Exposure-response Model Research Articles

A Population Pharmacokinetic and Exposure-Response Model of Golimumab for Targeting Endoscopic Remission in Patients With Ulcerative Colitis.

Unlike other anti-tumor necrosis factor alpha antibodies, golimumab does not deliver on its promise of effectiveness for treating patients with ulcerative colitis. We investigated the value of therapeutic drug monitoring for optimizing golimumab therapy. We analyzed the golimumab pharmacokinetics data of 56 patients with moderate to severe ulcerative colitis. Induction and maintenance golimumab concentrations (296 venipuncture, 414 serum) were used to develop a population pharmacokinetic model. Exposure-response relationships were analyzed using the data of 40/56 patients with available endoscopy data. Receiver operating characteristic curve analysis was performed, and an exposure-response Markov model was developed, linking golimumab exposure to probabilities of transitioning between Mayo endoscopic subscore (MES) states from baseline to week (w)14. Golimumab pharmacokinetics was best described by a 2-compartment model with linear absorption and elimination. Antibodies to golimumab and previous biological therapy reduced golimumab exposure. Still, interindividual pharmacokinetic variability (IIVPK) remained largely unexplained. Endoscopic remission (ER; MESw14 ≤ 1) was achieved in 14/40 (35%) patients. Golimumab serum trough concentration thresholds of 7.4 mg/L (w6) and 3.2 mg/L (w14) predicted ER at w14 (positive predictive values [pv+] 83% and 91%, pv- 82% and 67%, respectively). The 3.2-mg/L target predicted 38% and 44% chances of achieving ER in patients with MESbaseline of 3 and 2, respectively. Personalized, model-based induction dosing aiming at here-established target concentrations may account for IIVPK and thus provide patients with more equal chances of achieving ER. As <50% of patients attained the exposure targets, higher golimumab induction dosing requires investigation to secure its future in clinical practice.

A benchmark concentration analysis for manganese in drinking water and IQ deficits in children

BackgroundManganese is an essential nutrient, but in excess, can be a potent neurotoxicant. We previously reported findings from two cross-sectional studies on children, showing that higher concentrations of manganese in drinking water were associated with deficits in IQ scores. Despite the common occurrence of this neurotoxic metal, its concentration in drinking water is rarely regulated. ObjectiveWe aimed to apply a benchmark concentration analysis to estimate water manganese levels associated with pre-defined levels of cognitive impairment in children, i.e. drop of 1%, 2% and 5% in Performance IQ scores. MethodsData from two studies conducted in Canada were pooled resulting in a sample of 630 children (ages 5.9–13.7 years) with data on tap water manganese concentration and cognition, as well as confounders. We used the Bayesian Benchmark Dose Analysis System to compute weight-averaged median estimates for the benchmark concentration (BMC) of manganese in water and the lower bound of the credible interval (BMCL), based on seven different exposure-response models. ResultsThe BMC for manganese in drinking water associated with a decrease of 1% Performance IQ score was 133 μg/L (BMCL, 78 μg/L); for a decrease of 2%, this concentration was 266 μg/L (BMCL, 156 μg/L) and for a decrease of 5% it was 676 μg/L (BMCL, 406 μg/L). In sex-stratified analyses, the manganese concentrations associated with a decrease of 1%, 2% and 5% Performance IQ in boys were 185, 375 and 935 μg/L (BMCLs, 75, 153 and 386 μg/L) and 78, 95, 192 μg/L (BMCLs, 9, 21 and 74 μg/L) for girls. ConclusionStudies suggest that a maximum acceptable concentration for manganese in drinking water should be set to protect children, the most vulnerable population, from manganese neurotoxicity. The present risk analysis can guide decision-makers responsible for developing these standards.

Alternative Magnesium Sulfate Dosing Regimens for Women With Preeclampsia: A Population Pharmacokinetic Exposure-Response Modeling and Simulation Study.

Magnesium sulfate is the anticonvulsant of choice for eclampsia prophylaxis and treatment; however, the recommended dosing regimens are costly and cumbersome and can be administered only by skilled health professionals. The objectives of this study were to develop a robust exposure‐response model for the relationship between serum magnesium exposure and eclampsia using data from large studies of women with preeclampsia who received magnesium sulfate, and to predict eclampsia probabilities for standard and alternative (shorter treatment duration and/or fewer intramuscular injections) regimens. Exposure‐response modeling and simulation were applied to existing data. A total of 10 280 women with preeclampsia who received magnesium sulfate or placebo were evaluated. An existing population pharmacokinetic model was used to estimate individual serum magnesium exposure. Logistic regression was applied to quantify the serum magnesium area under the curve‐eclampsia rate relationship. Our exposure‐response model‐estimated eclampsia rates were comparable to observed rates. Several alternative regimens predicted magnesium peak concentration < 3.5 mmol/L (empiric safety threshold) and eclampsia rate ≤ 0.7% (observed response threshold), including 4 g intravenously plus 10 g intramuscularly followed by either 8 g intramuscularly every 6 hours × 3 doses or 10 g intramuscularly every 8 hours × 2 doses and 10 g intramuscularly every 8 hours × 3 doses. Several alternative magnesium sulfate regimens with comparable model‐predicted efficacy and safety were identified that merit evaluation in confirmatory clinical trials.

Global Effect Factors for Exposure to Fine Particulate Matter.

We evaluate fine particulate matter (PM2.5) exposure–response models to propose a consistent set of global effect factors for product and policy assessments across spatial scales and across urban and rural environments. Relationships among exposure concentrations and PM2.5-attributable health effects largely depend on location, population density, and mortality rates. Existing effect factors build mostly on an essentially linear exposure–response function with coefficients from the American Cancer Society study. In contrast, the Global Burden of Disease analysis offers a nonlinear integrated exposure–response (IER) model with coefficients derived from numerous epidemiological studies covering a wide range of exposure concentrations. We explore the IER, additionally provide a simplified regression as a function of PM2.5 level, mortality rates, and severity, and compare results with effect factors derived from the recently published global exposure mortality model (GEMM). Uncertainty in effect factors is dominated by the exposure–response shape, background mortality, and geographic variability. Our central IER-based effect factor estimates for different regions do not differ substantially from previous estimates. However, IER estimates exhibit significant variability between locations as well as between urban and rural environments, driven primarily by variability in PM2.5 concentrations and mortality rates. Using the IER as the basis for effect factors presents a consistent picture of global PM2.5-related effects for use in product and policy assessment frameworks.

Application of time-dependent modeling for the exposure-efficacy analysis of ceritinib in untreated ALK-rearranged advanced NSCLC patients.

Ceritinib 750mg/day was approved for the treatment of patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) based on ASCEND-4 study. The objective of this article is to introduce the use of time-dependent modeling approach in the updated exposure-efficacy analysis of ceritinib for the first-line indication. Exposure-efficacy analyses, including data from 156 patients, were first conducted using time-independent logistic regression model for response of complete or partial response and Cox regression model for progression-free survival (PFS). The exposure measure used was average Ctrough, which is defined as the geometric mean of all evaluable Ctrough for each patient. To further investigate the impact of exposure measure on exposure-efficacy analyses, a time-dependent modeling approach was used, where exposure at different time intervals was associated with the corresponding response endpoints in a longitudinal manner. With exposure measure being average Ctrough, it was observed that higher exposure was associated with reduced efficacy in terms of response (odds ratio = 0.77) and PFS [hazard ratio (HR) = 1.12]. These time-independent models do not account for the impact of time-varying concentration due to dose modifications. Subsequently, a new time-dependent modeling approach was used, where exposure and efficacy were associated longitudinally in the analyses. The results showed that the odds ratio of response became 1.07, and the HR of PFS became 1.04, indicating no apparent reverse relationship between exposure and efficacy across the exposure range studied. The drug effect on efficacy in clinical trials could be better characterized using time-dependent exposure-response models.

Behavioral responses of individual blue whales (Balaenoptera musculus) to mid-frequency military sonar.

This study measured the degree of behavioral responses in blue whales (Balaenoptera musculus) to controlled noise exposure off the southern California coast. High-resolution movement and passive acoustic data were obtained from non-invasive archival tags (n=42) whereas surface positions were obtained with visual focal follows. Controlled exposure experiments (CEEs) were used to obtain direct behavioral measurements before, during and after simulated and operational military mid-frequency active sonar (MFAS), pseudorandom noise (PRN) and controls (no noise exposure). For a subset of deep-feeding animals (n=21), active acoustic measurements of prey were obtained and used as contextual covariates in response analyses. To investigate potential behavioral changes within individuals as a function of controlled noise exposure conditions, two parallel analyses of time-series data for selected behavioral parameters (e.g. diving, horizontal movement and feeding) were conducted. This included expert scoring of responses according to a specified behavioral severity rating paradigm and quantitative change-point analyses using Mahalanobis distance statistics. Both methods identified clear changes in some conditions. More than 50% of blue whales in deep-feeding states responded during CEEs, whereas no changes in behavior were identified in shallow-feeding blue whales. Overall, responses were generally brief, of low to moderate severity, and highly dependent on exposure context such as behavioral state, source-to-whale horizontal range and prey availability. Response probability did not follow a simple exposure-response model based on received exposure level. These results, in combination with additional analytical methods to investigate different aspects of potential responses within and among individuals, provide a comprehensive evaluation of how free-ranging blue whales responded to mid-frequency military sonar.

Reducing Indoor Levels of "Outdoor PM2.5" in Urban China: Impact on Mortalities.

This study estimates adult mortalities attributed to PM2.5 across urban China in 2015 and the corresponding mortalities that might be avoided by meeting the yearly averaged indoor PM2.5 threshold in the newly established Assessment Standard for Healthy Building (ASHB) and seven other potential thresholds. We use outdoor PM2.5 concentrations from ∼1500 monitoring sites in 339 Chinese cities, coupled with a detailed exposure model, to estimate outdoor and indoor exposures to PM2.5 originating outdoors. We proceed to calculate premature mortality attributable to PM2.5 exposure using an integrated exposure-response model. Results indicate that indoor exposures accounted for 66%-87% of total exposure to PM2.5 of outdoor origin and 81% (95% confidence interval (CI), 71%-87%), i.e., 316 000 (95% CI, 176 000-435 000), of the 389 000 (95% CI, 245 000-501 000) mortalities attributable to "outdoor PM2.5" for the urban population ≥25 years of age in China in 2015. Potentially 14 000 (95% CI, 8000-20 000) deaths might be avoided if indoor PM2.5 of outdoor origin met the ASHB guideline of 35 μg/m3 for annual mean indoor PM2.5, and 162 000 (95% CI, 79 000-237 000) deaths might be avoided by meeting a 10 μg/m3 threshold. The analysis in this work should be helpful in formulating indoor air quality policies.

From Molecule to Patient and Ways to Get the Dose Precisely Right

From Molecule to Patient and Ways to Get the Dose Precisely Right

Optimising infliximab induction dosing for patients with ulcerative colitis.

The therapeutic failure of infliximab therapy in patients with ulcerative colitis remains a challenge even 2 decades after its approval. Therapeutic drug monitoring (TDM) has shown value during maintenance therapy, but induction therapy has still not been explored. Patients may be primary nonresponders or underexposed with the standard dosing regimen. We aimed to: (i) develop a population pharmacokinetic-pharmacodynamic model; (ii) identify the best exposure metric that predicts mucosal healing; and (iii) build an exposure-response (ER) model to demonstrate model-based dose finding during induction therapy with infliximab. Data were retrospectively collected from a clinical database. A total of 583 samples, from 204 patients, was used to develop a population pharmacokinetic model to generate exposure metrics for subsequent ER modelling. A subset of 159 patients was used to develop a logistic regression ER model, describing the relationship between infliximab exposure and ordered transitions between Mayo endoscopic subscore (MES) 3, 2 and ≤1 (baseline to post-induction). A 1-compartment population pharmacokinetic model with interindividual and interoccasion variability was found to fit the data best. Covariates influencing exposure were C-reactive protein, albumin, baseline MES, fat-free mass, concomitant corticosteroid use and pancolitis. The cumulative area under the infliximab concentration-time curve until endoscopy (CAUCendoscopy ) was found to be the best exposure metric for predicting mucosal healing (baseline MES >1 and post-induction MES ≤1). The model predicted that 70% of patients will attain mucosal healing with infliximab administered at days 0, 14 and 42 and a target CAUCendoscopy of 3752mg/L*day at day 84. TDM-based dose individualisation targeting CAUCendoscopy has the potential to improve the effectiveness of infliximab during induction therapy.

Estimation of PM2·5-associated disease burden in China in 2020 and 2030 using population and air quality scenarios: a modelling study

Air pollution and its adverse effects on public health remain a considerable problem in China, where policies have been implemented to improve the situation. We aimed to estimate the disease burden associated with particulate matter (PM)2·5 across China for 2020 and 2030 to identify the populations and regions most at risk, quantify the health benefits of air quality improvement targets, and determine the effect of population growth and ageing on this disease burden. In this modelling study, we investigated premature deaths associated with PM2·5 across China on the basis of air quality scenarios proposed by the expert group involved in the formulation of the 13th Five-Year Plan for Eco-Environmental Protection and population scenarios based on the Shared Socioeconomic Pathways of the Intergovernmental Panel on Climate Change. We used the integrated exposure-response model used for the Global Burden of Disease Study to estimate the number of PM2·5-related premature deaths under each scenario. The projected health benefits of the air-quality-improving targets are substantial, and could reduce the number of PM2.5-related premature deaths in China by approximately 129 278 by 2020 and 217 988 by 2030, compared with 2010. However, since China's population is increasing and ageing, the number of PM2.5-related premature deaths was estimated to increase by 84 102 by 2020 and by 244 191 by 2030, indicating that the health benefits induced by air quality improvements could be offset by the effect of the population increasing in size and ageing. To reduce the future disease burden in China, targets that are stricter than the interim target and stringent policies to improve air quality and protect public health are needed, especially for at-risk population groups, such as older individuals (aged >55 years) and patients with cardiovascular diseases, particularly in regions with a high disease burden. National Key Research and Development Program of China, National Natural Science Foundation of China, Beijing Natural Science Foundation, National High-level Talents Special Support Plan of China for Young Talents, and Special Foundation of Basic Science and Technology Resources Survey of Ministry of Science and Technology of China.

Health benefits and control costs of tightening particulate matter emissions standards for coal power plants - The case of Northeast Brazil

Exposure to ambient particulate matter (PM) caused an estimated 4.2 million deaths worldwide in 2015. However, PM emission standards for power plants vary widely. To explore if the current levels of these standards are sufficiently stringent in a simple cost-benefit framework, we compared the health benefits (avoided monetized health costs) with the control costs of tightening PM emission standards for coal-fired power plants in Northeast (NE) Brazil, where ambient PM concentrations are below World Health Organization (WHO) guidelines. We considered three Brazilian PM10 (PMx refers to PM with a diameter under x micrometers) emission standards and a stricter U.S. EPA standard for recent power plants. Our integrated methodology simulates hourly electricity grid dispatch from utility-scale power plants, disperses the resulting PM2.5, and estimates selected human health impacts from PM2.5 exposure using the latest integrated exposure-response model. Since the emissions inventories required to model secondary PM are not available in our study area, we modeled only primary PM so our benefit estimates are conservative. We found that tightening existing PM10 emission standards yields health benefits that are over 60 times greater than emissions control costs in all the scenarios we considered. The monetary value of avoided hospital admissions alone is at least four times as large as the corresponding control costs. These results provide strong arguments for considering tightening PM emission standards for coal-fired power plants worldwide, including in regions that meet WHO guidelines and in developing countries.

Exposure-Response Analysis of Venetoclax in Combination with Hypomethylating Agents or Low-Dose Cytarabine in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia

Introduction: Venetoclax, a selective BCL2 inhibitor, is approved for treatment of chronic lymphocytic leukemia in patients who received at least one prior therapy and is being studied in several other hematological malignancies including acute myeloid leukemia (AML). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships of venetoclax in patients with newly diagnosed AML who are not eligible for standard anthracycline-based induction therapy treated with venetoclax plus a hypomethylating agent (HMA) either azacitidine or decitabine, or low dose cytarabine (LDAC) to inform dose selection.Methods: A population pharmacokinetic model for venetoclax was developed using data from 336 AML subjects. Post hoc pharmacokinetic parameters generated from the model were used to calculate the exposure metric, steady-state area under the plasma concentration-time curve (AUCss), in the exposure-efficacy and exposure-safety analyses. Multivariate cumulative logistic regression analyses were performed using efficacy and safety data. In total, for the venetoclax plus HMA combination, 201 subjects were included in the exposure-efficacy and 212 subjects were included in the exposure-safety analyses. For the venetoclax plus LDAC combination, 83 subjects were included in the exposure-efficacy and 92 subjects were included in the exposure-safety analyses. Predictions based on the exposure-response model parameter estimates were used to explore the exposure- and dose-response relationships and select the optimal venetoclax dose.Results: Venetoclax in Combination with HMAs: Simulations indicated that venetoclax dosage of 400 mg once daily (QD) in combination with HMAs maximizes the probability of a typical subject achieving a response of complete remission (CR).. Venetoclax exposure-response relationship was similar for both azacitidine and decitabine combination (P > 0.05). For exposure-safety analyses, only treatment-emergent Grade ≥ 3 infections showed a statistically significant relationship with venetoclax exposures in combination with HMAs across the tested venetoclax dose range (400 - 1200 mg QD). The probability of occurrence of treatment-emergent Grade ≥ 3 infections at venetoclax dose of 400 mg and 800 mg was 51% (95% CI: [43, 58%]) and 59% (95% CI: [50, 66%]), respectively.Venetoclax in Combination with LDAC: A statistically significant association of best responses was determined with increasing steady-state area under the plasma concentration-time curve (AUCss). Based on the tolerability data, the probability of achieving CR with incomplete count recovery (CRi) or better, and CR was predicted for doses up to 600 mg. The predicted probability of achieving CRi or better was approximately 46% (95% CI: [37, 55%]) and 55% (95% CI: [45 - 66%]) at exposures associated with the 400 mg and 600 mg dosage regimen given once daily, respectively.Conclusions: The venetoclax exposure- efficacy and exposure-safety analyses supported the 400 mg QD dosage regimen of venetoclax in combination with the HMAs and 600 mg QD dosage regimen of venetoclax in combination with LDAC in treatment naïve AML patients who are ineligible for standard induction chemotherapy. DisclosuresAgarwal:AbbVie: Employment, Equity Ownership. Gopalakrishnan:AbbVie: Employment, Equity Ownership. Mensing:AbbVie: Employment, Equity Ownership. Potluri:AbbVie: Employment, Equity Ownership. Hayslip:AbbVie: Employment, Equity Ownership. Friedel:AbbVie: Employment, Equity Ownership. Menon:AbbVie: Employment, Equity Ownership. Salem:AbbVie: Employment, Equity Ownership.

Underlying causes of PM2.5-induced premature mortality and potential health benefits of air pollution control in South and Southeast Asia from 1999 to 2014

Quantification of spatial and temporal variations in premature mortality attributable to PM2.5 has important implications for air quality control in South and Southeast Asia (SSEA). The number of PM2.5-induced premature deaths during 1999–2014 in SSEA was estimated using an integrated exposure-response model based on 0.01° × 0.01° satellite-retrieved PM2.5 data, population density, and spatially and temporally variable baseline mortality data. The results showed extremely high premature death rates in North India and Bangladesh. PM2.5-induced premature deaths in SSEA increased with small interannual variations from 1999 to 2014 owing to the interannual variations in PM2.5 concentrations. Moreover, four scenarios on the effects of premature deaths by PM2.5 mitigation efforts based on World Health Organization (WHO) air quality guidelines (AQG) and interim targets (ITs) were investigated for each disease and each country during 1999–2014. Four scenarios based on WHO AQG (10 μg/m3), IT-3 (15 μg/m3), IT-2 (25 μg/m3), and IT-1 (35 μg/m3) resulted in 69.3%, 49.1%, 25.4%, and 12.8% reductions compared to the total reference premature deaths (1256,300), which was calculated using the original PM2.5 datasets. Overall, stroke was the most serious disease associated with air pollution, causing 40% of total premature deaths. Ischemic heart disease was the largest contributor (58%) to the deaths in relatively cleaner air (Scenario 1). The annual rate of change in premature deaths in South Asian countries (India, Bangladesh, and Pakistan) was higher than that in Southeast Asian countries under all scenarios. The results for different scenarios provide insight into the largest health benefits of PM2.5 reduction efforts.

Tightening Standards for Indoor Levels of PM2.5: A Promising Approach for Reducing PM2.5 Associated Mortalities in Urban China

Outdoor PM2.5 pollution in China has been estimated to cause more than one million premature mortalities annually. In urban areas residents spend a major fraction of their time indoors, meaning that a large fraction of urban exposure to &amp;#8220;outdoor PM2.5&amp;#8221; occurs indoors. This study estimates premature adult mortalities attributed to PM2.5 across urban China in 2015 and the corresponding mortality reductions achieved by meeting the yearly-averaged indoor PM2.5 threshold in the newly established Assessment Standard for Healthy Building (ASHB) and seven other potential thresholds. We use outdoor PM2.5 concentrations from 1497 monitoring sites in 366 cities in China, coupled with a detailed exposure model, to estimate outdoor and indoor exposures to PM2.5 originating outdoors. We proceed to calculate premature mortality attributable to PM2.5 exposure using an integrated exposure-response model. Results indicate that indoor exposures accounted for 66%-87% of total exposure to PM2.5 of outdoor origin and 76% (248,174) of the 328,362 premature mortalities attributable to &amp;#8220;outdoor PM2.5&amp;#8221; for the urban population &amp;#8805;25 years of age in China in 2015. Stroke, ischemic heart disease, chronic obstructive pulmonary disease, and lung cancer mortalities attributable to indoor exposure were 132,209, 71,960, 24,233 and 19,773, respectively. Potentially 10,172 deaths could be avoided if indoor PM2.5 of outdoor origin met the current ASHB standard of 35 &amp;#956;g/m3 as annual mean, and 113,219 deaths could be avoided by meeting a 10 &amp;#956;g/m3 threshold. The findings demonstrate the effectiveness of reducing indoor exposures to &amp;#8220;outdoor PM2.5&amp;#8221; in reducing premature mortalities attributable to urban PM2.5 pollution in China. Estimates of mortality reductions associated with various indoor PM2.5 thresholds can help formulate indoor air quality policies and practices, including building- or room-based filtration of ventilation air.

Exposure\u2013response analysis and simulation of lenvatinib safety and efficacy in patients with radioiodine-refractory differentiated thyroid cancer

PurposeOnce-daily lenvatinib 24 mg is the approved dose for radioiodine-refractory differentiated thyroid cancer. In a phase 3 trial with lenvatinib, the starting dose of 24 mg was associated with a relatively high incidence of adverse events that required dose reductions. We used an exposure–response model to investigate the risk–benefit of different dosing regimens for lenvatinib.MethodsA population pharmacokinetics/pharmacodynamics modeling analysis was used to simulate the potential benefit of lower starting doses to retain efficacy with improved safety. The seven lenvatinib regimens tested were: 24 mg; and 20 mg, 18 mg, and 14 mg, all with or without up-titration to 24 mg. Exposure–response models for efficacy and safety were created using a 24-week time course.ResultsThe approved dose of lenvatinib at 24 mg, predicted the best efficacy. However, the lenvatinib dosing regimens of 14 mg with up-titration or 18 mg without up-titration potentially provides comparable efficacy (objective response rate at 24 weeks) and a better safety profile.ConclusionsTreatment with lenvatinib at starting doses lower than the approved once-daily 24 mg dose could provide comparable antitumor efficacy and a similar or better safety profile. Based on the results from this modeling and simulation study, a comparator dose of lenvatinib 18 mg without up-titration was selected for evaluation in a clinical trial.

PM2.5-related health and economic loss assessment for 338 Chinese cities

China is in a critical stage of ambient air quality management after global attention on pollution in its cities. Industrial development and urbanization have led to alarming levels of air pollution with serious health hazards in densely populated cities. The quantification of cause-specific PM2.5-related health impacts and corresponding economic loss estimation is crucial for control policies on ambient PM2.5 levels. Based on ground-level direct measurements of PM2.5 concentrations in 338 Chinese cities for the year 2016, this study estimates cause-specific mortality using integrated exposure-response (IER) model, non-linear power law (NLP) model and log-linear (LL) model followed by morbidity assessment using log-linear model. The willingness to pay (WTP) and cost of illness (COI) methods have been used for PM2.5-attributed economic loss assessment. In 2016 in China, the annual PM2.5 concentration ranged between 10 and 157 μg/m3 and 78.79% of the total population was exposed to >35 μg/m3 PM2.5 concentration. Subsequently, the national PM2.5-attributable mortality was 0.964 (95% CI: 0.447, 1.355) million (LL: 1.258 million and NPL: 0.770 million), about 9.98% of total reported deaths in China. Additionally, the total respiratory disease and cardiovascular disease-specific hospital admission morbidity were 0.605 million and 0.364 million. Estimated chronic bronchitis, asthma and emergency hospital admission morbidity were 0.986, 1.0 and 0.117 million respectively. Simultaneously, the PM2.5 exposure caused the economic loss of 101.39 billion US$, which is 0.91% of the national GDP in 2016. This study, for the first time, highlights the discrepancies associated with the three commonly used methodologies applied for cause-specific mortality assessment. Mortality and morbidity results of this study would provide a measurable assessment of 338 cities to the provincial and national policymakers of China for intensifying their efforts on air quality improvement.

The impact of power generation emissions on ambient PM2.5 pollution and human health in China and India

Emissions from power plants in China and India contain a myriad of fine particulate matter (PM2.5, PM ≤ 2.5 μm in diameter) precursors, posing significant health risks among large, densely settled populations. Studies isolating the contributions of various source classes and geographic regions are limited in China and India, but such information could be helpful for policy makers attempting to identify efficient mitigation strategies. We quantified the impact of power generation emissions on annual mean PM2.5 concentrations using the state-of-the-art atmospheric chemistry model WRF-Chem (Weather Research Forecasting model coupled with Chemistry) in China and India. Evaluations using nationwide surface measurements show the model performs reasonably well. We calculated province-specific annual changes in mortality and life expectancy due to power generation emissions generated PM2.5 using the Integrated Exposure Response (IER) model, recently updated IER parameters from Global Burden of Disease (GBD) 2015, population data, and the World Health Organization (WHO) life tables for China and India. We estimate that 15 million (95% Confidence Interval (CI): 10 to 21 million) years of life lost can be avoided in China each year and 11 million (95% CI: 7 to 15 million) in India by eliminating power generation emissions. Priorities in upgrading existing power generating technologies should be given to Shandong, Henan, and Sichuan provinces in China, and Uttar Pradesh state in India due to their dominant contributions to the current health risks.

A Review and Meta-Analysis of Occupational Titanium Dioxide Exposure and Lung Cancer Mortality

A review of studies of occupational titanium dioxide (TiO2) exposure was conducted, and results from the three industry-based cohort mortality studies were summarized using meta-analysis. Summary standardized mortality ratios (SSMR) and summary Cox regression coefficients from exposure-response models were derived using random effects models. Results from studies of 24,312 TiO2 production workers were combined. SSMRs for lung cancer, all causes, all cancer, and non-malignant respiratory disease were 1.10 (95% confidence interval [CI]: 0.91 to 1.32), 0.85 (95% CI: 0.81 to 0.89), 0.92 (95% CI: 0.82 to 1.03), and 0.85 (95% CI: 0.71 to 1.02), respectively. For lung cancer, the summary hazard ratio for a 1 mg/m year increase in cumulative exposure was 0.999 (0.997 to 1.002). Consistent with other published qualitative reviews, there is no clear evidence of an association between occupational exposure to TiO2 and lung cancer.

Dapagliflozin Exposure Response in Japanese vs. Non-Japanese Patients with Type 1 Diabetes

Dapagliflozin (DAPA), an SGLT2 inhibitor, reduces blood glucose by increasing urinary glucose excretion (UGE). The pharmacokinetics and pharmacodynamics of DAPA in Japanese and non-Japanese patients (pts) with type 1 diabetes (T1D) have been evaluated in 2 studies (Japanese: NCT01498185, n=42, DAPA 5, 10 mg or placebo [PBO] for 14 days; Non-Japanese: NCT02582814, n=70, DAPA, 1, 2.5, 5, 10 mg or PBO for 7 days). A clear dose-response for 24-hour UGE was seen in the non-Japanese study but not in the Japanese study. An exposure-response model was used to characterize the relationship between DAPA exposure and 24-hour UGE using a nonlinear mixed-effect modeling approach, and the effect of patient-level characteristics (baseline and Day 7) on this was investigated. Covariates were identified using a stepwise procedure. Average self-monitored blood glucose (SMBG) at Day 7, Day 7 change from baseline in total insulin dose, and baseline eGFR all had a significant effect on UGE; SMBG was the most influential. When these covariates are included, the model fits the data well for both populations (Figure; for the Japanese study, 1 and 2.5 mg data were simulated using median AUC from non-Japanese pts, for 5 and 10 mg median covariate values were from the Japanese study). The lack of clear dose-response in UGE in Japanese pts may primarily be caused by high SMBG, which is likely a result of greater insulin dose reductions in the Japanese study. Disclosure V. Sokolov: None. T. Yakovleva: None. S. Ueda: Employee; Self; AstraZeneca. J.R. Parkinson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. R.C. Penland: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Novartis Pharmaceuticals Corporation. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. W. Tang: Employee; Self; AstraZeneca.

Dose-Response and Exposure-Response (HbA1c) of Dapagliflozin in T1DM Patients

Dapagliflozin is an inhibitor of the human renal sodium glucose co-transporter type 2 (SGLT2), which lowers plasma glucose by promoting urinary glucose excretion. Dapagliflozin is approved for the treatment of type 2 diabetes mellitus in adults. The effect of dapagliflozin in type 1 diabetes mellitus (T1DM) has been evaluated in 2 clinical trials: DEPICT 1 and DEPICT 2 (NCT02268214 and NCT02460978). The aim of this analysis was to use pooled data from both studies and assess the dose-response (DR) and exposure-response (ER) relationship for dapagliflozin on HbA1c reduction in T1DM patients. In both studies, T1DM patients underwent double-blinded 24-week treatment with either placebo, 5 or 10 mg dapagliflozin doses—plus adjustable insulin. Mixed-Effect Model Repeated Measures including DR/ER functions was used to describe the longitudinal HbA1c data. The DR and ER models described the data from T1DM patients well. DR model predicted HbA1c mean (95% CI) reductions at week 24 (placebo-corrected change from baseline) in T1DM patients to: -0.38% (-0.46, -0.3) and -0.43% (-0.52, -0.35) for 5 mg and 10 mg doses, respectively, which was in good agreement with the actual observations (-0.42% and -0.37% for 5 mg and -0.45% and -0.42% for 10 mg in DEPICT 1 and DEPICT 2 studies, respectively). The estimated ED50 was 1.39 mg and AUC50 (exposure resulting in half maximal effect) was 35.56 ng/ml*h. The effect of several covariates was assessed and the method of insulin administration was found to have an impact on dapagliflozin efficacy in T1DM patients. According to the model, patients who were using insulin pump were predicted to have somewhat larger HbA1c reductions compared to patients who used multiple daily injections. For example, following 10 mg dapagliflozin treatment, patients using pump were predicted to have mean HbA1c reduction of -0.47%, compared to -0.39% in patients without the pump. The difference in the maximum HbA1c reductions was however only approximately 20% and was not deemed to be clinically relevant. Disclosure J.R. Parkinson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Melin: Employee; Self; AstraZeneca. M. Åstrand: Employee; Self; AstraZeneca. B. Hamren: Employee; Self; AstraZeneca. Employee; Spouse/Partner; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. W. Tang: Employee; Self; AstraZeneca.