Atrasentan

Description: IC50 Value: 0.0551 nM (for ET A receptor) [1] Atrasentan (A-147627) is an endothelin antagonist receptor being developed at Abbott Laboratories for the treatment of prostate cancer. in vitro: The combination of Atrasentan with Taxotere was more effective in the inhibition of cell viability and induction of apoptosis in LNCaP and C4-2b cells (androgen receptor positive) but not in PC-3 cells[2]. Atrasentan profoundly induced several CYPs and drug transporters (e.g. 12-fold induction of CYP3A4 at 50 μM). It was a moderate P-gp inhibitor (IC(50) in P388/dx cells = 15.1 ± 1.6 μM) and a weak BCRP inhibitor (IC(50) in MDCKII-BCRP cells = 59.8 ± 11 μM). BCRP or P-gp overexpressing cells were slightly more resistant towards antiproliferative effects of atrasentan [5]. in vivo: ABT-627 did reduce the accumulation of macrophages in both stains (36 to 53%) whereas it blocked by 76% the influx of eosinophils in Balb/c but not in C57Bl/6 mice [3]. Atrasentan was administered orally via drinking water at 3 mg kg-1 per day over 28 days. All diabetic mice developed similar hyperglycaemia (27-30 mmol l-1). Atrasentan treatment significantly improved left ventricular systolic and diastolic function in response to exogenous norepinephrine, but there were no differences between genotypes [4]. Clinical trial: Atrasentan and Zometa for Men With Prostate Cancer Metastatic to Bone . Phase2

Comparison of exposure response relationship of atrasentan between North American and Asian populations.[Pubmed:27981738]

Diabetes Obes Metab. 2017 Apr;19(4):545-552.

AIMS: The selective endothelin (ET) A receptor antagonist Atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to Atrasentan. MATERIALS AND METHODS: Two 12-week double-blind randomised controlled trials were performed with Atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 Atrasentan-treated patients. RESULTS: Mean albuminuria reduction in Asian, compared to North American, patients was, respectively, -34.4% vs -26.3% for 0.75 mg/d ( P = .44) and -48.0% vs -28.9% for 1.25 mg/d ( P = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling Atrasentan concentration; P = .024). Body surface area (beta = -1.09 per m(2) ; P < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (beta = 0.69 per mg/dL increment; P = .010) were independent determinants of Atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations. CONCLUSION: The higher exposure and albuminuria reduction of Atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to Atrasentan-induced sodium retention.

The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy.[Pubmed:28019071]

Diabetes Obes Metab. 2017 May;19(5):749-753.

We assessed the effect of Atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of Atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m(2) . After 12 weeks of Atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m(2) , a single-value index of the metabolites changed by -0.31 (95%CI -0.60 to -0.02; P = .035), -0.08 (-12 to 0.29; P = .43) and 0.01 (-0.21 to 0.19; P = .913) in placebo, Atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (-0.17 to 0.43; P = .40) and 0.35 (0.05-0.65; P = .02) for Atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m(2) , suggesting that Atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with Atrasentan are indicated.

Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy.[Pubmed:27207530]

Diabetes. 2016 Aug;65(8):2429-39.

Atrasentan, a selective endothelin A receptor antagonist, has been shown to reduce albuminuria in type 2 diabetes. We previously showed that the structural integrity of a glomerular endothelial glycocalyx is required to prevent albuminuria. Therefore we tested the potential of Atrasentan to stabilize the endothelial glycocalyx in diabetic apolipoprotein E (apoE)-deficient mice in relation to its antialbuminuric effects. Treatment with Atrasentan (7.5 mg/kg/day) for 4 weeks reduced urinary albumin-to-creatinine ratios by 26.0 +/- 6.5% (P < 0.01) in apoE knockout (KO) mice with streptozotocin-induced diabetes consuming an atherogenic diet, without changes in gross glomerular morphology, systemic blood pressure, and blood glucose concentration. Endothelial cationic ferritin surface coverage, investigated using large-scale digital transmission electron microscopy, revealed that Atrasentan treatment increases glycocalyx coverage in diabetic apoE KO mice from 40.7 +/- 3.2% to 81.0 +/- 12.5% (P < 0.05). This restoration is accompanied by increased renal nitric oxide concentrations, reduced expression of glomerular heparanase, and a marked shift in the balance of M1 and M2 glomerular macrophages. In vitro experiments with endothelial cells exposed to laminar flow and cocultured with pericytes confirmed that Atrasentan reduced endothelial heparanase expression and increased glycocalyx thickness in the presence of a diabetic milieu. Together these data point toward a role for the restoration of endothelial function and tissue homeostasis through the antialbuminuric effects of Atrasentan, and they provide a mechanistic explanation for the clinical observations of reduced albuminuria with Atrasentan in diabetic nephropathy.