scholarly journals Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

2021 ◽  
Author(s):  
Marc Vanhove ◽  
Jean-Marc Wagner ◽  
Bernard Noppen ◽  
Bart Jonckx ◽  
Elke Vermassen ◽  
...  
Keyword(s):  
General Circulation ◽  
Pharmacokinetic Model ◽  
Systemic Exposure ◽  
Age Related Macular Degeneration ◽  
Whole Body ◽  
Pharmacological Agents ◽  
Age Related ◽  
Pharmacokinetic Properties ◽  
High Concentrations ◽  
Systemic Compartment

AbstractIntravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.

scholarly journals Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 1. THR-149

2021 ◽  
Author(s):  
Marc Vanhove ◽  
Bernard Noppen ◽  
Jean-Marc Wagner ◽  
Tine Van Bergen ◽  
Philippe Barbeaux ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Systemic Exposure ◽  
Mathematical Expression ◽  
Secondary Complications ◽  
Pharmacological Agents ◽  
Rabbit Eye ◽  
High Concentrations ◽  
Circulating Levels ◽  
Pharmacokinetic Approach ◽  
Systemic Compartment

AbstractIntravitreal (IVT) injection of pharmacological agents is an established and widely used procedure for the treatment of many posterior segment of the eye diseases. IVT injections permit drugs to reach high concentrations in the retina whilst limiting systemic exposure. Beyond the risk of secondary complications such as intraocular infection, the potential of systemic adverse events cannot be neglected. Therefore, a detailed understanding of the rules governing systemic exposure following IVT drug administration remains a prerequisite for the evaluation and development of new pharmacological agents intended for eye delivery. We present here a novel mathematical model to describe and predict circulating drug levels following IVT in the rabbit eye, a species which is widely used for drug delivery, pharmacokinetic, and pharmacodynamic studies. The mathematical expression was derived from a pharmacokinetic model that assumes the existence of a compartment between the vitreous humor compartment itself and the systemic compartment. We show that the model accurately describes circulating levels of THR-149, a plasma kallikrein inhibitor in development for the treatment of diabetic macular edema. We hypothesize that the model based on the rabbit eye has broader relevance to the human eye and can be used to analyze systemic exposure of a variety of drugs delivered in the eye.

scholarly journals Development of an ultra-sensitive human IL-33 biomarker assay for age-related macular degeneration and asthma drug development

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Elaine Mai ◽  
Joyce Chan ◽  
Levina Goon ◽  
Braeden K. Ego ◽  
Jack Bevers ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Age Related Macular Degeneration ◽  
Reduced Form ◽  
Enzyme Linked Immunosorbent Assay ◽  
Interleukin 33 ◽  
Age Related ◽  
Significant Difference ◽  
High Concentrations

Abstract Background Over the past decade, human Interleukin 33 (hIL-33) has emerged as a key contributor to the pathogenesis of numerous inflammatory diseases. Despite the existence of several commercial hIL-33 assays spanning multiple platform technologies, their ability to provide accurate hIL-33 concentration measurements and to differentiate between active (reduced) and inactive (oxidized) hIL-33 in various matrices remains uncertain. This is especially true for lower sample volumes, matrices with low hIL-33 concentrations, and matrices with elevated levels of soluble Interleukin 1 Receptor-Like 1 (sST2), an inactive form of ST2 that competes with membrane bound ST2 for hIL-33 binding. Results We tested the performance of several commercially available hIL-33 detection assays in various human matrices and found that most of these assays lacked the sensitivity to accurately detect reduced hIL-33 at biologically relevant levels (sub-to-low pg/mL), especially in the presence of human sST2 (hsST2), and/or lacked sufficient target specificity. To address this, we developed and validated a sensitive and specific enzyme-linked immunosorbent assay (ELISA) capable of detecting reduced and total hIL-33 levels even in the presence of high concentrations of sST2. By incorporating the immuno-polymerase chain reaction (iPCR) platform, we further increased the sensitivity of this assay for the reduced form of hIL-33 by ~ 52-fold. Using this hIL-33 iPCR assay, we detected hIL-33 in postmortem human vitreous humor (VH) samples from donors with age-related macular degeneration (AMD) and found significantly increased hIL-33 levels when compared to control individuals. No statistically significant difference was observed in aqueous humor (AH) from AMD donors nor in plasma and nasosorption fluid (NF) from asthma patients compared to control individuals. Conclusions Unlike existing commercial hIL-33 assays, our hIL-33 bioassays are highly sensitive and specific and can accurately quantify hIL-33 in various human clinical matrices, including those with high levels of hsST2. Our results provide a proof of concept of the utility of these assays in clinical trials targeting the hIL-33/hST2 pathway.

scholarly journals Systemic pharmacokinetic/pharmacodynamic analysis of intravitreal aflibercept injection in patients with retinal diseases

2019 ◽  
Vol 4 (1) ◽  
pp. e000185 ◽  
Author(s):  
Peter K Kaiser ◽  
Laurent Kodjikian ◽  
Jean-Francois Korobelnik ◽  
Julia Winkler ◽  
Albert Torri ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Plasma Concentrations ◽  
Diabetic Macular Oedema ◽  
Systemic Exposure ◽  
Compartmental Analysis ◽  
Age Related Macular Degeneration ◽  
Time Data ◽  
Age Related ◽  
Intravitreal Aflibercept ◽  
Change In Mean

ObjectiveExplore relationships between systemic exposure to intravitreal aflibercept injection (IAI) and systemic pharmacodynamic effects via post hoc analyses of clinical trials of IAI for neovascular age-related macular degeneration (nAMD) or diabetic macular oedema (DME).Methods and analysisAdults from VGFT-OD-0702.PK (n=6), VGFT-OD-0512 (n= 5), VIEW 2 (n=1204) and VIVID-DME (n=404) studies were included. Validated ELISAs were used to measure concentrations of free and bound aflibercept (reported as adjusted bound) in plasma at predefined time points in each study. Non-compartmental analysis of concentration–time data was obtained with dense sampling in VGFT-OD-0702.PK and VGFT-OD-0512. Sparse sampling was used in VIEW 2 and VIVID-DME. Blood pressure or intrarenal function changes were also investigated.ResultsFollowing intravitreal administration, free aflibercept plasma concentrations quickly decreased once maximum concentrations were achieved at 1–3 days postdose; pharmacologically inactive adjusted bound aflibercept concentrations increased over a longer period and reached plateau 7 days postdose. Ratios of free and adjusted bound aflibercept decreased over time. There were no meaningful changes in systolic/diastolic blood pressure over the duration of each study at all systemic aflibercept exposure levels. For all treatment arms in VIEW 2, there was no clinically relevant change in mean intrarenal function from baseline at week 52. Overall, incidence of systemic adverse events in VIEW 2 and VIVID-DME was low and consistent with the known safety profile of IAI.ConclusionIAI administration was not associated with systemic effects in patients with nAMD or DME as measured by blood pressure or intrarenal function, two known pharmacologically relevant effects of anti-vascular endothelial growth factor.

scholarly journals Associations Between Serum Lutein and Human Gut Microbiota (P02-004-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Andrew Dinsmoor ◽  
Sharon Thompson ◽  
Caitlyn Edwards ◽  
Nicholas Burd ◽  
Naiman Khan ◽  
...  
Keyword(s):  
Dietary Intervention ◽  
Adult Population ◽  
Venous Blood ◽  
Age Related Macular Degeneration ◽  
Leafy Vegetables ◽  
Whole Body ◽  
Rrna Gene ◽  
Protective Effects ◽  
Food Record ◽  
Age Related

Abstract Objectives Lutein is a carotenoid found in green leafy vegetables, avocados, and eggs, and is purported to have protective effects against age-related macular degeneration (AMD) as well as benefits for visual and cognitive health. Recent studies have indicated significant variation in serum lutein among individuals and that gastrointestinal (GI) microbial profile may potentially contribute to lutein status. However, the extent to which the GI microbiota contribute to lutein is unclear. The current study aimed to determine GI microbial predictors of serum lutein in a healthy young adult population. Methods Among adults ages 25–45 years (N = 105), venous blood was collected following a 10-hour fast. Serum lutein was determined using HPLC. Fecal DNA was extracted and the V4 region of the 16S rRNA gene was amplified. Amplicon sequence variants were assigned using the GreenGenes 13-8 database and DADA2, followed by analysis in QIIME2 and LDA Effect Size (LEfSe). Participants underwent DXA scan for whole body % fat (%Fat) and completed a 7-day food record to assess lutein consumption. Demographic information on participant's age and sex was also assessed and included in the statistical models. Results Four genera (Dialister, Ruminococcus, Gemmiger, and Phascolarctobacterium) and two species (Bacteroides eggerthii, Ruminococcus torques) were different between individuals in the highest and lowest quartiles of serum lutein. The genera Ruminococcus (Rho = −0.24, P = 0.02) and Phascolarctobacterium (Rho = −0.21, P = 0.03) and species R. torques (Rho = −0.35, P < 0.001) were inversely related to serum lutein. Linear regression modelling, adjusted for age, sex, %Fat, and dietary lutein, revealed that R. torques was the only significant predictor of serum lutein concentrations, accounting for 8.4% of the variance. Conclusions Our results reveal that individuals with lower serum lutein concentrations have a higher relative abundance of R. torques than those with higher lutein concentrations. As R. torques has been shown to be elevated in those with AMD, it is possible the relationship between this microbe and lutein is evident earlier in adulthood. However, further dietary intervention trials are warranted to clarify the relations among R. torques and serum lutein concentrations. Funding Sources This work was supported by funds provided by the Department of Kinesiology and Community Health at the University of Illinois and the USDA National Institute of Food and Agriculture, Hatch Project 1009249. Partial support was also provided by the Hass Avocado Board.

scholarly journals Why Is Zeaxanthin the Most Concentrated Xanthophyll in the Central Fovea?

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1333
Author(s):  
Justyna Widomska ◽  
John Paul SanGiovanni ◽  
Witold K. Subczynski
Keyword(s):  
Cell Function ◽  
Fold Increase ◽  
Redox Balance ◽  
Biochemical Properties ◽  
Age Related Macular Degeneration ◽  
Molar Ratio ◽  
Retinal Eccentricity ◽  
Age Related ◽  
High Concentrations ◽  
Central Fovea

Diet-based xanthophylls (zeaxanthin and lutein) are conditionally essential polar carotenoids preferentially accreted in high concentrations (1 mM) to the central retina, where they have the capacity to impart unique physiologically significant biophysical biochemical properties implicated in cell function, rescue, and survival. Macular xanthophylls interact with membrane-bound proteins and lipids to absorb/attenuate light energy, modulate oxidative stress and redox balance, and influence signal transduction cascades implicated in the pathophysiology of age-related macular degeneration. There is exclusive transport, sequestration, and appreciable bioamplification of macular xanthophylls from the circulating carotenoid pool to the retina and within the retina to regions required for high-resolution sensory processing. The distribution of diet-based macular xanthophylls and the lutein metabolite meso-zeaxanthin varies considerably by retinal eccentricity. Zeaxanthin concentrations are 2.5-fold higher than lutein in the cone-dense central fovea. This is an ~20-fold increase in the molar ratio relative to eccentric retinal regions with biochemically detectable macular xanthophylls. In this review, we discuss how the differences in the specific properties of lutein and zeaxanthin could help explain the preferential accumulation of zeaxanthin in the most vulnerable region of the macula.

scholarly journals Therapeutic Efficacy of a Novel Acetylated Tetrapeptide in Animal Models of Age-Related Macular Degeneration

2021 ◽  
Vol 22 (8) ◽  
pp. 3893
Author(s):  
Hye Cheong Koo ◽  
Yi-Yong Baek ◽  
Jun-Sup Choi ◽  
Young-Myeong Kim ◽  
Bokyung Sung ◽  
...  
Keyword(s):  
Animal Models ◽  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Systemic Exposure ◽  
Age Related Macular Degeneration ◽  
Vegf Receptor ◽  
Age Related ◽  
Human Plasminogen ◽  
Endothelial Growth Factor

It has been shown previously that a novel tetrapeptide, Arg-Leu-Tyr-Glu (RLYE), derived from human plasminogen inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis, suppresses choroidal neovascularization in mice by an inhibition of VEGF receptor-2 (VEGFR-2) specific signaling pathway. In this study, we report that a modified tetrapeptide (Ac-RLYE) showed improved anti-choroidal neovascularization (CNV) efficacy in a number of animal models of neovascular age-related macular degeneration (AMD) which include rat, rabbit, and minipig. The preventive and therapeutic in vivo efficacy of Ac-RLYE via following intravitreal administration was determined to be either similar or superior to that of ranibizumab and aflibercept. Assessment of the intraocular pharmacokinetic and toxicokinetic properties of Ac-RLYE in rabbits demonstrated that it rapidly reached the retina with minimal systemic exposure after a single intravitreal dose, and it did not accumulate in plasma during repetitive dosing (bi-weekly for 14 weeks). Our results suggested that Ac-RLYE has a great potential for an alternative therapeutics for neovascular (wet) AMD. Since the amino acids in human VEGFR-2 targeted by Ac-RLYE are conserved among the animals employed in this study, the therapeutic efficacies of Ac-RLYE evaluated in those animals are predicted to be observed in human patients suffering from retinal degenerative diseases.

scholarly journals High Concentrations of Plasma n3 Fatty Acids Are Associated with Decreased Risk for Late Age-Related Macular Degeneration

2013 ◽  
Vol 143 (4) ◽  
pp. 505-511 ◽  
Author(s):  
Bénédicte M. J. Merle ◽  
Marie-Noëlle Delyfer ◽  
Jean-François Korobelnik ◽  
Marie-Bénédicte Rougier ◽  
Florence Malet ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
High Concentrations

scholarly journals Zinc and Diabetic Retinopathy

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Xiao Miao ◽  
Weixia Sun ◽  
Lining Miao ◽  
Yaowen Fu ◽  
Yonggang Wang ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Age Related Macular Degeneration ◽  
Ocular Tissue ◽  
Zn Deficiency ◽  
Ocular Development ◽  
Age Related ◽  
Negative Effect ◽  
High Concentrations ◽  
Available Information

Zinc (Zn) is an important nutrient that is involved in various physiological metabolisms. Zn dyshomeostasis is often associated with various pathogeneses of chronic diseases, such as metabolic syndrome, diabetes, and related complications. Zn is present in ocular tissue in high concentrations, particularly in the retina and choroid. Zn deficiencies have been shown to affect ocular development, cataracts, age-related macular degeneration, and even diabetic retinopathy. However, the mechanism by which Zn deficiency increases the prevalence of diabetic retinopathy remains unclear. In addition, due to the negative effect of Zn deficiency on the eye, Zn supplementation should prevent diabetic retinopathy; however, limited available data do not always support this notion. Therefore, the goal of this paper was to summarize these pieces of available information regarding Zn prevention of diabetic retinopathy. Current theories and possible mechanisms underlying the role of Zn in the eye-related diseases are discussed. The possible factors that affect the preventive effect of Zn supplementation on diabetic retinopathy were also discussed.

scholarly journals HtrA1 alters endothelial tube formation characteristics in an in vitro model

2019 ◽  
Author(s):  
Harmeet Singh ◽  
Guiying Nie
Keyword(s):  
Endothelial Dysfunction ◽  
Capillary Tube ◽  
Tube Formation ◽  
Age Related Macular Degeneration ◽  
Tube Length ◽  
Age Related ◽  
Endothelial Tube Formation ◽  
High Concentrations ◽  
The Impact

AbstractHigh temperature requirement factor A1 (HtrA1) is a serine protease of the mammalian HtrA family. It is ubiquitously expressed with high levels in the placenta. Dysregulation of HtrA1 has been linked to a number of diseases, in particular age-related macular degeneration (AMD) and preeclampsia (PE) in which HtrA1 is significantly increased. AMD is the leading cause of irreversible visual impairment in older people, affecting millions across the globe. PE is a life-threatening pregnancy complication, affecting 2-7% of pregnant women worldwide. Although AMD and PE are very different diseases, both are associated with endothelial dysfunction and dysregulation of angiogenesis. Given HtrA1 is up-regulated in both AMD and PE, in this study we examined the impact of excessive HtrA1 on capillary tube formation of HUVECs as an in vitro angiogenesis model. HtrA1 at high concentrations significantly increased the total number of tube branch points and inter-tubular loops, but considerably decreased the mean tube length, resulting in more but much smaller tubes. However, these smaller tubes were incomplete/broken. These data demonstrated that high concentrations of HtrA1 altered endothelial tube formation characteristics of HUVEVs. Our results suggest that HtrA1 over-expression in AMD and PE may directly contribute to the endothelial dysfunction in these diseases.

Age related macular degeneration (ARMD) – pathophysiological and clinical features and therapeutic concepts

2001 ◽  
Vol 58 (1) ◽  
pp. 28-35 ◽  
Author(s):  
Ursula Körner-Stiefbold
Keyword(s):  
Macular Degeneration ◽  
Clinical Features ◽  
Altersbedingte Makuladegeneration ◽  
Age Related Macular Degeneration ◽  
Genetische Faktoren ◽  
Age Related ◽  
Therapeutic Concepts

Die altersbedingte Makuladegeneration (AMD) ist eine der häufigsten Ursachen für einen irreversiblen Visusverlust bei Patienten über 65 Jahre. Nahezu 30% der über 75-Jährigen sind von einer AMD betroffen. Trotz neuer Erkenntnisse in der Grundlagenforschung ist die Ätiologie, zu der auch genetische Faktoren gehören, noch nicht völlig geklärt. Aus diesem Grund sind die Behandlungsmöglichkeiten zum jetzigen Zeitpunkt noch limitiert, so dass man lediglich von Therapieansätzen sprechen kann. Die derzeit zur Verfügung stehenden Möglichkeiten wie medikamentöse, chirurgische und laser- und strahlentherapeutische Maßnahmen werden beschrieben.

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