Association of Antipsychotic Drugs with Venous Thromboembolism: Data Mining of Food and Drug Administration Adverse Event Reporting System and Mendelian Randomization Analysis.

AIMS: Past observational studies have reported on the association between antipsychotic drugs and venous thromboembolism (VTE); however, the conclusions remain controversial, and its mechanisms are yet to be fully understood. Thus, in this study, we aim to determine the associations of antipsychotic drugs with VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), and their potential mechanisms. METHODS: We first mined the adverse event signals of VTE, DVT, and PE caused by antipsychotic drugs in Food and Drug Administration Adverse Event Reporting System (FAERS). Next, we used two-sample Mendelian randomization (MR) method to investigate the association of antipsychotic drug target gene expression with VTE, DVT, and PE, using single-nucleotide polymorphisms as genetic instruments. We not only used the expression of all antipsychotic drug target genes as exposure to perform MR analyses but also analyzed the effect of single target gene expression on the outcomes. RESULTS: In the FAERS, 1694 cases of VTE events were reported by 16 drugs. However, using the MR approach, no significant association was determined between the expression of all antipsychotic target genes and VTE, DVT, or PE, either in blood or brain tissue. Although the analysis of single gene expression data showed that the expression of nine genes was associated with VTE events, these targets lacked significant pharmacological action. CONCLUSIONS: Adverse event mining results have supported the claim that antipsychotic drugs can increase the risk of VTE. However, we failed to find any genetic evidence for this causal association and potential mechanisms. Thus, vigilance is still needed for antipsychotic drug-related VTE despite the limited supporting evidence.

Identification of SARS-CoV-2 m6A modification sites correlate with viral pathogenicity.

It has recently been found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) m6A modifications can affect viral replication and function. However, no studies to date have shown a correlation between SARS-CoV-2 m6A modifications and viral pathogenicity. In this study, we analyzed m6A modification in 2,190,667 SARS-CoV-2 genomic RNAs. m6A modifications of SARS-CoV-2 from different lineages, causing mild or severe COVID-19 and showing breakthrough for different vaccines were analyzed to explore correlations with viral pathogenicity. The results suggested that the presence of more m6A modifications in the SARS-CoV-2 N region (positive strand) correlates with weaker pathogenicity. In addition, we identified three m6A modification sites correlating with weak pathogenicity (924 in ORF1ab, 15,659 in ORF1ab, 28,288 in N, 28,633 in N and 29,385 in N, 29,707 in 3'UTR) and one with strong pathogenicity (74 in 5'UTR). These results provide new information for understanding the prevalence of SARS-CoV-2 and controlling the virus.

Pharmacogenomics and adverse effects of anti-infective drugs in children.

Children, as a special group, have their own peculiarities in terms of individualized medication use compared to adults. Adverse drug reactions have been an important issue that needs to be addressed in the hope of safe medication use in children, and the occurrence of adverse drug reactions is partly due to genetic factors. Anti-infective drugs are widely used in children, and they have always been an important cause of the occurrence of adverse reactions in children. Pharmacogenomic technologies are becoming increasingly sophisticated, and there are now many guidelines describing the pharmacogenomics of anti-infective drugs. However, data from paediatric-based studies are scarce. This review provides a systematic review of the pharmacogenomics of anti-infective drugs recommended for gene-guided use in CPIC guidelines by exploring the relationship between pharmacogenetic frequencies and the incidence of adverse reactions, which will help inform future studies of individualized medication use in children.

The binding profile of SARS-CoV-2 with human leukocyte antigen polymorphisms reveals critical alleles involved in immune evasion.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), astonished the world and led to millions of deaths. Due to viral new mutations and immune evasion, SARS-CoV-2 ranked first in transmission and influence. The binding affinity of human leukocyte antigen (HLA) polymorphisms to SARS-CoV-2 might be related to immune escape, but the mechanisms remained unclear. In this study, we obtained the binding affinity of SARS-CoV-2 strains with different HLA proteins and identified 31 risk alleles. Subsequent structural predictions identified 10 active binding sites in these HLA proteins that may promote immune evasion. Particularly, we also found that the weak binding ability with HLA class I polymorphisms could contribute to the immune evasion of Omicron. These findings suggest important implications for preventing the immune evasion of SARS-CoV-2 and providing new insights for the vaccine design.

A two-stage genome-wide association study identifies novel germline genetic variations in CACNA2D3 associated with radiotherapy response in nasopharyngeal carcinoma.

BACKGROUND: Radiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC. METHODS: This was a large­scale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC. RESULTS: After genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10- 6), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy. CONCLUSION: Our study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients. TRIAL REGISTRATION NUMBER: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546 .

Drug-induced kidney injury in Chinese critically ill pediatric patients.

Background: Drug-induced acute kidney injury (DIKI) is a common adverse drug reaction event but is less known in pediatric patients. The study explored the DIKI in Chinese pediatric patients using the Pediatric Intensive Care database (PIC). Method: We screened pediatric patients with acute kidney injury (AKI) using the KDIGO criteria from the PIC and then assessed the relationship between their drugs and DIKI using the Naranjo scale. For the fifteen frequently used DIKI-suspected drugs, we divided patients into drug-exposed and non-exposed groups, using the outcome of whether DIKI was presented or not. Propensity score matching (PSM) was used to control for the effects of four confounders, age, gender, length of hospital stay, and major diagnosis. Unconditional logistic regression was used to identify statistically significant differences between the two groups. Results: A total of 238 drugs were used 1,863 times by the 81 patients with DIKI during their hospital stay. After screening the Naranjo scale to identify the top 15 suspected DIKI drugs with a high frequency of use, we found that furosemide injection (p = 0.001), midazolam injection (p = 0.001), 20% albumin prepared from human plasma injection (p = 0.004), fentanyl citrate injection (p = 0.001), compound glycyrrhizin injection (p = 0.026), vancomycin hydrochloride for intravenous (p = 0.010), and milrinone lactate injection (p = 0.009) were associated with DIKI. Conclusion: In critically ill pediatric patients, DIKI is more likely to occur after using furosemide injection, midazolam injection, 20% albumin prepared from human plasma injection, fentanyl citrate injection, compound glycyrrhizin injection, vancomycin hydrochloride for intravenous, milrinone lactate injection.

Clinically Significant Cytochrome P450-Mediated Drug-Drug Interactions in Children Admitted to Intensive Care Units.

Objectives: Children admitted to intensive care units (ICUs) often require multiple medications due to the complexity and severity of their disease, which put them at an increased risk for drug interactions. This study examined cytochrome P450-mediated drug-drug interactions (DDIs) based on the Pediatric Intensive Care (PIC) database, with the aim of analyzing the incidence of clinically significant potential drug-drug interactions (pDDIs) and exploring the occurrence of actual adverse reactions. Methods: The Lexicomp database was used to screen cytochrome P450-mediated DDI pairings with good levels of reliability and clear clinical phenotypes. Patients exposed to the above drug pairs during the same period were screened in the PIC database. The incidence of clinically significant pDDIs was calculated, and the occurrence of adverse reactions was explored based on laboratory measurements. Results: In total, 84 (1.21%) of 6920 children who used two or more drugs were exposed to at least one clinically significant pDDI. All pDDIs were based on CYP3A4, with nifedipine + voriconazole (39.60%) being the most common drug pair, and the most frequent being the J02 class of drugs. Based on laboratory measurements, 15 adverse reactions were identified in 12 patients. Conclusions: Clinically significant cytochrome P450-mediated pDDIs existed in the children admitted to ICUs, and some of the pDDIs led to adverse clinical outcomes. The use of clinical decision support systems can guide clinical medication use, and clinical monitoring of patients' needs has to be enhanced.

A two-stage genome-wide association study to identify novel genetic loci associated with acute radiotherapy toxicity in nasopharyngeal carcinoma.

BACKGROUND: Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown. METHODS: We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively. RESULTS: Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery (P = 1.27 × 10- 6, OR = 1.55) and validation (P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia). CONCLUSIONS: Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2).

Population Pharmacokinetic Modelling for Nifedipine to Evaluate the Effect of Parathyroid Hormone on CYP3A in Patients with Chronic Kidney Disease.

Purpose: Parathyroid hormone (PTH) can induce the downregulation of CYP3A in chronic kidney disease (CKD). Nevertheless, the effect of PTH on CYP3A-mediated clearance pathways from a clinical perspective remains unclear. Methods: This study employed population pharmacokinetic (PopPK) modeling to delineate potential changes in CYP3A activity in patients with CKD. Pharmacokinetic data for nifedipine, a typical CYP3A substrate, as well as covariate information, were prospectively collected from 157 patients with a total of 612 concentrations. PopPK data analysis was performed using a nonlinear mixed-effects model. Results: The pharmacokinetics of nifedipine were optimally described according to a one-compartment model with zero-order absorption and first-order elimination. The estimated population parameters (and interindividual variability) were apparent clearance (CL/F) 49.61 L/h (58.33%) and apparent volume of distribution (V/F) 2300.26 L (45.62%), and the PTH level negatively correlated with CL/F. In comparison with the reference level, it was observed that the dosage of nifedipine should be reduced with the maximum boundary value of PTH, after a Monte Carlo simulation. Conclusion: This study provides insight into the effects of PTH on CYP3A-mediated clearance pathways. Moreover, PTH could be used as a guide for the appropriate administration of CYP3A eliminated drugs in patients with CKD.

Long Short-Term Memory Network for Development and Simulation of Warfarin Dosing Model Based on Time Series Anticoagulant Data.

Background: Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index, and dosage can differ tremendously among individuals. The study aimed to develop an individualized international normalized ratio (INR) model based on time series anticoagulant data and simulate individualized warfarin dosing. Methods: We used a long short-term memory (LSTM) network to develop an individualized INR model based on data from 4,578 follow-up visits, including clinical and genetic factors from 624 patients whom we enrolled in our previous randomized controlled trial. The data of 158 patients who underwent valvular surgery and were included in a prospective registry study were used for external validation in the real world. Results: The prediction accuracy of LSTM_INR was 70.0%, which was much higher than that of MAPB_INR (maximum posterior Bayesian, 53.9%). Temporal variables were significant for LSTM_INR performance (51.7 vs. 70.0%, P < 0.05). Genetic factors played an important role in predicting INR at the onset of therapy, while after 15 days of treatment, we found that it might unnecessary to detect genotypes for warfarin dosing. Using LSTM_INR, we successfully simulated individualized warfarin dosing and developed an application (AI-WAR) for individualized warfarin therapy. Conclusion: The results indicate that temporal variables are necessary to be considered in warfarin therapy, except for clinical factors and genetic factors. LSTM network may have great potential for long-term drug individualized therapy. Trial Registration: NCT02211326; www.chictr.org.cn:ChiCTR2100052089.

Rare ocular toxicity induced by pertuzumab/QL1209 in healthy chinese subjects: case reports and whole-exome sequencing analysis.

Pertuzumab is a recombinant anti-HER2 humanized monoclonal antibody widely used for the adjuvant treatment of HER2-positive breast cancer. Its safety is well established with the most common adverse effects being diarrhea and rash. To our knowledge, severe pertuzumab-induced ocular adverse events have never been reported. Herein, we describe several cases of pertuzumab/QL1209 (pertuzumab biosimilar)-induced blurred vision in healthy Chinese male subjects after a single injection of 420 mg pertuzumab/QL1209. Persistent optic nerve damage and vision loss occurred in the most severe case even after ophthalmic treatment. We conducted whole-exome sequencing (WES) of DNA samples from 5 cases and 13 controls to analyze the potential genetic factors and identified some associated variants (rs80303690 in RBM24, rs117375173 in CASR, rs1805097 in IRS2, and rs1227049 in CDH23). Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) terms gene enrichment analyses were carried out for differentially expressed genes clustered in the PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways, which were exactly activated by HER2 phosphorylation. In summary, this is the first report describing the occurrence of ocular toxicity induced by pertuzumab in the Chinese population and exploring the possible genetic mechanisms. These findings could provide evidence for clinicians to raise concerns about the risk of ocular toxicity with the clinical use of pertuzumab.

Predictive Value of ERCC1 mRNA Level from Receiver-Operator Characteristic and Pretreatment EBV-DNA Virus Load in Stage II Nasopharyngeal Carcinoma Patients Receiving Intensity-Modulated Radiotherapy with Concurrent Cisplatin.

Background: The molecular mechanisms underlying chemoresistance are still poorly understood in nasopharyngeal cancer. The protein expression of ERCC1 in DNA repair genes has been reported related to resistance platinum and predicting treatment outcomes in various malignant carcinomas, but the benefit for predicting outcomes with optimal cutoff value of ERCC1mRNA is controversial. The level of plasma Epstein-Barr virus (EBV) DNA is positively correlated with clinical stages of nasopharyngeal carcinoma (NPC). The predictive value of ERCC1mRNA from receiver-operator characteristic (ROC) and EBV-DNA level for stratified treatment with stage II NPC is exactly unclear. This study aims to assess the predictive value of combined EBV-DNA and ERCC1 in stage II nasopharyngeal cancer (NPC) patients treated with intensity-modulated radiotherapy (IMRT) with concurrent cisplatin, and provide guidance for future stratified treatment. Methods: A total of 86 stage II NPC patients who received IMRT and concurrent cisplatin-based chemotherapy with or without cisplatin-based adjuvant chemotherapy had measurements of ERCC1 mRNA, and pretreatment EBV-DNA levels were analyzed by real-time PCR (RT-PCR). Associations of ERCC1 mRNA and pretreatment EBV-DNA levels with clinical characteristics and survivals were evaluated. Results: Cutoff value of ERCC1 mRNA obtained from ROC curve was used, and there were significant differences in progression-free survival (PFS) and overall survival (OS) and overall response rate (ORR) between high expression group and low expression group (p = 0.021 and 0.030 and 0.000, respectively). Patients with pretreatment EBV-DNA <2000 copies/mL had significantly better PFS and ORR (p = 0.024 and 0.043, respectively) and a marginally significant impact on OS (p = 0.062) than those with pretreatment EBV-DNA ≥2000 copies/mL. Patients were divided into three groups by combination of ERCC1 mRNA and EBV-DNA level: ERCC1 mRNA low expression/pre-EBV-DNA <2000 copies/mL, ERCC1 mRNA low expression/pre-EBV-DNA ≥2000 copies/mL, and ERCC1 mRNA high expression/pre-EBV-DNA ≥2000 copies/mL. There were significant differences in ORR among the three groups (p = 0.005). The median follow-up was 62 months (range 22-84) with a follow-up rate of 90.70%. In these groups by combination of ERCC1 mRNA and EBV-DNA level, 1, 3, 5-year OS were 100%, 100%, 100%; 100%, 94.1%, 90.9%; and 100%, 85%, 72.9%, respectively (p = 0.038); 1, 3, 5-year PFS were 100%, 100%, 100%; 97.1%, 91.2%, 84.8%; and 95%, 85%, 71.4%, respectively (p = 0.028). Multivariate analysis showed that combination of ERCC1 mRNA and EBV-DNA levels remained independent prognostic factor but not ERCC1 mRNA and EBV-DNA alone. Conclusions: Combined ERCC1 mRNA and pre-EBV-DNA is a better prognostic biomarker in stage II NPC patients treated with concurrent chemoradiation. Patients with ERCC1 mRNA high expression/pre-EBV-DNA ≥2000 copies/mL may benefit from more aggressive treatment.

Complex analysis of the personalized pharmacotherapy in the management of COVID-19 patients and suggestions for applications of predictive, preventive, and personalized medicine attitude.

AIMS: Coronavirus disease 2019 (COVID-19) is rapidly spreading worldwide. Drug therapy is one of the major treatments, but contradictory results of clinical trials have been reported among different individuals. Furthermore, comprehensive analysis of personalized pharmacotherapy is still lacking. In this study, analyses were performed on 47 well-characterized COVID-19 drugs used in the personalized treatment of COVID-19. METHODS: Clinical trials with published results of drugs use for COVID-19 treatment were collected to evaluate drug efficacy. Drug-to-Drug Interactions (DDIs) were summarized and classified. Functional variations in actionable pharmacogenes were collected and systematically analysed. "Gene Score" and "Drug Score" were defined and calculated to systematically analyse ethnicity-based genetic differences, which are important for the safer use of COVID-19 drugs. RESULTS: Our results indicated that four antiviral agents (ritonavir, darunavir, daclatasvir and sofosbuvir) and three immune regulators (budesonide, colchicine and prednisone) as well as heparin and enalapril could generate the highest number of DDIs with common concomitantly utilized drugs. Eight drugs (ritonavir, daclatasvir, sofosbuvir, ribavirin, interferon alpha-2b, chloroquine, hydroxychloroquine (HCQ) and ceftriaxone had actionable pharmacogenomics (PGx) biomarkers among all ethnic groups. Fourteen drugs (ritonavir, daclatasvir, prednisone, dexamethasone, ribavirin, HCQ, ceftriaxone, zinc, interferon beta-1a, remdesivir, levofloxacin, lopinavir, human immunoglobulin G and losartan) showed significantly different pharmacogenomic characteristics in relation to the ethnic origin of the patient. CONCLUSION: We recommend that particularly for patients with comorbidities to avoid serious DDIs, the predictive, preventive, and personalized medicine (PPPM, 3 PM) strategies have to be applied for COVID-19 treatment, and genetic tests should be performed for drugs with actionable pharmacogenes, especially in some ethnic groups with a higher frequency of functional variations, as our analysis showed. We also suggest that drugs associated with higher ethnic genetic differences should be given priority in future pharmacogenetic studies for COVID-19 management. To facilitate translation of our results into clinical practice, an approach conform with PPPM/3 PM principles was suggested. In summary, the proposed PPPM/3 PM attitude should be obligatory considered for the overall COVID-19 management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-021-00247-0.

A Survey of Pharmacogenomics Testing Among Physicians, Pharmacists, and Researchers From China.

To elucidate current domestic factors influencing pharmacogenomics (PGx) implementation and its future in China, we conducted a questionnaire survey on PGx applications and testing. A questionnaire-based survey was created on the popular online professional survey platform "Wenjuanxing" (www.wjx.cn) and performed via the social media platform WeChat. Among 422 participants, there were physicians (27.7%), pharmacists (31.3%), and researchers (41.0%). We found that less than 50% of physicians were aware of the importance of PGx in drug therapy, while over 50% of pharmacists and researchers recognized the importance. Only 38.5% of physicians, 40.9% of pharmacists, and 55.5% of researchers concurred that PGx analysis could lower the economic burdens for patients. However, most of the responders affirmed that PGx should be effectively implemented in clinical practices. A lack of sector standards, a lack of clinical research, and a lack of guidelines were found to be the major factors for hindering PGx clinical application. Among drugs associated with PGx assays, the most common were warfarin and clopidogrel. Although PGx research has advanced rapidly in recent years in mainland China, the clinical implementation of PGx has a long way to go.

Influence of renal insufficiency on anticoagulant effects and safety of warfarin in Chinese patients: analysis from a randomized controlled trial.

This study aimed to analyze the influence of renal insufficiency on the anticoagulant effects and safety of warfarin in Chinese patients. Data on the creatinine levels of participants enrolled in a randomized controlled study were screened and divided into the non-renal insufficiency group, mild renal insufficiency group, and moderate renal insufficiency group, according to the creatinine clearance rate. The primary outcome measures were stable dose and average daily dose of warfarin. Secondary outcome measures were percentage of time in the therapeutic international normalized ratio (INR) (%TTR), and the first time to reach the therapeutic INR. Adverse events included bleeding events, thromboembolic events, and mortality. All participants with renal function test results and a baseline INR of less than 1.5 were included in the primary and secondary outcome analysis. The SPSS Statistics 21.0 software was used for statistical analysis. The randomized controlled trial was registered in Clinicaltrials.gov (NCT02211326). A total of 571 patients were included in this analysis. Multiple regression analysis showed that the renal function was correlated with stable dose, average daily dose, and the first time to reach therapeutic INR after adjusting for confounding factors. However, no correlation was noted between kidney function and %TTR. No significant differences were observed across the various safety parameters among the three groups. Renal function is an important consideration in patients using warfarin.

Effect of CYP4F2 Polymorphisms on Ticagrelor Pharmacokinetics in Healthy Chinese Volunteers.

Background: Ticagrelor belongs to a new class of P2Y12 receptor inhibitor that has been widely used for antiplatelet therapy. This study aimed to explore the effect of single nucleotide polymorphisms (SNPs) in metabolic enzymes, transporters, and other relevant variants on the pharmacokinetics (PK) of ticagrelor and its active metabolite, AR-C124910XX. Methods: The study population comprised 68 healthy Chinese volunteers who were enrolled in a ticagrelor bioequivalence clinical trial. The PK profile of ticagrelor was evaluated after orally administering a single 90-mg dose of ticagrelor in tablet form. The plasma concentrations of ticagrelor and AR-C124910XX were determined through liquid chromatography-tandem mass spectrometry. Plasma DNA samples were used to explore the effect of gene polymorphisms on the PK of ticagrelor and AR-C124910XX with whole-exome sequencing. Results: Female participants had a higher maximum plasma concentration/weight ratio (C max/W; p < 0.001) and a shorter half-life (T 1/2; p < 0.05) for ticagrelor than their male counterparts. In addition, a higher area under the curve/weight ratio (AUC/W; p < 0.001), and longer T 1/2 (p < 0.001) and time to reach the maximum plasma concentration (T max; p < 0.001), as well as a lower apparent drug clearance (CL/F; p < 0.001), were observed among healthy volunteers in the fed trial compared to those enrolled in the fasting trial. For AR-C124910XX, higher C max/W (p < 0.001) and AUC/W (p < 0.001) but lower CL/F (p < 0.001) and apparent volume of distribution (V d/F; p < 0.001) were observed among female participants. Healthy volunteers enrolled in the fasting trial exhibited higher C max/W (p < 0.001) and AUC/W (p < 0.01), shorter T max (p < 0.001), and lower CL/F (p < 0.001) and V d/F (p < 0.001) than those enrolled in the fed trial. Upon confirmation through multivariate analysis, the CYP4F2 rs2074900 A/A carriers were associated with higher C max/W and AUC/W and lower CL/F and V d/F than the CYP4F2 rs2074900 A/G and G/G carriers. Conclusion: This study is the first to show that the CYP4F2 rs2074900 SNP had a remarkable effect on ticagrelor PK, which is significant since it adds to the limited pharmacogenetic information on ticagrelor.

Epidemiological and clinical features of pediatric COVID-19.

BACKGROUND: COVID-19 is an extremely severe infectious disease. However, few studies have focused on the epidemiological and clinical characteristics of pediatric COVID-19. This study conducted a retrospective review of the epidemiological and clinical features of COVID-19 in children. METHODS: A retrospective study was conducted on children with a definite diagnosis of COVID-19 in mainland China using the web crawler technique to collect anonymous COVID-19 updates published by local health authorities. RESULTS: Three hundred forty-one children aged 4 days to 14 years with a median age of 7 years were included. Sixty-six percent of pediatric patients were infected via family members with COVID-19. The median incubation period was 9 days (interquartile range, 6 to 13). Asymptomatic cases accounted for 5.9%, of which 30% had abnormal chest radiologic findings. A majority of pediatric COVID-19 cases showed mild to moderate clinical features, and only a few developed severe or critical diseases (0.6% and 0.3%, respectively). Fever (77.9%) and cough (32.4%) were the predominant presenting symptoms of pediatric COVID-19. The pediatric patients had fewer underlying diseases and complications than adults. The treatment modalities for pediatric COVID-19 patients were not as complex as those of adult COVID-19 patients. The overall prognosis of pediatric COVID-19 was benign with a decent recovery. The median time from onset to cure was 16 days (interquartile range, 13 to 21). CONCLUSIONS: Compared to adults, COVID-19 in children has distinct features of epidemiology and clinical manifestations. The findings from this study might help to guide the development of measures to prevent and treat this ongoing global pandemic. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( chictr.org.cn ) identifier: ChiCTR2000030464.

Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial.

BACKGROUND: Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients. METHODS: We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Eligible patients were ≥18 years of age, with atrial fibrillation or deep vein thrombosis without previous treatment of warfarin or a bleeding disorder. Nine follow-up visits were performed during the 12-week study period. The primary outcome measure was the percentage of time in the therapeutic range of the international normalized ratio during the first 12 weeks after starting warfarin therapy. RESULTS: A total of 660 participants were enrolled and randomly assigned to a genotype-guided dosing group or a control group under standard dosing. The genotype-guided dosing group had a significantly higher percentage of time in the therapeutic range than the control group (58.8% versus 53.2% [95% CI of group difference, 1.1-10.2]; P=0.01). The genotype-guided dosing group also achieved the target international normalized ratio sooner than the control group. In subgroup analyses, warfarin normal sensitivity group had an even higher percentage of time in the therapeutic range during the first 12 weeks compared with the control group (60.8% versus 48.9% [95% CI, 1.1-24.4]). The incidence of adverse events was low in both groups. CONCLUSIONS: The outcomes of genotype-guided warfarin dosing were superior to those of clinical standard dosing. These findings raise the prospect of precision warfarin treatment in China. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02211326.

First-in-human, phase I single-ascending-dose study of the safety, pharmacokinetics, and relative bioavailability of selatinib, a dual EGFR-ErbB2 inhibitor in healthy subjects.

We assessed the pharmacokinetics and safety of a single oral administration of selatinib to healthy Chinese subjects and evaluated the potential bioavailability advantage of selatinib relative to lapatinib. Healthy subjects aged 18-40 years were enrolled in this two-part study: Part 1, a single ascending dose (50-500 mg), randomized, double-blind, placebo-control study with 64 subjects; and Part 2, an open-label, positive control, randomized, three-treatment, three-period, three-sequence crossover design study, with 6 subjects administered a single 500-mg dose of selatinib tablets (A), selatinib suspension (B), or lapatinib tablets C) per cycle. In part 1, selatinib was well-tolerated up to the planned maximum dose of 500 mg; thus the maximum tolerated dose was not attained. Twenty-two adverse events were observed in 19 (36.5%) of the 52 subjects administered the test drug. The most common drug-related adverse event was diarrhea. The mean selatinib peak plasma concentration was 69.4-494 ng/mL, which was achieved in a median peak time of 3.5-4.5 h, with a mean elimination half-life between 13.8 and 15.8 h. In Part 2, A and B showed similar bioavailability. Plasma exposure to the active drug (selatinib plus the metabolite, lapatinib) after A intake was more than two-fold higher than that of the same dose of C. In the dose range of 50-500 mg, selatinib was safe and well-tolerated by healthy Chinese subjects, and it conformed with linear pharmacokinetics. Active exposure to selatinib was much greater than that to lapatinib, supporting its development as an adjuvant for anticancer treatment.