Approaches To Alleviate The Vigabatrin Induced Retinal Toxicity

Safety of therapeutics is one of the primary concerns during the treatment of any ailments. Most of the toxic effects of drugs occurs due to accumulation of drug in organs, which is dependent on the dosage of the drug. The ideal therapy should minimize the risk of causing adverse events at the same time elicit intended therapeutic effects. Vigabatrin (VGB) is an antiepileptic drug used primarily in the treatment of infantile spasms and it acts by inhibiting gamma amino butyric acid (GABA) transaminase thereby increasing inhibitory neurotransmitter GABA levels. At therapeutic doses, VGB accumulates in retina leading to peripheral visual field defects and retinal degeneration. To alleviate retinal toxicity of VGB, different approaches have been explored to decrease the ocular accumulation of VGB and to protect retina from deleterious effects of VGB. Intranasal administration approach was investigated to deliver VGB directly to brain via olfactory region. The in vivo acute, sub-acute and pharmacodynamic studies were performed in Sprague Dawley rats by administering VGB through intraperitoneal and intranasal routes. The mechanism of VGB transport across blood retinal barrier was studied using retinal epithelial cells (ARPE-19) cells. The in vitro and in vivo studies were performed to evaluate the mechanism involved in retinal uptake of VGB and identify approach to decrease VGB retinal uptake. The effects of VGB on retinal neuronal (R28) and ARPE-19 cells were studied. The cytoprotective effect of silymarin and taurine on VGB induced retinal toxicity was investigated. The subacute intranasal administration decreased retinal VGB levels and histological changes compared to intraperitoneal administration. Intranasal pharmacodynamic study demonstrated smaller dose produced significant antiepileptic activity with prolonged duration of VGB action. The ARPE19 cellular transport studies shoNa+/Cl- dependent transporter, TauT was involved in retinal VGB uptake. Further, in vitro cell uptake and in vivo SD rat studies demonstrated TauT inhibitors decreased VGB retinal uptake, thus confirming role of TauT in retinal uptake of VGB. The in vitro cell toxicity studies demonstrated, VGB treatment produced cell death in ARPE19 and R28 cells are due to apoptosis and necrosis, respectively. Further, studies demonstrated antioxidants silymarin and taurine constituents decreased VGB induced cell toxicity. The study results demonstrate intranasal administration of VGB along with a safe TauT inhibitor and an antioxidant as a supplement would be beneficial to prevent the VGB induced retinal toxicity

Preclinical assessment of ulixertinib, a novel ERK1/2 inhibitor

Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. In xenograft studies it inhibited tumor growth in BRAF-mutant melanoma and colorectal xenografts as well as KRAS-mutant colorectal and pancreatic models. Ulixertinib is currently in Phase I clinical development for the treatment of advance solid tumors. The objective of the study is to assess the metabolic stability (in various pre-clinical and human liver microsomes/hepatocytes), permeability, protein binding, CYP inhibition, CYP induction and CYP phenotyping of ulixertinib. We have also studied the oral and intravenous pharmacokinetics of ulixertinib in mice, rats and dogs. Ulixertinib was found to be moderately to highly stable in various liver microsomes/hepatocytes tested. It is a medium permeable (2.67 x 10-6 cm /sec) drug and a substrate for efflux (efflux ratio: 3.02) in Caco-2 model. Ulixertinib was highly bound to plasma proteins. CYPs involved in its limited metabolism and it is CYP inhibition IC50 ranged between 10-20 μM. Post oral administration ulixertinib exhibited early Tmax (0.50-0.75 h) in mice and rats indicating absorption was rapid, however in dogs Tmax attained at 2 h. The half-life (t½) of ulixertinib by intravenous and oral routes ranged between 1.0-2.5 h across the species. Clearance and volume of distribution by intravenous route for ulixertinib were found to be 6.24 mL/min/kg and 0.56 L/kg; 1.67 mL/min/kg and 0.36 L/kg and 15.5 mL/min/kg and 1.61 L/kg in mice, rats and dogs, respectively. Absolute oral bioavailability in mice and rats was > 92 %, however in dogs it was 34 %

Preclinical assessment of ulixertinib, a novel ERK1/2 inhibitor

Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. In xenograft studies it inhibited tumor growth in BRAF-mutant melanoma and colorectal xenografts as well as KRAS-mutant colorectal and pancreatic models. Ulixertinib is currently in Phase I clinical development for the treatment of advance solid tumors. The objective of the study is to assess the metabolic stability (in various pre-clinical and human liver microsomes/hepatocytes), permeability, protein binding, CYP inhibition, CYP induction and CYP phenotyping of ulixertinib. We have also studied the oral and intravenous pharmacokinetics of ulixertinib in mice, rats and dogs. Ulixertinib was found to be moderately to highly stable in various liver microsomes/hepatocytes tested. It is a medium permeable (2.67 x 10-6 cm /sec) drug and a substrate for efflux (efflux ratio: 3.02) in Caco-2 model. Ulixertinib was highly bound to plasma proteins. CYPs involved in its limited metabolism and it is CYP inhibition IC50 ranged between 10-20 µM. Post oral administration ulixertinib exhibited early Tmax (0.50-0.75 h) in mice and rats indicating absorption was rapid, however in dogs Tmax attained at 2 h. The half-life (t½) of ulixertinib by intravenous and oral routes ranged between 1.0-2.5 h across the species. Clearance and volume of distribution by intravenous route for ulixertinib were found to be 6.24 mL/min/kg and 0.56 L/kg; 1.67 mL/min/kg and 0.36 L/kg and 15.5 mL/min/kg and 1.61 L/kg in mice, rats and dogs, respectively. Absolute oral bioavailability in mice and rats was > 92 %, however in dogs it was 34 %