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 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.

Intravitreal Aflibercept for Treatment-Resistant Neovascular Age-Related Macular Degeneration: 12-Month Safety and Efficacy Outcomes

2015 ◽  
Vol 55 (2) ◽  
pp. 84-90 ◽  
Author(s):  
Andrew A. Chang ◽  
Geoffrey K. Broadhead ◽  
Thomas Hong ◽  
Nichole Joachim ◽  
Adil Syed ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Treatment Resistant ◽  
Safety And Efficacy ◽  
Age Related ◽  
Intravitreal Aflibercept

Comparative effectiveness and harms of intravitreal antivascular endothelial growth factor agents for three retinal conditions: a systematic review and meta-analysis

2018 ◽  
Vol 103 (4) ◽  
pp. 442-451 ◽  
Author(s):  
Allison Low ◽  
Ambar Faridi ◽  
Kavita V Bhavsar ◽  
Glenn C Cockerham ◽  
Michele Freeman ◽  
...  
Keyword(s):  
Systematic Review ◽  
Visual Acuity ◽  
Growth Factor ◽  
Adverse Events ◽  
Meta Analysis ◽  
Diabetic Macular Oedema ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Antivascular Endothelial Growth Factor ◽  
Endothelial Growth Factor

Intravitreal antivascular endothelial growth factor (VEGF) agents are widely used to treat ocular conditions but the benefits and harms of these treatments are uncertain. We conducted a systematic review to compare the effects of aflibercept, bevacizumab and ranibizumab on best-corrected visual acuity (BCVA) changes, quality of life and ocular or systemic adverse events in patients with neovascular age-related macular degeneration (NVAMD), diabetic macular oedema (DME) and central or branch retinal vein occlusion (RVO). We searched published and unpublished literature sources to February 2017 for randomised controlled trials and cohort or modelling studies reporting comparative costs in the USA. Two reviewers extracted data and graded the strength of the evidence using established methods. Of 17 included trials, none reported a clinically important difference (≥ 5 letters) in visual acuity gains between agents. Nine trials provide high-strength evidence of no difference between bevacizumab and ranibizumab for NVAMD. Three trials provide moderate-strength evidence of no difference between bevacizumab and ranibizumab for DME. There was low-strength evidence of similar effects between aflibercept and ranibizumab for NVAMD, aflibercept and bevacizumab for RVO and all three agents for DME. There was insufficient evidence to compare bevacizumab and ranibizumab for RVO. Rates of ocular adverse events were low, and systemic harms were generally similar between groups, although 1 DME trial reported more arterial thrombotic events with ranibizumab versus aflibercept. Overall, no agent had a clear advantage over another for effectiveness or safety. Aflibercept and ranibizumab were significantly less cost-effective than repackaged bevacizumab in two trials. Systematic review registration number: CRD42016034076.

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