BACKGROUND: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/ACTG A5349 represents the largest Phase 3 randomized controlled therapeutic trial to date for such investigation.
OBJECTIVE: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure with efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits.
METHODS: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome.
RESULTS: Among 2255 participants with 6978 plasma samples, pyrazinamide displayed 7-fold exposure variability (151-1053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in a therapeutic window of 231-355 mg·h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1000 mg would have permitted an additional 13.1% (n=96) participants allocated to the control and 9.2% (n=70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared to the current weight-banded dosing.
CONCLUSIONS: Flat dosing of pyrazinamide at 1000 mg daily would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registration available at www.
RESULTS: gov, ID: NCT02410772. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND: Anemia is common in low- and middle-income countries (LMICs), causing significant health issues and social burdens. Exposure to household air pollution from using biomass fuels for cooking and heating has been associated with anemia, but the exposure-response association has not been studied.
OBJECTIVE: We evaluated the associations between personal exposure to air pollution and both hemoglobin levels and anemia prevalence among pregnant women in a multi-country randomized controlled trial.
METHODS: We studied 3,163 pregnant women aged 18-35 years with 9-20 weeks of gestation, recruited as part of the Household Air Pollution Intervention Network (HAPIN) randomized controlled trial in Guatemala, India, Peru, and Rwanda. We assessed 24-hour personal exposures to fine particulate matter (PM2.5), black carbon (BC), and carbon monoxide (CO), and measured hemoglobin levels at baseline (15 ± 3 weeks gestation). Linear and logistic regression models were used to examine the associations of measured pollutants with hemoglobin levels and anemia prevalence, adjusting for confounding.
RESULTS: Single-pollutant models showed associations of CO with higher hemoglobin levels and lower anemia prevalence. Bipollutant models involving CO and PM2.5 also revealed that an interquartile range (IQR) increase in CO concentrations (2.26 ppm) was associated with higher hemoglobin levels [β = 0.04; 95 % confidence interval (CI): 0.01, 0.07], and a lower odds of anemia prevalence [odds ratios (OR) = 0.90; 95 % CI: 0.83, 0.98]. PM2.5 was inversely related to hemoglobin and positively associated with anemia, but results were not statistically significant at the 0.05 alpha level. County-specific results showed that 3 of 4 countries showed a similar association between CO and hemoglobin. We found no association of BC levels with hemoglobin levels or with anemia prevalence.
CONCLUSIONS: Our findings suggest that exposure to CO is associated with higher hemoglobin and lower anemia prevalence among pregnant women, whereas PM2.5 showed the opposite associations.

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OBJECTIVE: Mycophenolic acid (MPA) is recommended for lupus nephritis (LN) treatment, but with large inter-individual variability in pharmacokinetics (PK). The aim of this study is to reveal the relationship between MPA exposure and disease response and adverse drug reactions in pediatric LN patients.
METHODS: This was a population-based observational cohort study. A total of 86 pediatric LN patients treated with mycophenolate mofetil (MMF) for induction therapy were enrolled. The area-under the concentration-time curve (AUC) was calculated using MPA concentrations according to a limited sampling strategy. Receiver operating characteristic analysis was performed to assess the MPA-AUC threshold values. The cumulative incidence of renal remission and inactive SLE over time was evaluated by Kaplan-Meier\'s analysis.
RESULTS: MPA-AUC was identified as an independent factor associated with renal remission and lupus activity at 6 and 12 months after MMF treatment, and the improved renal remission rates was correlated with higher MPA-AUC, with thresholds of 29.81 and 30.63 μg·h·mL - 1 at 6 and 12 months, respectively. Furthermore, the thresholds for maintaining the hypoactive state of LN were 30.96 and 31.19 μg·h·mL - 1at 6 months and 12 months, respectively. Patients reaching target thresholds for MPA-AUC achieved renal response or stable disease earlier. In addition, the MPA-AUC threshold for decreasing MMF-related adverse reactions was 50.80 μg·h·mL - 1.
CONCLUSIONS: The initial and long-term treatments of pediatric LN patients with MMF should be individualized according to the MPA-AUC, and the recommended MPA exposure is 31.19-50.80 μg·h·mL - 1.

BACKGROUND: While the adverse health effects of civil aircraft noise are relatively well studied, impacts associated with more intense and intermittent noise from military aviation have been rarely assessed. In recent years, increased training at Naval Air Station Whidbey Island, USA has raised concerns regarding the public health and well-being implications of noise from military aviation.
OBJECTIVE: This study assessed the public health risks of military aircraft noise by developing a systematic workflow that uses acoustic and aircraft operations data to map noise exposure and predict health outcomes at the population scale.
METHODS: Acoustic data encompassing seven years of monitoring efforts were integrated with flight operations data for 2020-2021 and a Department of Defense noise simulation model to characterize the noise regime. The model produced contours for day-night, nighttime, and 24-h average levels, which were validated by field monitoring and mapped to yield the estimated noise burden. Established thresholds and exposure-response relationships were used to predict the population subject to potential noise-related health effects, including annoyance, sleep disturbance, hearing impairment, and delays in childhood learning.
RESULTS: Over 74,000 people within the area of aircraft noise exposure were at risk of adverse health effects. Of those exposed, substantial numbers were estimated to be highly annoyed and highly sleep disturbed, and several schools were exposed to levels that place them at risk of delay in childhood learning. Noise in some areas exceeded thresholds established by federal regulations for public health, residential land use and noise mitigation action, as well as the ranges of established exposure-response relationships.
UNASSIGNED: This study quantified the extensive spatial scale and population health burden of noise from military aviation. We employed a novel GIS-based workflow for relating mapped distributions of aircraft noise exposure to a suite of public health outcomes by integrating acoustic monitoring and simulation data with a dasymetric population density map. This approach enables the evaluation of population health impacts due to past, current, and future proposed military operations. Moreover, it can be modified for application to other environmental noise sources and offers an improved open-source tool to assess the population health implications of environmental noise exposure, inform at-risk communities, and guide efforts in noise mitigation and policy governing noise legislation, urban planning, and land use.

UNASSIGNED: Pharmacokinetic (PK)-Pharmacodynamic (PD) and exposure-response (E-R) modeling are critical parts of pediatric drug development. By integrating available knowledge and supportive data to support the design of future studies and pediatric dose selection, these techniques increase the efficiency of pediatric drug development and lowers the risk of exposing pediatric study participants to suboptimal or unsafe dose regimens.
UNASSIGNED: The role of PK, PK-PD and E-R modeling within pediatric drug development and pediatric dose selection is discussed. These models allow investigation of the impact of age and bodyweight on PK and PD in children, despite the often sparse data on the pediatric population. Also discussed is how E-R analyses strengthen the evidence basis to support (full or partial) extrapolation of drug efficacy from adults to children, and between different pediatric age groups.
UNASSIGNED: Accelerated pediatric drug development and optimized pediatric dosing guidelines are expected from three future developments: (1) Increased focus on E-R modeling of currently approved drugs in children resulting in (novel) E-R modeling techniques and best practices, (2) increased use of real-world data for E-R (3) increased implementation of available population PK and E-R information in pediatric drug dosing guidelines.

Venetoclax, a potent BCL-2 inhibitor, is currently under development for treatment of t(11;14) Multiple myeloma (MM). The objective of this research was to investigate the exposure-response relationships of venetoclax for a phase 1/2 study evaluating venetoclax monotherapy or in combination with dexamethasone in relapsed or refractory MM. A total of 117 patients receiving venetoclax at 300, 600, 800, 900, or 1200 mg were included in the analysis. The impact of venetoclax exposures on efficacy (objective response rate [ORR], progression-free survival [PFS] and overall survival [OS]) as well as safety (treatment-emergent adverse effects (grade ≥3) of neutropenia, infection, and any grade of serious treatment-emergent adverse effects) was evaluated. In the t(11;14)-positive subpopulation, venetoclax exposure relationships to PFS and OS indicated a trend of longer PFS and OS with higher exposures. Moreover, logistic regression analyses for clinical response (ORR and ≥VGPR rate) demonstrated a statistically significant (p < 0.05) relationship with exposure. Evaluation of the exposure-safety relationships demonstrated a lack of a relationship between venetoclax exposures (AUCavg ) and grade ≥3 infections, grade ≥3 neutropenia, grade ≥3 treatment-emergent adverse events or any grade serious treatment-emergent adverse events. These findings support further study of venetoclax at 800 mg QD dose in combination with dexamethasone in the t(11;14)-positive patient population where increased efficacy was observed without an increase in safety events.Clinical Trial: NCT01794520 registered 20 February 2013.

Here, we report the clinical pharmacology data from LUMINA-1 (NCT03188666), a Phase 2 trial that evaluated garetosmab (a monoclonal antibody against activin A) in patients with fibrodysplasia ossificans progressiva. Forty-four patients were randomly assigned to intravenous 10 mg/kg of garetosmab or placebo every 4 weeks in a double-blind 28-week treatment period, followed by a 28-week open-label treatment period with garetosmab, and subsequent open-label extension. Serum samples were obtained to assess pharmacokinetics (PK), immunogenicity, and bone morphogenetic protein 9 (BMP9). Comparative exposure-response analyses for efficacy and safety were performed with trough concentrations (Ctrough ) of garetosmab prior to dosing. Steady-state PK was reached 12-16 weeks after the first dose of garetosmab, with mean (standard deviation) Ctrough of 105 ± 30.8 mg/L. Immunogenicity assessments showed anti-garetosmab antibody formation in 1 patient (1/43; 2.3%); titers were low, and did not affect PK or clinical efficacy. Median concentrations of BMP9 in serum were approximately 40 pg/mL at baseline. There were no meaningful differences in PK or BMP9 concentration-time profiles between patients who did and did not experience epistaxis or death. The comparative exposure-response analyses demonstrated no association between Ctrough and efficacy or safety. PK findings were consistent with prior data in healthy volunteers and were typical for a monoclonal antibody administered at doses sufficient to saturate target-mediated clearance. There were no trends that suggested patients with higher serum exposures to garetosmab were more likely to experience a reduction in heterotopic ossification or adverse events. Garetosmab is being further evaluated in the Phase 3 OPTIMA trial.

Chronic spontaneous urticaria (CSU), a long-lasting disease in children, impacts their quality of life. We report the results of a phase 2b dose-finding trial of ligelizumab (NCT03437278) and a high-affinity humanized monoclonal anti-IgE antibody, in adolescents with CSU, supported by modeling and simulation analyses, mitigating challenges in pediatric drug development.
This multicenter, double-blind, placebo-controlled trial, randomized H1-antihistamine-refractory adolescent CSU patients (12-18 years) 2:1:1 to ligelizumab 24 mg, 120 mg, or placebo every 4 weeks for 24 weeks. Patients on placebo transitioned to ligelizumab 120 mg at week 12. Integrating data from the previous adult and present adolescent trial of ligelizumab, a nonlinear mixed-effects modeling described the longitudinal changes in ligelizumab pharmacokinetics, and its effect on weekly Urticaria Activity Score (UAS7).
Baseline UAS7 (mean ± SD) was 30.5 ± 7.3 (n = 24), 29.3 ± 7.7 (n = 13), and 32.5 ± 9.0 (n = 12) for patients (median age, 15 years) on ligelizumab 24 mg, 120 mg, and placebo, respectively. Change from baseline in UAS7 at week 12 with ligelizumab 24 mg, 120 mg, and placebo was -15.7 ± 10.9, -18.4 ± 12.3, and -13.0 ± 13.0, respectively. Ligelizumab was well-tolerated. The modeling analysis showed that body weight, but not age, affected ligelizumab\'s apparent clearance. No significant differences between adolescents and adults were detected on the model-estimated maximum effect and potency.
Ligelizumab exhibited efficacy and safety in adolescent CSU patients, consistent with that in adults. The PK and potency of ligelizumab were not impacted by age, and the same dose of ligelizumab can be used for treating adolescents and adults with CSU. Our study shows how modeling and simulation can complement pediatric drug development.

BACKGROUND: Workers in the salmon processing industry have an increased risk of developing respiratory diseases and other hypersensitivity responses due to occupational exposure to bioaerosols containing fish proteins and microorganisms, and related allergens. Little is known about effective measures to reduce bioaerosol exposure and about the extent of skin complaints among workers. In addition, while identification of risk factors is a core activity in disease prevention strategies, there is increasing interest in health-promoting factors, which is an understudied area in the salmon processing industry.
OBJECTIVE: The overall aim of this ongoing study is to generate knowledge that can be used in tailored prevention of development or chronification of respiratory diseases, skin reactions, protein contact dermatitis, and allergy among salmon processing workers. The main objective is to identify effective methods to reduce bioaerosol exposure. Further objectives are to identify and characterize clinically relevant exposure agents, identify determinants of exposure, measure prevalence of work-related symptoms and disease, and identify health-promoting factors of the psychosocial work environment.
METHODS: Data are collected during field studies in 9 salmon processing plants along the Norwegian coastline. Data collection comprises exposure measurements, health examinations, and questionnaires. A wide range of laboratory analyses will be used for further analysis and characterization of exposure agents. Suitable statistical analysis will be applied to the various outcomes of this comprehensive study.
RESULTS: Data collection started in September 2021 and was anticipated to be completed by March 2023, but was delayed due to the COVID-19 pandemic. Baseline data from all 9 plants included 673 participants for the health examinations and a total of 869 personal exposure measurements. A total of 740 workers answered the study\'s main questionnaire on demographics, job characteristics, lifestyle, health, and health-promoting factors. Follow-up data collection is not completed yet.
CONCLUSIONS: This study will contribute to filling knowledge gaps concerning salmon workers\' work environment. This includes effective workplace measures for bioaerosol exposure reduction, increased knowledge on hypersensitivity, allergy, respiratory and dermal health, as well as health-promoting workplace factors. Together this will give a basis for improving the work environment, preventing occupational health-related diseases, and developing occupational exposure limits, which in turn will benefit employees, employers, occupational health services, researchers, clinicians, decision makers, and other stakeholders.
BACKGROUND: ClinicalTrials.gov NCT05039229; https://www.clinicaltrials.gov/study/NCT05039229.
UNASSIGNED: DERR1-10.2196/48790.