Exposure-effect Relationships Research Articles

Model-informed drug development for antimicrobials: translational pharmacokinetic-pharmacodynamic modelling of apramycin to facilitate prediction of efficacious dose in complicated urinary tract infections.

The use of mouse models of complicated urinary tract infection (cUTI) has usually been limited to a single timepoint assessment of bacterial burden. Based on longitudinal in vitro and in vivo data, we developed a pharmacokinetic-pharmacodynamic (PKPD) model to assess the efficacy of apramycin, a broad-spectrum aminoglycoside antibiotic, in mouse models of cUTI. Two Escherichia coli strains were studied (EN591 and ATCC 700336). Apramycin exposure-effect relationships were established with in vitro time-kill data at pH 6 and pH 7.4 and in mice with cUTI. Immunocompetent mice were treated with apramycin (1.5-30 mg/kg) starting 24 h post-infection. Kidney and bladder tissue were collected 6-96 h post-infection for cfu determination. A PKPD model integrating all data was developed and simulations were performed to predict bacterial burden in humans. Treatment with apramycin reduced the bacterial load in kidneys and bladder tissue up to 4.3-log compared with vehicle control. In vitro and in vivo tissue time-course efficacy data were integrated into the PKPD model, showing 76%-98% reduction of bacterial net growth and 3- to 145-fold increase in apramycin potency in vivo compared with in vitro. Simulations suggested that an 11 mg/kg daily dose would be sufficient to achieve bacterial stasis in kidneys and bladder in humans. PKPD modelling with in vitro and in vivo PK and PD data enabled simultaneous evaluation of the different components that influence drug effect, an approach that had not yet been evaluated for antibiotics in the cUTI model and that has potential to enhance model-informed drug development of antibiotics.

Abstract 4118766: Lower Winter and Higher Summer Temperatures Increase the Risk of Hospitalization With Aortic Aneurysm or Aortic Dissection

Background: Seasonal variation in aortic dissection incidence are well-documented. This study utilized a high-resolution surface temperature model and state-specific administrative medical data to investigate the relationship between long-term exposure to winter and summer temperature averages and hospitalization rates for aortic aneurysm or dissection. Methods: Using data from the 2000-2016 State Inpatient Databases (SID), 265,795 hospitalizations with a principal diagnosis of aortic aneurysm or dissection for residents of 19 U.S. states were identified via ICD-9 and 10 codes. Daily surface temperature data, extracted from Oak Ridge National Laboratory’s Daymet weather model on a 1-km grid, were aggregated to zip codes to match SID's spatial resolution. Linear regressions, adjusted for demographics, comorbidities (including hypertension, hyperlipidemia, atherosclerosis, smoking, and genetic disorders), air pollution, and neighborhood socioeconomic status, estimated absolute changes in annual hospitalization rates associated with variations in winter and summer temperature averages. Nonlinear exposure-effect relationships were assessed using penalized cubic splines with at most nine degrees of freedom. Results: Each Celsius degree decrease in winter and increase in summer was associated with 19.0 (95% CI: 17.5, 20.8, p<0.001) and 10.4 (95% CI: 8.0, 12.7, p<0.001) additional hospitalizations per one million person-years, respectively. These statistically significant associations were consistent across subgroups, including thoracic vs. abdominal and aneurysm vs. dissection. Further analysis revealed that cooler-than-average winter temperatures consistently correlated with increased hospitalization rates for overall aortic aneurysms or dissections and their subtypes. Conclusion: Colder winter and hotter summer temperatures significantly increase the risk of hospitalization for aortic aneurysm or dissection. This emphasizes the importance of understanding how environmental factors contribute to aortic disease.

Analysis of Nirmatrelvir Entry into Pulmonary Lining Fluid in Patients with COVID-19: A Unique Perspective to Explore and Understand the Target Plasma Concentration of 292 ng/mL in Antiviral Activity.

Currently, the applicant has chosen a target plasma trough concentration for nirmatrelvir, which is adjusted to 292 ng/mL based on the drug's molecular weight (499.54 Daltons), its binding to human plasma proteins (69%), and the in vitro antiviral EC90 value (181 nM). However, the current exposure-effect relationships (ER) analysis of viral load in patients enrolled in the EPIC-HR study has not revealed clinically significant trends in the ER. Given that the lungs are the primary site of COVID-19 infection, we aim to further understand this exposure relationship by exploring and analyzing the penetration characteristics of nirmatrelvir in the lungs. To explore and understand the target plasma concentration of 292 ng/mL in antiviral activity. We identified all critically ill patients with coronavirus disease 2019 who received nirmatrelvir/ritonavir treatment in the respiratory intensive care unit of Changhai hospital between January 2023 and October 2023. Samples of plasma and bronchoalveolar lavage fluid were obtained at pre-dose trough concentrations after administration of nirmatrelvir (NMV). The relationship between NMV levels in plasma and the epithelial lining fluid (ELF) was assessed by determining concentrations of NMV. There was a significant relationship between NMV levels in plasma and ELF (ELF = 0.4976*PLASMA- 204; R = 0.96), with a correlation whose slope (0.4976) suggested that the blood-to-ELF ratio of drug penetration was 2:1. A negative value from the equation indicates that NMV requires to reach baseline concentration to penetrate the ELF. The relationship between NMV levels in plasma and ELF with low permeability and a negative baseline value suggests that the target plasma concentration of 292 ng/mL is insufficient for antiviral activity. This study provides a unique perspective to explore and understand no clinically meaningful trend of exposure-response relationships in patients enrolled in EPIC-HR.

Predictive noise annoyance and noise-induced health effects models for road traffic noise in NCT of Delhi, India

Abstract The present study analyzed the effect of noise annoyance due to road traffic based on a comprehensive socio-acoustics survey at a large number of sites in the NCT of Delhi. This study presents the development of exposure–effect relationships and noise annoyance models using the Structural Equation Modeling (SEM) approach. The study assesses the traffic noise annoyance caused by road traffic at various sites in NCT of Delhi, India. Exposure–effect relationships correlate the noise annoyance and traffic noise levels. The Structural Equation Model depicts the relationship between noise annoyance and various psychological factors. The effect of noise annoyance and awareness level was determined using a socio-acoustic questionnaire survey among the community of NCT of Delhi. The various parameters undertaken were demographic, honking, health impacts, and psychological perception. The developed PLS (Partial Least Square)–SEM model predicted that noise sensitivity and road traffic noise remarkably affected the noise-induced annoyance.

Population pharmacokinetic/pharmacodynamic modeling of H018, a selective JAK1 inhibitor, in healthy Chinese volunteers

H018 is an orally administered, selective, small-molecule inhibitor of Janus kinase 1 (JAK1) made for the treatment of rheumatoid arthritis. A population pharmacokinetic/pharmacodynamic analysis was conducted to characterize the pharmacokinetic and pharmacodynamic profile of H018 and its active metabolite using data from 48 healthy Chinese volunteers who received a single dose of 10–160 mg of H018 in a phase I clinical study. A two-compartment model with delayed absorption and linear elimination adequately described the pharmacokinetic data of H018. The apparent clearance of H018 was estimated to be 39.0 L/h, and triglyceride was identified as a covariate on it. Pharmacokinetic data of the active metabolite could be well described by a two-compartment model with linear elimination. The exposure–effect relationships in terms of pSTAT1 inhibition were well described by a direct response model, with exposure captured by an active moiety that consisted of H018 and its metabolite, weighted by the ratio of in vitro JAK1 inhibitory activity (1.13). The estimated EC50 value for the active moiety is 601 nM. In the simulation using the final model, the inhibitory effect appeared to have reached a plateau in the high-dose groups, with max inhibition rates of 81.42 %, 88.42 %, and 91.89 % for 80, 120, and 160 mg dose groups, respectively. Taken together, this study will provide an instructive reference of dose selection for subsequent clinical trials.

Population Pharmacokinetic/Pharmacodynamic Models for P2Y12 Inhibitors: A Systematic Review and Clinical Appraisal Using Exposure Simulation.

Recent research indicates a correlation between plasma concentration of P2Y12 inhibitors and clinical events, particularly bleeding, which significantly impeded their clinical therapeutic performance. It is therefore vital to delve into the factors that might affect the plasma concentration. The study aims to summarize population pharmacokinetics/pharmacodynamics (PopPKPD) models for commonly prescribed P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) and assess bleeding risk in specific individual groups. The PopPKPD models of P2Y12 inhibitors were collected and summarized based on predetermined inclusion and exclusion criteria. The collected models were replicated in simulations, which were used to assess factors affecting plasma concentrations of P2Y12 inhibitors. Simulation results for special populations were compared to therapeutic window based on reported exposure-effect relationships (PK/PD-related bleeding and thrombotic clinical outcomes) to predict bleeding risk in special populations with different dosing regimens and cumulative covariates. Finally, 12 studies were included for PK simulation, 7 of which that also included PD data were subjected to further analysis, with the majority being based on Phase I or II trials. Simulations showed that several covariates such as female gender, weight, elderly can significantly impact on exposure, with special populations reaching up to 179% of the general population. However, after dose adjustment, blood concentrations for special populations can reach approximately ±20% of general population exposure. Therefore, lowering the maintenance dose of ticagrelor from 90 to 60 mg bid was first recommended to reduce bleeding risk without significantly increasing ischemic risk, particularly in elderly, small-weight Asian females. Lowering the maintenance dose of ticagrelor from 90 to 60 mg bid effectively reduces bleeding risk without increasing thrombotic infarction risk in elderly, small-weight Asian females.

Systematic review and model-based analysis to identify whether renal safety risks of URAT1 inhibitors are fully determined by uric acid-lowering efficacies

ObjectiveRenal safety risk is currently an important factor that hinders the development of uric acid transporter 1 (URAT1) inhibitors. This study aimed to compare the renal safety and uric acid-lowering efficacy of different URAT1 inhibitors and clarify the association between them. MethodsA systematic review of published randomized controlled trials on URAT1 inhibitors was conducted to investigate the incidence of renal safety events. A model-based analysis was performed to predict the uric acid-lowering efficacy of representative URAT1 inhibitors. ResultsThe overall renal safety event incidences of lesinurad, verinurad, dotinurad, SHR4640, and benzbromarone in patients with hyperuricemia were 11.2 % (142/1264), 12.0 % (34/284), 0.5 % (2/421), 2.3 % (5/213), and 1.3 % (5/393), respectively. A semi-mechanistic pharmacokinetic/pharmacodynamic model was used to establish the dose–exposure–effect relationship of lesinurad, verinurad, dotinurad, and SHR4640 with or without the combination of xanthine oxidase inhibitors (XOIs). The efficacy ranking of the intermediate dose of URAT1 inhibitors with once-daily dosing was 2 mg dotinurad > 10 mg verinurad > 5 mg SHR4640 > 400 mg lesinurad. The combination of 80 mg febuxostat and 600 mg allopurinol reduced the 24-h cumulative renal uric acid excretion by 48.4 % and 48.3 %, respectively. ConclusionUric acid-lowering efficacy is not an independent factor for the renal safety risk of different URAT1 inhibitors, and structural differences could be responsible for the difference. The adverse renal effects of URAT1 inhibitors are dose-dependent, and the combination with high doses of XOIs can significantly reduce the renal safety risk by reducing uric acid excretion by the kidneys.

Aluminum exposure and cognitive performance: A meta-analysis

BackgroundAluminum is increasingly used in various industrial processes due to its beneficial properties. Occupational exposure to aluminum, however, has been linked to several adverse health effects. The impact of occupational aluminum exposure on worker's cognitive performance and its contribution in developing neurodegenerative diseases is highly discussed with competing results. MethodWe conducted a literature search via online databases until June 2023. Applicable studies fulfilling inclusion criteria investigating the effects of occupational aluminum exposure on cognitive functions were gathered. Results were aggregated using random effects meta-analysis and the effect size g. We further explored types of publication biases, moderating variables and exposure-effect relationships using meta-regressions. ResultsThe final sample consisted of 18 studies with 87 effect sizes for seven cognitive functions. We found significant worse performances in workers occupationally exposed to aluminum regarding processing speed, working memory, attention, and reaction time after exclusion of outliers. Additionally, we found increased blood plasma aluminum significantly predicting decreased cognitive performance in exposed workers. ConclusionOur results show decreased performance levels in processing speed, working memory, attention and reaction time in workers occupationally exposed to aluminum compared to controls. Furthermore, we found that aluminum in blood plasma was the only biomarker as significant predictor of cognitive performance. We discuss recommendations for further research in relation to occupational health and safety. Finally, we extend the discourse between occupational aluminum exposure and development of neurodegenerative diseases like Alzheimer's disease.

Development of an in vitro pharmacokinetic/pharmacodynamic model in the presence of serum for studying micafungin activity against Candida albicans: a need for revision of CLSI susceptibility breakpoints.

The CLSI breakpoint for micafungin and Candida albicans is 0.25 mg/L, higher than the CLSI epidemiological cut-off value (0.03 mg/L) whereas the EUCAST values are identical (0.016 mg/L). We developed a novel in vitro dialysis-diffusion pharmacokinetic/pharmacodynamic (PK/PD) model, confirmed correlation to in vivo outcome and studied micafungin pharmacodynamics against Canida albicans. Four C. albicans isolates, including a weak (F641L) and a strong (R647G) fks1 mutants, were studied using a 104 cfu/mL inoculum and RPMI medium with and without 10% pooled human serum. The exposure-effect relationship fAUC0-24/MIC was described for CLSI and EUCAST methodology. Monte Carlo simulation analysis included standard (100 mg i.v.) and higher (150-300 mg) doses q24h to determine the corresponding probability of target attainment (PTA). The in vitro PK/PD targets for stasis/1-log kill were 36/57 fAUC0-24/MIC in absence and 2.8/9.2 fAUC0-24/MIC in the presence of serum, and similar for wild-type and fks mutant isolates. The PTAs for both PK/PD targets were high (>95%) for EUCAST susceptible isolates but not for CLSI susceptible non-wild-type isolates (CLSI MICs 0.06-0.25 mg/L). 300 mg q24h was needed to attain PK/PD targets for non-wild-type isolates with CLSI MICs 0.06-0.125 mg/L and EUCAST MICs 0.03-0.06 mg/L. The in vitro 1-log kill effect corresponded to stasis in animal model and mycological response in patients with invasive candidiasis, thereby validating the model for studying pharmacodynamics of echinocandins in vitro. EUCAST breakpoints were well supported by our findings but our data questions whether the current CLSI breakpoint, which is higher than the epidemiological cut-off values, is appropriate.

Burden of lung cancer and predicted costs of occupational exposure to hexavalent chromium in the EU – The impact of different occupational exposure limits

BackgroundExposure to hexavalent chromium [Cr(VI)] occurs widely in occupational settings across the EU and is associated with lung cancer. In 2025, the occupational exposure limit is set to change to 5 μg/m3. Current exposure limits are higher, with 10 μg/m3 as a general limit and 25 μg/m3 for the welding industry. We aimed to assess the current burden of lung cancer caused by occupational exposure to Cr(VI) and to evaluate the impact of the recently established EU regulation by analysing different occupational exposure limits. MethodsData were extracted from the literature, the Global Burden of Disease 2019) study, and Eurostat. We estimated the cases of cancer attributable to workplace exposure to Cr(VI) by combining exposure-effect relationships with exposure data, and calculated related DALYs and health costs in scenarios with different occupational exposure limits. ResultsWith current EU regulations, 253 cases (95%UI 250.96–255.71) of lung cancer were estimated to be caused by Cr(VI) in 2019, resulting in 4684 DALYs (95%UI 4683.57–4704.08). In case the welding industry adopted 10 μg/m3, a decrease of 43 cases and 797 DALYs from current values is expected. The predicted application of a 5 μg/m3 limit would cause a decrease of 148 cases and 2746 DALYs. Current costs are estimated to amount to 12.47 million euros/year (95%UI 10.19–453.82), corresponding to 39.97 million euros (95%UI 22.75–70.10) when considering costs per DALY. The limits implemented in 2025 would lead to a decrease of 23.35 million euros when considering DALYs, with benefits of introducing a limit value occurring after many decades. Adopting a 1 μg/m3 limit would lower costs to 1.04 million euros (95%UI 0.85–37.67) and to 3.33 million euros for DALYs (95%UI 1.89–5.84). DiscussionAssessing different scenarios with different Cr(VI) occupational exposure limits allowed to understand the impact of EU regulatory actions. These findings make a strong case for adapting even stricter exposure limits to protect workers’ health and avoid associated costs.

Relationship between factor VIII levels and bleeding for rFVIII-SingleChain in severe hemophilia A: A repeated time-to-event analysis.

Publications on the exposure-effect relationships of factor concentrates for hemophilia treatment are limited, whereas such analyses give insight on treatment efficacy. Our objective was to examine the relationship between the dose, factor VIII (FVIII) levels and bleeding for rFVIII-SingleChain (lonoctocog alfa, Afstyla). Data from persons with severe hemophilia A on rFVIII-SingleChain prophylaxis from three clinical trials were combined. The published rFVIII-SingleChain population pharmacokinetic (PK) model was evaluated and expanded. The probability of bleeding was described with a parametric repeated time-to-event (RTTE) model. Data included 2080 bleeds, 2545 chromogenic stage assay, and 3052 one-stage assay FVIII levels from 241 persons (median age 19 years) followed for median 1090 days. The majority of the bleeds occurred in joints (65%) and the main bleeding reason was trauma (44%). The probability of bleeding decreased during follow-up and a FVIII level of 8.9IU/dL (95% confidence interval: 6.9-10.9) decreased the bleeding hazard by 50% compared to a situation without FVIII in plasma. Variability in bleeding hazard between persons with similar FVIII levels was large, and the pre-study annual bleeding rate explained part of this variability. When a FVIII trough level of 1 or 3IU/dL is targeted during prophylaxis, simulations predicted two (90% prediction interval [PI]: 0-17) or one (90% PI: 0-11) bleeds per year, respectively. In conclusion, the developed PK-RTTE model adequately described the relationship between dose, FVIII levels and bleeds for rFVIII-SingleChain. The obtained estimates were in agreement with those published for the FVIII concentrates BAY 81-8973 (octocog alfa) and BAY 94-9027 (damoctocog alfa pegol), indicating similar efficacy to reduce bleeding.

The association between air pollutants and hospitalizations for asthma: an evidence from Chengdu, China.

Exposure to air pollutants has been linked to the exacerbation of asthma, and it has become a risk to human welfare and health throughout the globe. Previous works did not achieve a systematic study by considering interactive effects of age, gender, and meteorological factors on the exposure-effect relationship between air pollutants and asthma. We aimed to quantitatively investigate the effects of air pollutants on hospitalizations for asthma in Chengdu, China. This is a retrospective and population-based study. Data of asthma hospitalization records for residents, the average daily concentrations of air pollutants including SO2, CO, NO2, O3, PM10, and PM2.5, and meteorological variables from 1 January 2014 to 31 December 2014 in Chengdu, China, were obtained from several government departments. A generalized additive model (GAM) was used to analyze the exposure-effect relationship between air pollutants and daily asthma hospitalizations after controlling the long-time seasonal trend, "day-of-week (DOW)" effect, holiday effect, and confounding meteorological factors. A total of 7,503 hospitalizations were assessed. Significant associations between hospitalizations and air pollutants were found. The relative risk (RR) for hospitalizations for every 10 µg/m3 increase in PM2.5 and PM10 for the male group were 1.0121 [95% confidence interval (CI): 1.0012-1.0232] and 1.0075 (95% CI: 1.0001-1.015), respectively. The elderly (≥65 years old) tended to have a higher RR (1.0022; 95% CI: 1.0001-1.0043) for each 10 mg/m3 increase in CO than the other age groups. All pollutants had slightly protective effects on the younger age group (≤14 years old). O3 had more significant effects in cold season, whereas SO2 impacted more significantly in warm seasons, particularly for females and adults (14-65 years old). Adverse effects of ambient concentrations of air pollutants on hospitalizations for asthma are evident, especially in specific population groups. Male patients were more susceptible to PM2.5 and PM10, and the elderly were more sensitive to CO. The effects of O3 in China were significant in the cold season, whereas SO2 impacted more significantly in the warm season particularly on females and adults. The study would be meaningful for asthma intervention and corresponding healthcare resource management.

Machine-Learning Exploration of Exposure-Effect Relationships of Cisplatin in Head and Neck Cancer Patients.

Cisplatin is a pivotal drug in the treatment of head and neck cancer, and personalized dosage should help the preservation of an optimal toxicity-efficacy ratio. We analyzed the exposure-effect relationships of 80 adult patients with head and neck cancers and treated with standard Cisplatin-based regimen administered as three-hour infusion. Individual pharmacokinetics (PK) parameters of Cisplatin were identified using a Bayesian approach. Nephrotoxicity and ototoxicity were considered as typical Cisplatin-related toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) standards. Efficacy was evaluated based upon Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Up to nine different machine-learning algorithms were tested to decipher the exposure-effect relationships with Cisplatin. The generalized linear model was the best algorithm with an accuracy of 0.71, a recall of 0.55 and a precision of 0.75. Among the various metrics for exposure (i.e., maximal concentration (Cmax), area-under-the-curve (AUC), trough levels), Cmax, comprising a range between 2.4 and 4.1 µg/mL, was the best one to be considered. When comparing a consequent, model-informed dosage with the standard dosage in 20 new patients, our strategy would have led to a reduced dosage in patients who would eventually prove to have severe toxicities while increasing dosage in patients with progressive disease. Determining a target Cmax could pave the way for PK-guided precision dosage with Cisplatin given as three-hour infusion.

Occupational exposure to nickel and hexavalent chromium and the risk of lung cancer in a pooled analysis of case-control studies (SYNERGY).

There is limited evidence regarding the exposure-effect relationship between lung-cancer risk and hexavalent chromium (Cr(VI)) or nickel. We estimated lung-cancer risks in relation to quantitative indices of occupational exposure to Cr(VI) and nickel and their interaction with smoking habits. We pooled 14 case-control studies from Europe and Canada, including 16 901 lung-cancer cases and 20 965 control subjects. A measurement-based job-exposure-matrix estimated job-year-region specific exposure levels to Cr(VI) and nickel, which were linked to the subjects' occupational histories. Odds ratios (OR) and associated 95% confidence intervals (CI) were calculated by unconditional logistic regression, adjusting for study, age group, smoking habits and exposure to other occupational lung carcinogens. Due to their high correlation, we refrained from mutually adjusting for Cr(VI) and nickel independently. In men, ORs for the highest quartile of cumulative exposure to CR(VI) were 1.32 (95% CI 1.19-1.47) and 1.29 (95% CI 1.15-1.45) in relation to nickel. Analogous results among women were: 1.04 (95% CI 0.48-2.24) and 1.29 (95% CI 0.60-2.86), respectively. In men, excess lung-cancer risks due to occupational Cr(VI) and nickel exposure were also observed in each stratum of never, former and current smokers. Joint effects of Cr(VI) and nickel with smoking were in general greater than additive, but not different from multiplicative. In summary, relatively low cumulative levels of occupational exposure to Cr(VI) and nickel were associated with increased ORs for lung cancer, particularly in men. However, we cannot rule out a combined classical measurement and Berkson-type of error structure, which may cause differential bias of risk estimates.

Impact of diurnal temperature range on hospital admissions for cerebrovascular disease among farmers in Northwest China

Diurnal temperature range (DTR) is an appropriate indicator for reflecting climate change. Many previous studies have examined the relationship between DTR and mortality. Cerebrovascular disease (CVD) have a higher mortality than other diseases, with mortality from CVD higher in rural areas than in urban areas. A distributed lag non-linear model (DLNM) was used to analyze the exposure-effect relationship between DTR and hospital admissions for CVD from 2018 to 2020 in the population living in rural areas of Tianshui, Gansu Province, China. We investigated the effects of extreme DTR in groups stratified according to gender and age. A U-shape relationship was observed between DTR and hospital admissions for CVD. Both high DTR (19 °C) and low DTR (3 °C) were significantly associated significantly with CVD hospital admissions. When the lag period was 0–21 days, the impact of high DTR (1.595 [95% CI 1.301–1.957]) was slightly more significant than that of a low DTR (1.579 [95% CI − 1.202 to 2.075]). The effect of DTR on CVD varied in different populations. Males and adults were more sensitive to DTR than females and elderly people. It is necessary to make preventive measures to protect vulnerable populations from the adverse effects of extreme DTR.

Association between air pollutants and neural tube defects during pregnancy in Lanzhou, China: a time series analysis.

Few studies have evaluated the association between air pollutants and neural tube defects (NTDs). Moreover, the existing research ignores the lag effect of air pollution on health and provides inconsistent epidemiological evidence. We aim to estimate the association between air pollution and NTDs during the first trimester of pregnancy and identify specific susceptible windows. Birth data was collected from the Birth Defects Surveillance Network in Lanzhou from September 1, 2014, to December 31, 2019. Air quality and meteorological data were collected from ambient air monitoring stations and China Meteorological Data Network. The log connection function of the Poisson distribution function is used to establish a DLNM model to estimate the exposure-effect relationship and exposure-lag relationship association between air pollutants levels and NTDs. There were 320,787 perinatal infants in Lanzhou from September 1, 2014, to December 31, 2019, and 486 cases of NTDs (1.5‰). The result indicates that exposure to inhalable particles (PM10) at lag 2-4 weeks was significantly associated with the risk of NTDs, with the most significant impact at the lag 2 week (RR=1.048, 95%CI, 1.015-1.084). Exposure to fine particulate matter (PM2.5)at the lag 2 weekwas significantly associated with the risk of NTDs, with the most significant impact at the lag 2 week (RR=1.077, 95%CI, 1.004-1.155). Exposure to sulfur dioxide (SO2) andnitrogen dioxide (NO2)at lag 3-6weeks was significantly associated with the risk of NTDs, with the most significant impact at the lag 4 week (RR=1.220, 95%CI, 1.105-1.348; RR=1.143, 95%CI, 1.048-1.245). This study provides further evidence that exposure to air pollutants in the first trimester of pregnancy significantly increases the risk of neural tube defects.

Design and Measurement of Drug Tissue Concentration Asymmetry and Tissue Exposure-Effect (Tissue PK-PD) Evaluation.

The "free drug hypothesis" assumes that, in the absence of transporters, the steady state free plasma concentrations equal to that at the site of action that elicit pharmacologic effects. While it is important to utilize the free drug hypothesis, exceptions exist that the free plasma exposures, either at Cmax, Ctrough, and Caverage, or at other time points, cannot represent the corresponding free tissue concentrations. This "drug concentration asymmetry" in both total and free form can influence drug disposition and pharmacological effects. In this review, we first discuss options to assess total and free drug concentrations in tissues. Then various drug design strategies to achieve concentration asymmetry are presented. Last, the utilities of tissue concentrations in understanding exposure-effect relationships and translational projections to humans are discussed for several therapeutic areas and modalities. A thorough understanding in plasma and tissue exposures correlation with pharmacologic effects can provide insightful guidance to aid drug discovery.

Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome

BackgroundA higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose–response relationship between ketamine and bilirubin levels.MethodsPost hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure–effect relationship between ketamine infusion and total bilirubin levels.ResultsTwo-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9–2.0] mg/kg/h for 9 [4–18] days. The mixed-effects model revealed a positively correlated infusion duration–effect as well as dose–effect relationship between ketamine infusion and rising bilirubin levels (p < 0.0001). In comparison, long-term infusion of propofol and sufentanil, even at high doses, was not associated with increasing bilirubin levels (p = 0.421, p = 0.258). Patients having received ketamine infusion had a multivariable adjusted competing risk hazard of developing a cholestatic liver injury during their ICU stay of 3.2 [95% confidence interval, 1.3–7.8] (p = 0.01).ConclusionsA causally plausible, dose–effect relationship between long-term infusion of ketamine and rising total bilirubin levels, as well as an augmented, ketamine-associated, hazard of cholestatic liver injury in critically ill COVID-19 patients could be shown. High-dose ketamine should be refrained from whenever possible for the long-term analgosedation of mechanically ventilated COVID-19 patients.

Feasibility of therapeutic drug monitoring of sunitinib and its implications on response and toxicity in patients with metastatic renal cell cancer.

Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). High variability in pharmacokinetics coupled with a proven exposure-effect relationship makes sunitinib an ideal candidate for therapeutic drug monitoring (TDM). The feasibility of TDM of sunitinib in patients with mRCC was evaluated in this prospective observational study in a real-world scenario. Seventy patients with mRCC treated with sunitinib at a fixed dose of 50mg per day were enrolled in the study. Total trough plasma level (TTL) of sunitinib (sunitinib and its active metabolite, SU12662), was measured between days 14/15 of cycle 1. The discriminatory potential of TTL of sunitinib for the prediction of responders and occurrence of grade ≥ 3 toxicity was determined using receiver operating characteristic (ROC) curve. The median TTL of sunitinib was 76ng/mL. Forty six out of 70 patients were evaluable for response, whereas 60 out of 70 patients were evaluable for toxicity. Threshold concentrations obtained from ROC analysis showed that TTL of 60.75ng/mL and 82.3ng/mL was discriminatory for response and occurrence of grade ≥ 3 toxicity respectively. 31/34 (91.7%) patients having TTL ≥ 60.75ng/mL responded to treatment, while only 5/12 (41.6%) responded when TTL was < 60.75ng/mL (P = 0.001). On the other hand, the incidence of grade ≥ 3 toxicity was 9/24 (37.7%) in patients with TTL ≥ 82.3ng/mL compared to 4/36 (11.1%) in patients with TTL < 82.3ng/mL (P = 0.024). The TTL range of 60.75-82.3ng/mL was found to be optimal in terms of safety and efficacy. More than 50% of patients in our cohort attained TTL of sunitinib outside the optimal range, thus demonstrating the feasibility of TDM to improve safety and efficacy of sunitinib in mRCC.

Establishment of an in vitro method of rabbit embryo toxicity with toxicokinetics study.

This report introduces a novel method, rabbit whole embryo culture (WEC) combined with toxicokinetics (TK), for toxicity testing. Rodent WEC has been extensively used for in vitro screening of developmental toxicity. To improve the reliability of in vitro data, it is important to consider TK and species specificity. To test the utility and effectiveness of this method, we investigated the toxic effect of thalidomide on rabbit embryos and its behavior in test systems both in vitro and in vivo under the same experimental condition. The data showed that thalidomide induced embryo malformations such as embryonic brain hypoplasia, short limb buds, and declined embryonic growth both in vitro and in vivo. The toxic effect increased with the increasing exposure of the embryo to thalidomide. In addition, we observed similar toxic effects and exposure-effect relationships in vivo and in vitro. Therefore, we preliminarily conclude that this new method can effectively predict and explain thalidomide toxicity. Furthermore, we investigated the behavior of test compounds in the WEC system for the first time, and this method is expected to be an important technique for in vitro toxicity study after extensive verification.