Atrasentan: Uses, Dosage, Side Effects and Interactions

Atrasentan is an oral, selective endothelin A (ETA) receptor antagonist developed primarily for its renoprotective and anti-tumor properties. Over the past two decades, atrasentan has been evaluated in a range of clinical and preclinical studies, particularly for diabetic nephropathy and various cancers. This article provides a comprehensive overview of atrasentan’s uses, recommended dosages, side effect profile, and known drug interactions, synthesizing the latest scientific evidence to help clinicians, patients, and researchers understand its therapeutic potential and considerations.

Uses of Atrasentan

Atrasentan's clinical journey spans nephrology and oncology, targeting mechanisms underlying both chronic kidney disease and cancer progression. Its main uses are as an adjunct therapy in diabetic nephropathy and as a targeted treatment for certain types of cancer, such as prostate and ovarian carcinoma.

Indication	Target Mechanism	Clinical Setting	Evidence Source(s)
Diabetic Nephropathy	ETA receptor antagonism	Add-on to RAS inhibitors	1, 3, 4, 7, 11, 12
Prostate Cancer	Inhibition of tumor progression	Hormone-refractory, with/without bone metastases	2, 5, 6, 8, 9
Ovarian Cancer	Tumor growth and angiogenesis inhibition	Experimental/Preclinical	10, 13

Table 1: Principal Therapeutic Uses of Atrasentan

Diabetic Nephropathy

Atrasentan has shown significant benefits in reducing albuminuria—the leakage of albumin into urine, a marker for kidney damage—in patients with type 2 diabetes and chronic kidney disease (CKD). This effect is observed even in those already receiving maximum doses of renin-angiotensin system (RAS) inhibitors, highlighting atrasentan’s role as an adjunctive therapy 1, 3, 7. Studies demonstrate that atrasentan not only reduces albuminuria but also offers long-term renal protection by decreasing the risk of doubling of serum creatinine and progression to end-stage kidney disease 7. Mechanistically, atrasentan restores glomerular endothelial function, reduces renal inflammation, and modulates microRNAs crucial for kidney cell survival 4, 11, 12.

Prostate Cancer

Atrasentan’s antitumor activity has been most extensively studied in hormone-refractory prostate cancer (HRPC), including both metastatic and nonmetastatic forms. By blocking the ETA receptor, atrasentan interferes with tumor growth, bone metastasis, and pain modulation driven by endothelin-1 signaling 2, 5, 6. Clinical trials report delayed disease progression, particularly in bone metastases, and attenuation of tumor marker elevations 5, 6. Its favorable tolerability profile further supports its use in this patient population.

Ovarian Cancer

In preclinical models, atrasentan inhibits ovarian cancer cell proliferation, angiogenesis, and tumor invasiveness. When combined with cytotoxic agents like paclitaxel or cisplatin, atrasentan enhances antitumor efficacy, suggesting its potential as part of combination chemotherapy regimens 10, 13.

Dosage of Atrasentan

Determining the optimal dosing of atrasentan is vital for maximizing efficacy while minimizing side effects. Doses vary by indication and patient population, with most clinical studies converging on daily oral administration.

Patient Group	Common Dosage Range	Dosage Adjustments	Source(s)
Diabetic Nephropathy	0.75–1.25 mg/day	Adjust for response and fluid retention	1, 3, 7
Prostate Cancer	2.5–10 mg/day	Up to 60 mg/day tested in trials; higher doses limited by headache	2, 6, 8, 9
Ovarian Cancer	Preclinical: 2–7.5 mg/kg/day (animal models)	None specified (clinical use not established)	10, 13

Table 2: Dosage Ranges for Atrasentan by Indication

Dosing in Diabetic Nephropathy

• Standard Dose: Most trials utilized atrasentan at 0.75 mg or 1.25 mg once daily for up to 12 weeks or longer 1, 3, 7.
• Dose Selection: The 0.75 mg daily dose strikes a balance between efficacy and tolerability, especially regarding fluid retention. Higher doses may increase side effects without proportional benefit 3, 7.
• Individualization: Dosage adjustments are made based on albuminuria response and the emergence of side effects, particularly fluid overload 7.
• Pharmacokinetics: Atrasentan is rapidly absorbed (peak plasma concentration ~1–1.5 hours), with a half-life of approximately 24 hours, supporting once-daily dosing 8, 9.

Dosing in Prostate Cancer

• Clinical Trials: Doses from 2.5 mg to 10 mg daily are common, with some studies escalating up to 60 mg daily 6, 8, 9.
• Tolerance: Headache is the main dose-limiting toxicity at higher doses; 10 mg daily is often used for sustained therapy 8.
• Extended Dosing: No maximum tolerated dose was found up to 95 mg in some studies, but side effect risk rises with higher doses 9.

Dosing in Ovarian Cancer

• Experimental Models: Animal studies use 2–7.5 mg/kg/day. Clinical dosing in humans for ovarian cancer is not established 10, 13.

Side Effects of Atrasentan

As with all medications, understanding the side effect profile is essential for safe administration. Atrasentan is generally well-tolerated, but certain adverse effects—particularly fluid retention—warrant careful monitoring.

Side Effect	Frequency/Severity	Dose-Dependence	Source(s)
Peripheral Edema	Common, dose-related	Higher at >0.75 mg/day	1, 3, 6, 7, 8, 9
Headache	Mild–moderate	Dose-limiting at higher doses	6, 8, 9
Rhinitis	Mild, reversible	Not strongly dose-related	6, 8, 9
Weight Gain	Moderate, reversible	Linked to fluid retention	1, 3, 8
Anemia	Mild, reversible	Hemodilution effect	1, 7, 8, 9
Heart Failure	Uncommon, increased risk in predisposed patients	Related to fluid retention	7

Table 3: Common Adverse Effects of Atrasentan

Fluid Retention and Edema

• Peripheral Edema: The most frequently reported side effect, especially at doses above 0.75 mg/day. Incidence increases with higher doses (up to 46% at 1.75 mg) 3.
• Weight Gain: Tied to sodium and fluid retention; typically reversible after discontinuation 1, 3, 7.
• Heart Failure Risk: Slightly higher incidence of heart failure hospitalizations in atrasentan-treated patients with diabetic nephropathy, though not statistically significant 7.

Other Adverse Effects

• Headache and Rhinitis: Common but usually mild and reversible upon drug withdrawal. Headache is dose-limiting at high doses 6, 8, 9.
• Anemia: Mild, reversible decrease in hemoglobin due to hemodilution rather than true bone marrow suppression 1, 7, 8, 9.
• Other: Fatigue and asthenia are reported infrequently 8.

Safety Monitoring

• Fluid Status: Regular monitoring for edema and weight gain, especially in patients with pre-existing heart disease or CKD.
• Hemoglobin: Periodic checks to detect anemia.
• Blood Pressure and Lipids: Atrasentan may lower blood pressure and improve lipid profiles, offering additional benefits 1.

Interactions of Atrasentan

While atrasentan has a generally favorable interaction profile, certain considerations are warranted, especially regarding co-administration with drugs affecting fluid balance and cancer therapies.

Interaction Type	Clinical Implication	Evidence/Details	Source(s)
RAS Inhibitors	Additive renal benefit	Used concomitantly in CKD trials	1, 3, 7
Diuretics	Fluid retention management	May be added to mitigate edema	1, 3, 7
Cytotoxic Agents	Enhanced antitumor effect	Synergy with taxanes/platinum	10, 13
Other Antihypertensives	BP lowering effect	Monitor for hypotension	1, 3

Table 4: Notable Drug Interactions with Atrasentan

Renin-Angiotensin System (RAS) Inhibitors

• Synergistic Renoprotection: Atrasentan is designed as an adjunct to RAS inhibitors in diabetic nephropathy, further reducing albuminuria and slowing CKD progression 1, 3, 7.
• No Negative Interaction: No evidence of adverse pharmacokinetic or pharmacodynamic interactions when used together 1, 3.

Diuretics

• Managing Edema: Diuretics may be required to counteract fluid retention. No pharmacological antagonism, but therapeutic monitoring is necessary 1, 3, 7.

Cytotoxic Cancer Therapies

• Combination Therapy: In ovarian carcinoma models, atrasentan enhances the efficacy of taxanes (e.g., paclitaxel) and platinum-based agents (e.g., cisplatin). This synergistic effect is due to increased tumor cell apoptosis and reduced angiogenesis 10, 13.
• Clinical Implications: While promising, these interactions are primarily preclinical. Monitoring for overlapping toxicities is advised.

Other Considerations

• Antihypertensive Drugs: Given atrasentan’s potential to lower blood pressure, co-administration with other antihypertensives may require dose adjustments to prevent hypotension 1, 3.
• No Major CYP Interactions: Pharmacokinetic studies indicate dose-proportionality and a lack of significant drug-drug interactions, but comprehensive data in polypharmacy settings are limited 8, 9.

Conclusion

Atrasentan stands at the intersection of nephrology and oncology as a targeted therapy with demonstrated efficacy in reducing residual albuminuria in diabetic nephropathy and in delaying disease progression in certain cancers. Its selective action on the ETA receptor underpins both its benefits and its side effect profile.

Summary of Key Points:

• Therapeutic Uses:
  • Adjunct to RAS inhibitors for diabetic nephropathy, reducing albuminuria and renal risk 1, 3, 7.
  • Investigational/adjunct therapy in hormone-refractory prostate and ovarian cancers 2, 5, 6, 10, 13.
• Dosage:
  • 0.75 mg once daily is standard for kidney disease; up to 10 mg or higher tested for cancer, with dose selection guided by tolerance 1, 3, 6, 8, 9.
• Side Effects:
  • Most common are peripheral edema, headache, weight gain, and mild anemia; fluid retention is dose-limiting 1, 3, 6, 8, 9.
• Interactions:
  • Safe with RAS inhibitors; synergistic with cytotoxic agents in cancer; monitor fluid status and blood pressure when combined with related drugs 1, 3, 7, 10, 13.

Atrasentan exemplifies the promise of targeted therapies, but optimal patient selection and vigilant monitoring are essential to maximize its benefits. Ongoing research will determine its broader role in clinical practice.