Roxadustat: Indications, Mechanism of Action and Side Effects

Indications

Roxadustat (FG-4592) is an oral, bioavailable and reversible inhibitor of hypoxia-inducible factor-prolinyl hydroxylases (HIF-PHIs). It was developed by FibroGen in collaboration with Astellas and AstraZeneca. It is approved in China, Japan, Chile, Korea and the European Union (under the trade name Evrenzo) for the treatment of chronic kidney disease (CKD) anaemia in non-dialysis-dependent (NDD) and dialysis-dependent (DD) adult patients. It is also used to treat EPO-resistant anaemia, post-transplant anaemia (PTA) and chemotherapy-induced anaemia, but is still in clinical studies.

Mechanism of Action

Roxadustat's mechanism of action is to promote erythropoiesis by participating in HIF degradation, stimulating endogenous production of erythropoietin (EPO), improving iron absorption and mobilisation, and reducing haemoglobin.

Roxadustat is a potent inhibitor of HIF-PHD. Under normoxic conditions, the prolyl hydroxylase structural domain (PHD) hydroxylates the oxygen-sensitive alpha subunit of hypoxia-inducible factor (HIF-alpha), and von Hippel-Lindau tumour suppressor (VHL) recognises hydroxylated HIF-alpha, which is then ubiquitinated and degraded by ubiquitin. In contrast, Roxadustat (or hypoxia) inhibits PHD activity, leading to accumulation of HIF-α, which subsequently enters the nucleus and forms a transcriptional complex with HIF-β and the aryl hydrocarbon receptor nuclear transporter (ARNT), which then binds to hypoxia-responsive elements, thereby stimulating increased EPO production, enhanced erythropoiesis and indirectly inhibiting haemoglobin, an iron-regulated protein that is increased during the inflammatory process of chronic kidney disease. It also regulates iron transport proteins and modulates iron metabolism in patients with dialysis-dependent or dialysis-independent CKD-associated anaemia by increasing serum transferrin, intestinal iron absorption and release of stored iron.

Side Effects

The most common side effects of Roxadustat include:

• gastrointestinal disorders: nausea, diarrhoea, vomiting, constipation

• Vascular disorders: hypertension, vascular access thrombosis (VAT)

• metabolic and nutritional disorders: hyperkalaemia

• Others: peripheral oedema, headache, back pain, fatigue

Common

• septicaemia

• insomnia

• Seizures

• Headaches

• Deep Vein Thrombosis (DVT)

Severe Adverse Reactions

• Generalised exfoliative dermatitis

Other unknown side effects

• Secondary hypothyroidism

• Reduced blood thyroid stimulating hormone (TSH)

• Hyperbilirubinaemia

• Pulmonary embolism

Overdose of Roxadustat may cause with increased heart rate, mild to moderate musculoskeletal pain, headache, increased frequency of sinus tachycardia, and less commonly, hypotension.

References

[1] XIAOYU ZHU. Roxadustat: Not just for anemia.[J]. Frontiers in Pharmacology, 2022: 971795. DOI:10.3389/fphar.2022.971795.

[2] TANG X, LIU F, LI Q, et al. Roxadustat for Patients with Post-transplant Anemia: A Narrative Review[J]. Kidney Diseases, 2023. DOI:10.1159/000535071.

[3] TADAO AKIZAWA. Factors affecting the doses of roxadustat vs darbepoetin alfa for anemia treatment in hemodialysis patients.[J]. Therapeutic Apheresis and Dialysis, 2021. DOI:10.1111/1744-9987.13609.

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