Drug-like properties of tyrosine kinase inhibitors in ophthalmology: Formulation and topical availability

Jansook, Phatsawee; Loftsson, Thorsteinn; Stefánsson, Einar

doi:10.1016/j.ijpharm.2024.124018

Cited by 3 publications

(2 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thereby, compared to sunitinib, axitinib would be more suitable for pharmaceutical development of an ocular topical formulation for treatment of retinal proliferative diseases, also based on its established pharmacodynamic profile as potent VEGFR inhibitor, although several chemical-physical properties of axitinib make the design of eye drops formulation challenging (Jansook et al, 2024). Besides its validated activity as tyrosine kinase receptor inhibitor, we found in our in vitro models of diabetic retinopathy that axitinib exerts antioxidant, anti-inflammatory and antiangiogenic effects, also regulating Nrf2 expression, likely through covalent binding to Keap1-BTB domain.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, axitinib and sunitinib ocular adverse events were correlated to the dose ( Dib et al, 2012 ; Jenkins et al, 2021 ). Thereby, compared to sunitinib, axitinib would be more suitable for pharmaceutical development of an ocular topical formulation for treatment of retinal proliferative diseases, also based on its established pharmacodynamic profile as potent VEGFR inhibitor, although several chemical-physical properties of axitinib make the design of eye drops formulation challenging ( Jansook et al, 2024 ).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-angiogenic and antioxidant effects of axitinib in human retinal endothelial cells: implications in diabetic retinopathy

Lazzara,

Conti,

Sasmal

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

Diabetic retinopathy is a secondary microvascular complication of diabetes mellitus. This disease progresses from two stages, non-proliferative and proliferative diabetic retinopathy, the latter characterized by retinal abnormal angiogenesis. Pharmacological management of retinal angiogenesis employs expensive and invasive intravitreal injections of biologic drugs (anti-vascular endothelial growth factor agents). To search small molecules able to act as anti-angiogenic agents, we focused our study on axitinib, which is a tyrosine kinase inhibitor and represents the second line treatment for renal cell carcinoma. Axitinib is an inhibitor of vascular endothelial growth factor receptors, and among the others tyrosine kinase inhibitors (sunitinib and sorafenib) is the most selective towards vascular endothelial growth factor receptors 1 and 2. Besides the well-known anti-angiogenic and immune-modulatory functions, we hereby explored the polypharmacological profile of axitinib, through a bioinformatic/molecular modeling approach and in vitro models of diabetic retinopathy. We showed the anti-angiogenic activity of axitinib in two different in vitro models of diabetic retinopathy, by challenging retinal endothelial cells with high glucose concentration (fluctuating and non-fluctuating). We found that axitinib, along with inhibition of vascular endothelial growth factor receptors 1 (1.82 ± 0.10; 0.54 ± 0.13, phosphorylated protein levels in fluctuating high glucose vs. axitinib 1 µM, respectively) and vascular endothelial growth factor receptors 2 (2.38 ± 0.21; 0.98 ± 0.20, phosphorylated protein levels in fluctuating high glucose vs. axitinib 1 µM, respectively), was able to significantly reduce (p < 0.05) the expression of Nrf2 (1.43 ± 0.04; 0.85 ± 0.01, protein levels in fluctuating high glucose vs. axitinib 1 µM, respectively) in retinal endothelial cells exposed to high glucose, through predicted Keap1 interaction and activation of melanocortin receptor 1. Furthermore, axitinib treatment significantly (p < 0.05) decreased reactive oxygen species production (0.90 ± 0.10; 0.44 ± 0.06, fluorescence units in high glucose vs. axitinib 1 µM, respectively) and inhibited ERK pathway (1.64 ± 0.09; 0.73 ± 0.06, phosphorylated protein levels in fluctuating high glucose vs. axitinib 1 µM, respectively) in HRECs exposed to high glucose. The obtained results about the emerging polypharmacological profile support the hypothesis that axitinib could be a valid candidate to handle diabetic retinopathy, with ancillary mechanisms of action.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anti-angiogenic and antioxidant effects of axitinib in human retinal endothelial cells: implications in diabetic retinopathy

Lazzara,

Conti,

Sasmal

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

Role of EYP-1901 in neovascular age-related macular degeneration and diabetic eye diseases: review of Phase I/II trials

Sayed,

Ravichandran,

Canizela

et al. 2024

Therapeutic Delivery

View full text Add to dashboard Cite

Phase Separation Investigation of Axitinib in Supersaturated Solution

Xu,

Su,

Zhang

et al. 2024

Crystals

View full text Add to dashboard Cite

Phase separation is quite common in formulations for hydrophobic active pharmaceutical ingredients (APIs) due to their thermodynamic instability in a supersaturated state during in vitro dissolution or in vivo absorption. Phase separation possibly accompanies the formation of a disordered drug-rich phase, but this is still not thoroughly understood. In this study, the phase separation of supersaturated axitinib (Axi) in media with or without polymers was evaluated via multiple analytical methods, including UV–vis and fluorescence spectroscopy, dynamic light scattering, and microscopy. The phase separation of Axi occurred at an Axi concentration of 25–30 µg/mL in the media, while the addition of quantitative hypromellose acetate succinate (HPMCAS) MG and povidone (PVP) K30 did not alter its phase separation concentration. The second scattering dispersion phase of the system exhibited superior stability and reversibility as the formative filamentous crystalline condensates could disintegrate upon dilution. These disparate analyses consistently detected the phase separation of Axi. This manuscript could provide a better understanding of the supersaturation state of hydrophobic APIs upon pharmaceutical application.

show abstract

Drug-like properties of tyrosine kinase inhibitors in ophthalmology: Formulation and topical availability

Cited by 3 publications

References 72 publications

Anti-angiogenic and antioxidant effects of axitinib in human retinal endothelial cells: implications in diabetic retinopathy

Anti-angiogenic and antioxidant effects of axitinib in human retinal endothelial cells: implications in diabetic retinopathy

Role of EYP-1901 in neovascular age-related macular degeneration and diabetic eye diseases: review of Phase I/II trials

Phase Separation Investigation of Axitinib in Supersaturated Solution

Contact Info

Product

Resources

About