNN) was applied to analyze overreporting caused by risk factors and MACEs, including TRT, morbidities, and ages. The ROR and the BCPNN were also applied to investigate the annually developing trend of pharmacovigilance (PV) signals in the real world, retrospectively. Results: A total of 3,057 cases referring to MACEs, with a median age of 57 years old (yo), were identified from 28,921 cases of testosterone users. MACEs related to PV signals have emerged since 2014, including cardiac death, non-fatal myocardial infarction, and non-fatal stroke. Myocardial infarction (MI) (ROR: 9.46; IC025: 3.08), acute myocardial infarction (AMI) (ROR: 16.20; IC025: 3.72), ischemic cardiomyopathy (ROR: 11.63; IC025: 2.20), and cardiomyopathy (ROR: 5.98; IC025: 1.96) were the most significant signals generated, and weaker signals included cardiac failure acute (ROR: 4.01; IC025: 0.71), cardiac arrest (ROR: 1.88; IC025: 0.56), and ventricular fibrillation (VF) (ROR: 2.38; IC025: 0.38). The time-to-onset (TTO) of MACEs was calculated with a median of 246 days for AMI. Conclusion: For myocardial infarction and cardiomyopathy, TRT statistically tended to increase the risk of MACEs, while for cardiac arrhythmia, cardiac failure, and stroke, TRT demonstrated beneficial effects among the population with morbidities, such as testosterone deficiency (TD), diabetes mellitus (DM), and hypertension. MACEs were rare but led to serious outcomes including significant increase in death and disability. Since 2018, and before 2014, reports referring to TRT associated with MACEs were relatively scarce, which indicated that there might be a considerable number of cases that went unrecorded, due to neglection. Health workers and testosterone users might pay more attention to testosterone-induced MACEs.

Handling Delayed or Missed Dose of Antiseizure Medications: A Model-Informed Individual Remedial Dosing.

BACKGROUND AND OBJECTIVES: Delayed or missed antiseizure medications (ASMs) doses are common during long-term or lifelong antiepilepsy treatment. This study aims to explore optimal individualized remedial dosing regimens for delayed or missed doses of 11 commonly used ASMs. METHODS: To explore remedial dosing regimens, Monte Carlo simulation was used based on previously identified and published population pharmacokinetic models. Six remedial strategies for delayed or missed doses were investigated. The deviation time outside the individual therapeutic range was used to evaluate each remedial regimen. The influences of patients' demographics, concomitant medication, and scheduled dosing intervals on remedial regimens were assessed. RxODE and Shiny in R were used to perform Monte Carlo simulation and recommend individual remedial regimens. RESULTS: The recommended remedial regimens were highly correlated with delayed time, scheduled dosing interval, and half-life of the ASM. Moreover, the optimal remedial regimens for pediatric and adult patients were different. The renal function, along with concomitant medication that affects the clearance of the ASM, may also influence the remedial regimens. A web-based dashboard was developed to provide individualized remedial regimens for the delayed or missed dose, and a user-defined module with all parameters that could be defined flexibly by the user was also built. DISCUSSION: Monte Carlo simulation based on population pharmacokinetic models may provide a rational approach to propose remedial regimens for delayed or missed doses of ASMs in pediatric and adult patients with epilepsy.

Population Pharmacokinetic Modeling Combined With Machine Learning Approach Improved Tacrolimus Trough Concentration Prediction in Chinese Adult Liver Transplant Recipients.

This study aimed to develop and evaluate a population pharmacokinetic (PPK) combined machine learning approach to predict tacrolimus trough concentrations for Chinese adult liver transplant recipients in the early posttransplant period. Tacrolimus trough concentrations were retrospectively collected from routine monitoring records of liver transplant recipients and divided into the training data set (1287 concentrations in 145 recipients) and the test data set (296 concentrations in 36 recipients). A PPK model was first established using NONMEM. Then a machine learning model of Xgboost was adapted to fit the estimated individual pharmacokinetic parameters obtained from the PPK model with Bayesian forecasting. The performance of the final PPK model and Xgboost model was compared in the test data set. In the final PPK model, tacrolimus daily dose, postoperative days, hematocrit, aspartate aminotransferase, and concomitant voriconazole, were identified to significantly influence the clearance. The postoperative days along with hematocrit significantly influence the volume of distribution. In the Xgboost model, the first 5 predictors for predicting the clearance were concomitant with voriconazole, sex, single nucleotide polymorphisms of CYP3A4*1G and CYP3A5*3 in recipients, and tacrolimus daily dose, for the volume of distribution were postoperative days, age, weight, total bilirubin and graft : recipient weight ratio. In the test data set, the Xgboost model showed the minimum median prediction error of tacrolimus concentrations, less than the PPK model with or without Bayesian forecasting. In conclusion, a PPK combined machine learning approach could improve the prediction of tacrolimus concentrations for Chinese adult liver transplant recipients in the early posttransplant period.

Skin cancer signal associated with phosphodiesterase inhibitors: gaining insight through the FDA pharmacovigilance database.

BACKGROUND: Panoramic views of post-marketing safety profiles, such as cancer signal, of phosphodiesterase 5A (PDE5A) inhibitors have yet to be fully evaluated. RESEARCH DESIGN AND METHODS: Data from the FDA Adverse Event Reporting System (FAERS) concerning the timeframe between January 1st, 2004 to 30 June 2022 was analyzed through a disproportionality study to understand the association between sildenafil, tadalafil, and vardenafil and cancer. This association was identified using the Reporting odds ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) approaches. RESULTS: Sildenafil associated ROR values and IC025 ranged from 9.19 (95% CI 7.72-10.94, IC025 2.77) for metastatic malignant melanoma to 132.23 (95% CI 95.49-183.11, IC025 4.69) for malignant melanoma stage II. Tadalafil associated ROR and IC025 ranged from 6.79 (95% CI 5.41-8.54, IC025 2.27) for metastatic malignant melanoma to 180.17 (95% CI 130.11-249.50, IC025 4.89) for malignant melanoma stage II. Vardenafil associated ROR and IC025 ranged from 23.38 (95% CI 15.20-35.96, IC025 2.63) for metastatic malignant melanoma to 245.77 (95% CI 154.42-391.16, IC025 2.10) for malignant melanoma stage III. CONCLUSIONS: This study supports the association between sildenafil, tadalafil, and vardenafil with skin cancer signal in erectile dysfunction (ED) patients.

Individual dose recommendations for drug interaction between tacrolimus and voriconazole in adult liver transplant recipients: A semiphysiologically based population pharmacokinetic modeling approach.

The magnitude of drug-drug interaction between tacrolimus and voriconazole is highly variable, and individually tailoring the tacrolimus dose when concomitantly administered with voriconazole remains difficult. This study aimed to develop a semiphysiologically based population pharmacokinetic (semi-PBPK) model and a web-based dashboard to identify the dynamic inhibition of tacrolimus metabolism caused by voriconazole and provide individual tacrolimus regimens for Chinese adult liver transplant recipients. A total of 264 tacrolimus concentrations and 146 voriconazole concentrations were prospectively collected from 32 transplant recipients. A semi-PBPK model with physiological compartments including the gut wall, portal vein, and liver was developed using the nonlinear mixed-effects modeling software NONMEM (version 7.4). A web-based dashboard was established in R software (version 3.6.1) to recommend the individual tacrolimus regimens when concomitantly administered with voriconazole. The reversible inhibition of tacrolimus metabolism caused by voriconazole was investigated in both the liver and the gut wall. Moreover, voriconazole could highly inhibit the CYP3A activity in the gut wall more than in the liver. BMI and postoperative days were identified as significant covariates on intrinsic intestinal and hepatic clearance of tacrolimus, respectively. Age and postoperative days were identified as significant covariates on the volume of distribution of voriconazole. The individual tacrolimus regimens when concomitantly administered with voriconazole could be recommended in the dashboard (https://tac-vor-ddi.shinyapps.io/shinyapp3/). In conclusion, the semi-PBPK model successfully described the dynamic inhibition process between tacrolimus and voriconazole, and the web-based dashboard could provide individual tacrolimus regimens when concomitantly administered with voriconazole.