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.

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.

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.

A high-performance liquid chromatography-tandem mass spectrometry method for quantification of perampanel in human plasma: Effect of concomitant anti-seizure medications on perampanel concentration in patients with epilepsy.

Perampanel is a first-in-class α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist and a novel anti-seizure medication. It is currently used as adjunctive treatment for partial seizures in patients over 12 years of age. With the increasing clinical application of perampanel, monitoring its concentration under certain clinical conditions is important. This study developed a rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry method to quantify perampanel in human plasma. Protein precipitation with acetonitrile was performed for sample preparation. Perampanel and perampanel-d5 (internal standard) were analyzed under gradient conditions using a C18 column. The mobile phase was composed of 0.1% (v/v) formic acid in water (solvent A) and 0.1% (v/v) formic acid in acetonitrile (solvent B) at a flow rate of 0.4 mL/min. Mass detection was performed using multiple reaction monitoring in the positive ionization mode. The proposed method was validated over a range of 0.5-500 ng/mL for perampanel. The linearity (r2 value) was higher than 0.999, and the linear equation was y = 0.00116x + 0.0116. The accuracy of the low-, middle-, and high-quality control samples was between 103% and 113%, and the intra- and inter-day precisions were below 6.81%. The quality of the proposed method was evaluated in accordance with the US Food and Drug Administration Bioanalytical Method Validation Guidance for Industry. The plasma concentrations of perampanel in 25 patients were successfully determined to be 38.7-577.7 ng/mL using the validated method.

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.

Serious adverse reaction associated with the COVID-19 vaccines of BNT162b2, Ad26.COV2.S, and mRNA-1273: Gaining insight through the VAERS.

Background and purpose: Serious adverse events following immunization (AEFI) associated with the COVID-19 vaccines, including BNT162b2 (Pfizer-BioNTech), Ad26.COV2.S (Janssen), and mRNA-1273 (Moderna), have not yet been fully investigated. This study was designed to evaluate the serious AEFI associated with these three vaccines. Methods: A disproportionality study was performed to analyze data acquired from the Vaccine Adverse Event-Reporting System (VAERS) between 1 January 2010 and 30 April 2021. The reporting odds ratio (ROR) method was used to identify the association between the COVID-19 vaccines BNT162b2, Ad26.COV2.S, and mRNA-1273 and each adverse event reported. Moreover, the ratio of the ROR value to the 95% CI span was applied to improve the credibility of the ROR. The median values of time from vaccination to onset (TTO) for the three vaccines were analyzed. Results: Compared with BNT162b2 and mRNA-1273, Ad26.COV2.S vaccination was associated with a lower death frequency (p < 0.05). Ad26.COV2.S vaccination was associated with a lower birth defect and emergency room visit frequency than BNT162b2 (p < 0.05). There were 6,605, 830, and 2,292 vaccine recipients who suffered from COVID-19-related symptoms after vaccination with BNT162b2, Ad26.COV2.S, and mRNA-1273, respectively, including people who were infected by COVID-19, demonstrated a positive SARS-CoV-2 test, and were asymptomatic. Serious AEFI, including thromboembolism, hemorrhage, thrombocytopenia, cardiac arrhythmia, hypertension, and hepatotoxicity, were associated with all three vaccines. Cardiac failure and acute renal impairment events were associated with BNT162b2 and mRNA-1273, while seizure events were associated with BNT162b2 and Ad26.COV2.S. The median values of TTO associated with the three vaccinations were similar. Conclusion: These findings may be useful for health workers and the general public prior to inoculation, especially for patients with underlying diseases; however, the risk/benefit profile of these vaccines remains unchanged. The exact mechanism of SARS-CoV-2 vaccine-induced AEFI remains unknown, and further studies are required to explore these phenomena.

Real-World Prescription Patterns For Patients With Young-Onset Parkinson's Disease in China: A Trend Analysis From 2014 to 2019.

Introduction Pharmacotherapy is one of the main treatments for patients with young-onset Parkinson's disease (YOPD). Although numerous studies on the treatment of YOPD have been published, the real-world prescription patterns of these populations remain unclear in China. Methods A national comprehensive evaluation was performed to reveal the pharmacological treatment patterns in Chinese patients with Parkinson's disease from 1 January 2014 to 31 December 2019, with patients aged 21-50 years classified as having YOPD for the subgroup analysis. Information on patients and drugs was extracted to analyse the demographic characteristics, prescription patterns, and levodopa equivalent daily dose (LED) during disease progression. Results A total of 1,134 patients with YOPD were included, and the majority were aged 41-50 years. Prescription of L-DOPA/benserazide and pramipexole accounted for more than 30 and 20%, respectively, in each year from 2014 to 2019. There was no difference in prescription patterns in terms of age, sex and geographical areas. Half of the patients with YOPD were on monotherapy, but the proportion decreased from 2016. Correspondingly, the proportion of patients receiving polytherapy increased, especially those who were prescribed more than two anti-Parkinson's disease drugs. During the disease course, LED showed high variability, which increased over time. Conclusion L-DOPA/benserazide and pramipexole were the most frequently prescribed anti-PD drugs for patients with YOPD in China. There was a slight trend in the transition from monotherapy to polytherapy. LED increased with disease duration. Thus, we provided an overview of the prescription patterns for patients with YOPD in China.

A novel epigenetic marker, Ten-eleven translocation family member 2 (TET2), is identified in the intractable epileptic brain and regulates ATP binding cassette subfamily B member 1 (ABCB1) in the blood-brain barrier.

Drug-resistant epilepsy (DRE) is a chronic condition derived from spontaneous changes and regulatory effects in the epileptic brain. As demethylation factors, ten-eleven translocation (TET) family members have become a focus in recent studies of neurological disorders. Here, we quantified and localized TET1, TET2 and 5-hydroxymethylcytosine (5-hmC) in the temporal lobe cortex of DRE patients (n = 27) and traumatic brain hemorrhage controls (n = 10) by immunochemical staining. TET2 and ATP binding cassette subfamily B member 1 (ABCB1) expression patterns were determined in the isolated brain capillaries of DRE patients. TET2 expression was significantly increased in the temporal cortical tissue of DRE patients with or without hippocampal sclerosis (HS) compared to control patients, while TET1 and 5-hmC showed no differences in expression. We also found that a particularly strong expression of TET2 in the vascular tissue of DRE patients. ABCB1 and TET2 have evidently higher expression in the vascular endothelium from the neocortex of DRE patients. In blood-brain barrier (BBB) model, TET2 depletion can cause attenuated expression and function of ABCB1. Data from a cohort study and experiments in a BBB model suggest that TET2 has a specific regulatory effect on ABCB1, which may serve as a potential mechanism and target in DRE.

Population pharmacokinetic and pharmacodynamic analysis of rivaroxaban in Chinese patients with non-valvular atrial fibrillation.

Rivaroxaban, a direct factor Xa inhibitor, is widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to conduct a population pharmacokinetic-pharmacodynamic (PK-PD) analysis of rivaroxaban in Chinese patients with NVAF to assess ethnic differences and provide model-based precision dosing. A total of 256 rivaroxaban plasma concentrations and 244 prothrombin time (PT) measurements were obtained from 195 Chinese NVAF patients from a prospective clinical trial. The population PK-PD model was developed using nonlinear mixed effects modeling (NONMEM) software. The PK of rivaroxaban was adequately described using a one-compartment model with first-order adsorption and elimination. Estimated glomerular filtration rate (eGFR) was identified as a major covariate for apparent clearance. No single nucleotide polymorphism was identified as a significant covariate. PT exhibited a linear relationship with rivaroxaban concentration. Total bilirubin (TBIL) and eGFR were identified as significant covariates for baseline PT. According to the Monte Carlo simulation, 15 mg for Chinese patients with eGFR ≥50 mL/min and normal liver function yielded an exposure comparable to 20 mg for Caucasian patients. Patients with moderately impaired renal function may require a lower dose of rivaroxaban to avoid overexposure. Moreover, there was an approximate 26% increase in PT levels in patients with TBIL of 34 µmol/L and eGFR of 30 mL/min, which could increase the risk of major bleeding. The established population PK-PD model could inform individualized dosing for Chinese NVAF patients who are administered rivaroxaban.

Association between cyclin-dependent kinase 4/6 inhibitors and venous thromboembolism: analysis of F.A.E.R.S. data.

OBJECTIVES: Real world studies have started to emerged on occurrence of venous thromboembolism (VTE) with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, but still deserve constant surveillance and evaluation. This study was to analyze this association. METHODS: Adverse event cases were acquired from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database betweenJanuary 1st 2015 and December 31st 2020.Signals indicating association between CDK 4/6 inhibitors and VTE were identified by reporting odds ratio (ROR). RESULTS:  CDK 4/6 inhibitors had a total of 631 reports of VTE (ROR 1.44, 95% CI 1.33-1.55) compared with non-CDK 4/6 inhibitors. Palbociclib (ROR 1.42, 95% CI 1.09-1.88) demonstratedthe highest number of VTE reports, followed by ribociclib (ROR 1.41, 95% CI 1.29-1.54) and abemaciclib (ROR 0.92, 95% CI 0.72-1.17). CONCLUSIONS: Although it is not able to confirm the casual relationship between VTE and CDK4/6 inhibitors, this study suggested signal of VTE reporting in patients receiving CDK4/6 inhibitors, which is likely to reflect a potential association. The results may enhance physicians' awareness of the potential side effect of VTE associated with CDK 4/6 inhibitors. An early recognition of VTE signs/symptoms could decrease the morbidity and severity of such adverse events.

Rationale and design of a prospective study evaluating population pharmacokinetics and pharmacodynamics of rivaroxaban in Chinese patients with non-valvular atrial fibrillation.

INTRODUCTION: Rivaroxaban is one of the most commonly used non-vitamin K antagonists for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Different individual exposures exist for Asian and non-Asian populations, and dose selection is different for Japanese and non-Japanese subjects. Few studies have investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in Chinese patients and provided a solid reference for dose selection and individualised therapy. METHODS AND ANALYSIS: This is a single-centre prospective study. Rivaroxaban-treated Chinese NVAF patients will be recruited according to predetermined inclusion criteria. Blood samples will be collected from both outpatients and inpatients with different sampling strategies at steady state. Rivaroxaban plasma concentration, factor Xa activity, prothrombin time and single-nucleotide polymorphisms of candidate genes will be evaluated. Follow-up will be conducted following 3 and 6 months after enrolment to collect information about the safety and efficacy outcomes. A nonlinear mixed-effects modelling strategy will be used to develop a population PK-PD model of rivaroxaban. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of Huashan Hospital, Fudan University (KY2020-016). The study findings will be submitted to peer-reviewed journals and shared with public health authorities. TRIAL REGISTRATION NUMBER: ChiCTR2100046685.

Risk for Cardiovascular Adverse Events Associated With Sphingosine-1-Phosphate Receptor Modulators in Patients With Multiple Sclerosis: Insights From a Pooled Analysis of 15 Randomised Controlled Trials.

Background: All agents engaging sphongosine-1-phospate receptors (S1PRs) will have some cardiovascular effect. This study aimed to elucidate the risk of cardiovascular adverse events (AEs) in patients with multiple sclerosis (MS) treated with S1PR modulators (S1PRMs). Methods: We systematically searched the PubMed, EMBASE, and Cochrane Library databases for randomised controlled trials (RCTs) published through January 5, 2021. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. Sensitivity analyses and meta-regression were performed. Results: Seventeen RCTs (12 for fingolimod; 3 for ozanimod; 2 for siponimod) involving 13,295 patients were included. Compared with the control treatment, S1PRMs significantly increased the risk of cardiovascular AEs (RR, 2.21; 95% CI, 1.58-3.10; I2, 75.6%). Notably, the high-risk cardiovascular AEs associated with S1PRMs were primarily bradyarrhythmia (RR, 2.92; 95% CI, 1.91-4.46; I2, 30.8%) and hypertension (RR, 2.00; 95% CI, 1.49-2.67; I2, 56.5%). Subgroup analysis results were consistent with the primary outcomes except that ozanimod was associated with a higher risk of hypertension only (RR, 1.76; 95% CI, 1.10-2.82; I2, 0.0%), while siponimod was associated with a higher risk of bradyarrhythmia only (RR, 2.75; 95% CI, 1.75-4.31; I2, 0.0%). No significant inter-subgroup differences were observed (Pinteraction > 0.05). Conclusions: S1PRM use increased the risk of cardiovascular AEs by 1.21 times in patients with MS, and increased risks for bradyarrhythmia and hypertension were at 2.92- and 2.00-fold, respectively. These findings can help clinicians assess the risk of cardiovascular AEs in patients treated with S1PRMs. Systematic Review Registration: The PROSPERO ID is CRD42020183215.

Development and validation of an ultra-high performance liquid chromatography with tandem mass spectrometry method for the simultaneous quantification of direct oral anticoagulants in human plasma.

Direct oral anticoagulants are widely used to treat and prevent thromboembolic disorders. With rising clinical application, monitoring concentrations of direct oral anticoagulants are necessary in certain clinical conditions. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of dabigatran etexilate, dabigatran, rivaroxaban, edoxaban, and apixaban, in human plasma. Protein precipitation with methanol was performed for sample preparation. The direct oral anticoagulants and internal standards were separated under gradient conditions using a C18 column, at an analytical run time of 8 min. The mobile phase was composed of 0.1% (v/v) formic acid in water (solvent A) and 0.1% (v/v) formic acid in acetonitrile (solvent B) at a flow rate of 0.3 mL/min. Mass detection was performed in multiple reaction monitoring using positive ionization mode. The method was validated over a range of 1.0-500 ng/mL for dabigatran etexilate, 0.1-500 ng/mL for dabigatran, and 0.5-500 ng/mL for edoxaban, rivaroxaban, and apixaban. The method detection limits of five analytes were in the range of 0.05-0.5 ng/mL. The lower limits of quantification of five analytes ranged from 0.1 to 1 ng/mL. The linearity (r2 values) was higher than 0.997. The accuracy of the low, medium, and high quality control samples were between 85.9 and 114%, and intra- and inter-day precision were below 9.47%. This validated method was successfully used to determine the plasma concentrations of rivaroxaban in 32 patients, and of dabigatran etexilate and dabigatran in 1 patient.

Incidence and Risk of Infection Associated With Fingolimod in Patients With Multiple Sclerosis: A Systematic Review and Meta-Analysis of 8,448 Patients From 12 Randomized Controlled Trials.

Background and Aims: There is a controversy regarding whether fingolimod is associated with an increased risk of infection in patients with multiple sclerosis (MS). We performed a systematic review and meta-analysis of data from randomized controlled trials (RCTs) to determine the risk of infection in these patients. Methods: We systematically searched PubMed, EMBASE, the Cochrane Library, and clinicaltrials.gov from inception to April 8, 2020, to identify RCTs that reported the occurrence of infection in patients with MS treated with fingolimod. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated using the random-effects model. Results: Twelve RCTs including 8,448 patients were eligible. Compared with the control (placebo and other active treatments), fingolimod significantly increased the risk of infection (RR, 1.16; 95% CI, 1.07-1.27; I2, 81%), regardless of whether the infection was a general infection (RR, 1.14; 95% CI, 1.05-1.25; I2, 78%), or a serious infection (RR, 1.49; 95% CI, 1.06-2.10; I2, 0%). Analyses of subgroups found that fingolimod significantly increased the risk of lower respiratory infection (RR, 1.48; 95% CI, 1.19-1.85; I2, 0%) and herpes virus infection (RR, 1.34; 95% CI, 1.01-1.78; I2, 9%). There appears to be no dose-dependent increase in the risk of infection associated with fingolimod (0.5 mg: RR, 1.15; 95% CI, 1.07-1.25; I2, 91%; 1.25 mg: RR, 1.11; 95% CI, 0.97-1.28; I2, 81%; Pinteraction = 0.66). Conclusions: Compared with a placebo and other active treatments, fingolimod was associated with a 16% increase in the risk of infection, especially lower respiratory infection and herpes virus infection. The risk of infection associated with fingolimod might not be dose related.

Association of xenobiotic receptor polymorphisms with carbamazepine response in epilepsy patients.

PURPOSE: Drug-resistant epilepsy is a problem worldwide. Xenobiotic receptors may play a significant role in the establishment of resistance to antiepileptic agents. Previous studies have confirmed that the metabolism and efficacy of carbamazepine (CBZ) can be influenced by xenobiotic receptors, especially pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AHR). Therefore, this study intends to elucidate the pharmacogenomic associations of polymorphisms of these xenobiotic receptors with the CBZ response in epilepsy patients, and these genetic data may be useful for the treatment of clinical prophylaxis and individualized treatment of intractable epilepsy. METHODS: Adult patients with epilepsy who were on CBZ-based monotherapy and combination therapy (n = 257) were genotyped, and the patients were divided into drug-responsive and drug-resistant groups according to the International League Against Epilepsy criteria. We sought to tag single-nucleotide polymorphisms (SNPs) of PXR, CAR and AHR that principally represent alleles associated with drug resistance risk; in addition, a gene interaction analysis reference panel was constructed for SNP-based imputation. RESULTS: No significant effects of PXR or AHR polymorphisms were observed. However, an interaction between the CAR rs2502815 variant and CBZ response was observed: in CBZ-based monotherapy and combination therapy patients, the GG genotype of the CAR rs2502815 variant (vs. wild-type homozygous) was independently associated with CBZ response after adjusting for variables [odds ratio (OR) = 0.389, 95% confidence interval (CI) 0.203-0.743, p = 0.004]. The results of the haplotype and gene interaction case-control analyses of the CBZ response were negative. Our results provide clinical data regarding the genetic possibilities of drug responses related to CAR variation in epilepsy patients. CONCLUSION: This study is the first to indicate a potentially relevant interaction between the CAR rs2502815 polymorphism and the CBZ response in epilepsy patients.

Epigenetic Effects Mediated by Antiepileptic Drugs and their Potential Application.

An epigenetic effect mainly refers to a heritable modulation in gene expression in the short term but does not involve alterations in the DNA itself. Epigenetic molecular mechanisms include DNA methylation, histone modification, and untranslated RNA regulation. Antiepileptic drugs have drawn attention to biological and translational medicine because their impact on epigenetic mechanisms will lead to the identification of novel biomarkers and possible therapeutic strategies for the prevention and treatment of various diseases ranging from neuropsychological disorders to cancers and other chronic conditions. However, these transcriptional and posttranscriptional alterations can also result in adverse reactions and toxicity in vitro and in vivo. Hence, in this review, we focus on recent findings showing epigenetic processes mediated by antiepileptic drugs to elucidate their application in medical experiments and shed light on epigenetic research for medicinal purposes.

Lower clearance of sodium tanshinone IIA sulfonate in coronary heart disease patients and the effect of total bilirubin: a population pharmacokinetics analysis.

This study developed a population pharmacokinetic model for sodium tanshinone IIA sulfonate (STS) in healthy volunteers and coronary heart disease (CHD) patients in order to identify significant covariates for the pharmacokinetics of STS. Blood samples were obtained by intense sampling approach from 10 healthy volunteers and sparse sampling from 25 CHD patients, and a population pharmacokinetic analysis was performed by nonlinear mixed-effect modeling. The final model was evaluated by bootstrap and visual predictive check. A total of 230 plasma concentrations were included, 137 from healthy volunteers and 93 from CHD patients. It was a two-compartment model with first-order elimination. The typical value of the apparent clearance (CL) of STS in CHD patients with total bilirubin (TBIL) level of 10 µmol(L-1 was 48.7 L(h-1 with inter individual variability of 27.4%, whereas that in healthy volunteers with the same TBIL level was 63.1 L(h-1. Residual variability was described by a proportional error model and estimated at 5.2%. The CL of STS in CHD patients was lower than that in healthy volunteers and decreased when TBIL levels increased. The bootstrap and visual predictive check confirmed the stability and validity of the final model. These results suggested that STS dosage adjustment might be considered based on TBIL levels in CHD patients.

Population pharmacokinetics and dosing regimen optimisation of lopinavir in Chinese adults infected with HIV.

Lopinavir (LPV) is a protease inhibitor (PI) for the treatment of human immunodeficiency virus (HIV) infections. Current studies on LPV are mainly focused on Caucasians, and none have investigated the population pharmacokinetics (PPK) of LPV in Chinese population. The present study aimed to develop a PPK model for oral LPV in Chinese adults who are HIV-infected. A total of 460 LPV concentrations from 174 Chinese patients who received LPV/ritonavir (LPV/r) 400/100 mg orally every 12 hours (q12h) were analysed using the non-linear mixed-effects modelling approach. Simulations of the LPV concentration profile were performed with different dosing regimens. A one-compartment model with first-order absorption and elimination process described the data. The estimated apparent clearance (CL/F) and volume of distribution (V/F) (% relative standard error [RSE]) for oral LPV were 5.9 L/h (3%) and 117 L (8%), respectively. Body-weight was identified as a covariate on CL/F. In patients who weighed between 45 and 115 kg and received the standard 400/100 mg q12h regimen, the probability of achieving target trough concentration (Ctrough ) of 1 mg/L was >98% for PI-naïve patients and the probability of achieving target Ctrough of 4 mg/L was <80% for PI-pretreated patients. This is the first population pharmacokinetic study to characterise the PK of LPV in Chinese patients with HIV infection. There were no obvious ethnic differences in the PK of LPV between the Chinese population and Caucasian population. The simulations demonstrated that the standard dosing regimen of 400/100 mg q12h (LPV/r tablets) appears to be sufficient for PI-naïve patients but suboptimal for PI-pretreated patients. Therefore, the regimen of 800/200 mg q12h was recommended for PI-pretreated patients. Further investigation of dosage recommendation could be helpful in optimising LPV therapy for HIV infections.

Safety assessment of concurrent statin treatment and evaluation of drug interactions in China.

OBJECTIVES: Acute muscle injury and potentially fatal rhabdomyolysis may occur with the use of statins and certain enzyme inhibitors, but data on this topic from China are quite limited. This study aimed to measure the concomitant exposure of patients to different statins and their enzyme inhibitors or interacting medications in 76 hospitals in six Chinese cities. METHODS: Prescription database was retrieved from Hospital Prescription Analysis Cooperation Project from January 2015 to December 2015, covering 76 tertiary facilities in six cities in China. Every evidence-based enzyme inhibitor was included, and labeled enzyme inhibitors and other relevant information were identified and obtained using the Drug Safety Update from the UK Medicines and Healthcare Products Regulatory Agency. The proportions of different statin types among all patients and those co-medicated with their inhibitors were examined. RESULTS: A total of 296,765 patients exposed to statins were included in this study. 80% of patients (n = 144,863, 80.5%) were concomitantly prescribed a CYP3A4-metabolized statin with an interacting drug during the study period. Among those prescribed a non-CYP3A4-metabolized statin, 40.0% of patients were concomitantly given an interacting drug, and approximately 20% of patients were concomitantly given a labeled inhibitor, predominantly calcium channel blockers, other statins, and fibrates. Rates of co-prescription were higher in patients aged over 65 years and in patients taking high-dose statins. CONCLUSION: Statins were frequently co-prescribed with metabolic inhibitors in China, where drug safety strategy on highlighting warnings and contraindications of statins are still lacking. For high-dose statins patients who are over 65 years and co-administered with any metabolic inhibitors, prescribers and pharmacists should be more concerned in order to prevent adverse drug reactions.