Cedirogant Population Pharmacokinetics and Pharmacodynamic Analyses of Interleukin-17A Inhibition in Two Phase 1 Studies in Healthy Participants and Participants with Moderate to Severe Psoriasis.

Cedirogant (ABBV-157) is an orally bioavailable inverse agonist of retinoic acid-related orphan receptor gamma thymus. Data from 2 Phase 1 studies were used to characterize cedirogant pharmacokinetics and evaluate target engagement. Cedirogant plasma concentrations and ex vivo interleukin 17A (IL-17A) concentrations from healthy participants and participants with moderate to severe psoriasis (PsO) were analyzed in a population pharmacokinetic and pharmacodynamic modeling framework to characterize cedirogant pharmacokinetics following single and multiple doses and assess ex vivo IL-17A inhibition in relation to cedirogant exposure. Cedirogant population pharmacokinetics were best described by a 2-compartment pharmacokinetic model with delayed absorption and an enzyme turnover compartment to describe cytochrome P450 3A autoinduction. The pharmacokinetics of cedirogant were comparable between healthy participants and participants with PsO. Cedirogant steady-state average and maximum plasma concentrations were predicted to be 7.56 and 11.8 mg/L, respectively, for participants with PsO for the 375 mg once-daily regimen on Day 14. The apparent clearance and apparent volume of distribution for cedirogant were estimated to be 24.5 L/day and 28.2 L, respectively. A direct maximum inhibition model adequately characterized the exposure-response relationship of cedirogant and ex vivo IL-17A inhibition, indicating no temporal delay between exposure and response with a saturable inhibition of IL-17A. Model-estimated half-maximal inhibitory concentration and maximum inhibition values for cedirogant inhibition of ex vivo IL-17A were 0.56 mg/L and 0.76, respectively. The established relationship between cedirogant exposure and biomarker effect supported dose selection for the Phase 2 dose-ranging study in patients with PsO.

Improved diet quality is associated with decreased concentrations of inflammatory markers in adults with uncontrolled asthma.

BACKGROUND: Asthma has become one of the major public health challenges, and recent studies show promising clinical benefits of dietary interventions, such as the Dietary Approaches to Stop Hypertension (DASH) diet. OBJECTIVE: The objective of this study was to examine whether changes in diet quality are associated with changes in inflammatory markers important in asthma pathophysiology. METHODS: In this exploratory study in patients with poorly controlled asthma participating in a randomized controlled trial of a DASH intervention study, changes in concentrations of a broad panel of serum proteins (51-plex Luminex assay, Affymetrix) were determined, and their relation to diet quality (DASH score) assessed by combining data of both intervention and usual-care control groups. Second, the relation between the serum proteins, other biomarkers of inflammation and nutrition, and Asthma Control Questionnaire (ACQ) was assessed. RESULTS: During the first 3 mo, diet quality (DASH scores) were inversely associated (P < 0.05, false discovery rate P < 0.09) with serum concentrations of a large number serum proteins, reflecting not only general proinflammatory markers such as IL-1ß, transforming growth factor α (TGF-α), and IL-6 (r = -0.31 to -0.39) but also a number of proteins associated with asthmatic conditions, specifically several T-helper (Th) 2 (Th2; r = -0.29 to -0.34) and Th17 (r = -0.4) associated cytokines and growth factors. Monokine induced by gamma/chemokine (C-X-C motif) ligand 9 (CXCL9) (MIG/CXCL9), a T-cell attractant induced by IFN-γ previously linked to asthma exacerbations, appeared to be the marker most consistently associated with DASH diet quality for the entire 6-mo study period (r = -0.40 and -0.30 for 0-3 and 3-6 mo, respectively, and standardized coefficient loadings -0.13 in the partial least squares analyses). Decreases in 19 serum protein concentrations were also correlated with improved asthma control during the 6-mo study period. CONCLUSIONS: Our data in adult patients with poorly controlled asthma suggest that dietary changes, like the introduction of DASH, may have beneficial effects on reducing inflammatory status. This trial was registered at http://www.clinicaltrials.gov as NCT01725945.

Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children's Environmental Health Studies: The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group.

BACKGROUND: Characterization of the epigenome is a primary interest for children's environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early-life exposures on later-in-life health outcomes. OBJECTIVES: Our objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children's Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis. METHODS: We address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research. DISCUSSION: A common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children's health. CONCLUSION: The dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.