Relationship Between Atrasentan Concentrations and Urinary Albumin to Creatinine Ratio in Western and Japanese Patients With Diabetic Nephropathy

Lin, Chih‐Wei; Mostafa, Nael M.; Andress, Dennis L.; Brennan, John J.; Klein, Colin; Awni, Walid M.

doi:10.1016/j.clinthera.2017.07.011

Cited by 15 publications

(15 citation statements)

References 20 publications

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“…The population pharmacokinetic model was previously published . The original data file and model results were combined to generate a simulation dataset (data transformations and visualisations were performed in R3.4.2 [R Foundation for Statistical Computing, Vienna, Austria]).…”

Section: Methodsmentioning

confidence: 99%

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Determining the optimal dose of atrasentan by evaluating the exposure‐response relationships of albuminuria and bodyweight

Koomen

Stevens

Mostafa

et al. 2018

Diabetes Obesity Metabolism

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This study aimed to identify the optimal dose of the endothelin‐1 receptor antagonist atrasentan with maximal albuminuria reduction and minimal signs of sodium retention, as manifested by increase in bodyweight. Data from the RADAR‐JAPAN studies were used, evaluating the effect of 0.75 or 1.25 mg/d of atrasentan in 161 patients with type 2 diabetes and kidney disease. Individual pharmacokinetic parameters were estimated using a population pharmacokinetic approach. Subsequently, changes in the urinary albumin‐to‐creatinine ratio (UACR) and bodyweight from baseline after 2 weeks' exposure were modelled as a function of the pharmacokinetic parameters. The 0.75 and 1.25 mg doses showed a mean UACR reduction of 34.0% and 40.1%, whereas mean bodyweight increased by 0.9 and 1.1 kg, respectively. A large variation between individuals was observed in the UACR and bodyweight responses. Individual pharmacokinetic parameters correlated significantly with both individual UACR and bodyweight responses (P < .01). The individual response curves for UACR and bodyweight crossed at approximately the mean trough concentration of 0.75 mg atrasentan, indicating that 0.75 mg/d of atrasentan is the optimal dose for kidney protection with maximal efficacy (albuminuria reduction) and safety (minimal sodium retention).

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Section: Methodsmentioning

confidence: 99%

“…The population pharmacokinetic model was previously published. 6 The original data file and model results were combined to generate a…”

Section: Pharmacokinetic and Pharmacodynamic Analysesmentioning

confidence: 99%

Determining the optimal dose of atrasentan by evaluating the exposure‐response relationships of albuminuria and bodyweight

Koomen

Stevens

Mostafa

et al. 2018

Diabetes Obesity Metabolism

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“…No significant association between atrasentan exposure and peripheral edema was found (doses: 0.5, 0.75, 1.25 mg). The rates of peripheral edema were comparable in patients receiving active treatment and placebo [146]. Earlier results proposed that ET A antagonism is reducing circulating lipids [161].…”

Section: Rapids-2mentioning

confidence: 72%

“…Moreover, the albuminuria-reducing efficacy of atrasentan is not impaired by fluid retention [148]. Lin et al [146] demonstrated the results from three phase II trials with 257 participants (NCT01356849, NCT01399580, and NCT01424319). No significant association between atrasentan exposure and peripheral edema was found (doses: 0.5, 0.75, 1.25 mg).…”

Section: Rapids-2mentioning

confidence: 99%

Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy

Enevoldsen

Sahana

Wehland

et al. 2020

JCM

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The endothelin axis, recognized for its vasoconstrictive action, plays a central role in the pathology of pulmonary arterial hypertension (PAH). Treatment with approved endothelin receptor antagonists (ERAs), such as bosentan, ambrisentan, or macitentan, slow down PAH progression and relieves symptoms. Several findings have indicated that endothelin is further involved in the pathogenesis of certain other diseases, making ERAs potentially beneficial in the treatment of various conditions. In addition to PAH, this review summarizes the use and perspectives of ERAs in cancer, renal disease, fibrotic disorders, systemic scleroderma, vasospasm, and pain management. Bosentan has proven to be effective in systemic sclerosis PAH and in decreasing the development of vasospasm-related digital ulcers. The selective ERA clazosentan has been shown to be effective in preventing cerebral vasospasm and delaying ischemic neurological deficits and new infarcts. Furthermore, in the SONAR (Study Of Diabetic Nephropathy With Atrasentan) trial, the selective ERA atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease. These data suggest atrasentan as a new therapy in the treatment of diabetic nephropathy and possibly other renal diseases. Preclinical studies regarding heart failure, cancer, and fibrotic diseases have demonstrated promising effects, but clinical trials have not yet produced measurable results. Nevertheless, the potential benefits of ERAs may not be fully realized.

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“…For example ETRA blockers have shown to restore the endothelial glycocalyx and to reduce albuminuria in diabetic mice ( Boels et al., 2016 ). In diabetic patients, the ETRA blocker atrasentan reduced urinary albumin to creatinine ratios ( Lin et al., 2018 ). Furthermore, renal elevation of cGMP, a key messenger for NO signaling, resulted in a reduction of glomerulosclerosis in rats with DN ( Boustany-Kari et al., 2016 ).…”

Section: Genc Dysfunction In Dn and Fsgsmentioning

confidence: 99%

Glomerular Endothelial Cells as Instigators of Glomerular Sclerotic Diseases

et al. 2020

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Glomerular endothelial cell (GEnC) dysfunction is important in the pathogenesis of glomerular sclerotic diseases, including Focal Segmental Glomerulosclerosis (FSGS) and overt diabetic nephropathy (DN). GEnCs form the first cellular barrier in direct contact with cells and factors circulating in the blood. Disturbances in these circulating factors can induce GEnC dysfunction. GEnC dysfunction occurs in early stages of FSGS and DN, and is characterized by a compromised endothelial glycocalyx, an inflammatory phenotype, mitochondrial damage and oxidative stress, aberrant cell signaling, and endothelial-to-mesenchymal transition (EndMT). GEnCs are in an interdependent relationship with podocytes and mesangial cells, which involves bidirectional cross-talk via intercellular signaling. Given that GEnC behavior directly influences podocyte function, it is conceivable that GEnC dysfunction may culminate in podocyte damage, proteinuria, subsequent mesangial activation, and ultimately glomerulosclerosis. Indeed, GEnC dysfunction is sufficient to cause podocyte injury, proteinuria and activation of mesangial cells. Aberrant gene expression patterns largely contribute to GEnC dysfunction and epigenetic changes seem to be involved in causing aberrant transcription. This review summarizes literature that uncovers the importance of cross-talk between GEnCs and podocytes, and GEnCs and mesangial cells in the context of the development of FSGS and DN, and the potential use of GEnCs as efficacious cellular target to pharmacologically halt development and progression of DN and FSGS.

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Relationship Between Atrasentan Concentrations and Urinary Albumin to Creatinine Ratio in Western and Japanese Patients With Diabetic Nephropathy

Cited by 15 publications

References 20 publications

Determining the optimal dose of atrasentan by evaluating the exposure‐response relationships of albuminuria and bodyweight

Determining the optimal dose of atrasentan by evaluating the exposure‐response relationships of albuminuria and bodyweight

Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy

Glomerular Endothelial Cells as Instigators of Glomerular Sclerotic Diseases

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