Roxadustat and thyroid-stimulating hormone suppression

Tokuyama, Atsuyuki; Kadoya, Hiroyuki; Obata, Atsushi; Obata, Takahiro; Sasaki, Tatsuya; Kashihara, Naoki

doi:10.1093/ckj/sfab007

Cited by 28 publications

(16 citation statements)

References 5 publications

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“…Similar findings have been obtained from smaller studies of roxadustat in comparison to findings of studies of daprodustat and vadadustat [60].…”

Section: Potential and Investigational Agents 71 Hypoxia-inducible Fa...supporting

confidence: 87%

Hyporesponsiveness to Erythropoietin-Stimulating Agents: Possible Solutions

Yasin¹,

Omran²

2023

Updates on Hemodialysis

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Almost 80% of dialysis patients have anemia of different severity, with its pathogenesis of multifactorial nature. Relative insufficiency of erythropoietin leading to hyperproliferative erythropoiesis is considered the main underlying cause. Management of anemia has several therapeutic implications, including reasonable quality of life and avoidance of repeated blood transfusions, among others. Optimal maintenance of hemoglobin target levels is not easy, even with the implementation of different therapeutic options, including erythropoietin-stimulating agents (ESAs). Approximately 5–10% of patients are not responding adequately, despite incremental dosing of ESA therapy. That inadequate response has multiple heterogeneous causes, making anemia management rather difficult. Hyporesponsiveness to ESAs is a challenge requiring a proper approach.

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“…Similar findings have been obtained from smaller studies of roxadustat in comparison to findings of studies of daprodustat and vadadustat [60].…”

Section: Potential and Investigational Agents 71 Hypoxia-inducible Fa...supporting

confidence: 87%

Hyporesponsiveness to Erythropoietin-Stimulating Agents: Possible Solutions

Yasin¹,

Omran²

2023

Updates on Hemodialysis

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“…Clinically, it is noteworthy that in Japan the prescribing information for roxadustat clearly states that it may cause hypothyroidism (which apparently means low serum free T4 and free T3) and reduce serum TSH and LDL-C [8]. In fact, there are two case reports in PubMed in which roxadustat affected thyroid function; in one report, roxadustat administration suppressed TSH and reduced free T4 and cholesterol [14], and in the other, roxadustat suppressed TSH and decreased free T4 and free T3 [15]. These pieces of information are consistent with TRβ activation in the pituitary and liver.…”

Section: Discussionmentioning

confidence: 99%

Roxadustat activates thyroid hormone receptors α and β at clinically relevant concentrations

Morita

Uchino

Edo

et al. 2022

Preprint

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Purpose A few previous basic and clinical reports implied that roxadustat, a drug recently approved for treating renal anemia, might activate thyroid hormone receptors (TRα and TRβ). We thus investigated the direct effects of roxadustat on intact TRα and TRβ in vitro. Methods U2OS, MCF-7, COS-7 and Caco-2 cells were transiently transfected with a firefly luciferase reporter plasmid highly responsive to activation of TRα and TRβ, along with a plasmid overexpressing either TRα or TRβ. Transfected cells were incubated for 3 h in 100% thyroid hormone-stripped fetal bovine serum (FBS) with or without either roxadustat or triiodothyronine (T3). Also, transfected U2OS cells were placed for 3 h in 100% unprocessed normal adult human serum with or without the addition of either roxadustat or T3. Cell lysates were measured for firefly luciferase activities. Results Roxadustat induced firefly luciferase activities when added at clinically achievable serum concentrations in TRα- or TRβ-transfected U2OS, MCF-7, COS-7 and Caco-2 cells placed in thyroid hormone-deprived FBS. The induction was comparable to or greater than that observed with T3 added at normal or even supranormal serum concentrations. Roxadustat also increased firefly luciferase activities in TRα- or TRβ-transfected U2OS cells in adult human serum. Conclusions Roxadustat does activate TRα and TRβ at clinically relevant concentrations. Physicians prescribing roxadustat should be aware of its thyromimetic activity.

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“…Recently, two cases of reversible central hypothyroidism were reported following roxadustat therapy [170,171]. The effect is probably mediated by the fact that roxadustat is a selective ligand of the thyroid hormone receptor-β (THRβ), due to its structural similarities with 3,3′,5-triiodothyronine (T3) [172].…”

Section: Other Safety Issuesmentioning

confidence: 99%

Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors

Locatelli

Minutolo²,

Nicola³

et al. 2022

Drugs

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Chronic kidney disease (CKD) affects approximately 10% of the worldwide population; anaemia is a frequent complication. Inadequate erythropoietin production and absolute or functional iron deficiency are the major causes. Accordingly, the current treatment is based on iron and erythropoiesis stimulating agents (ESAs). Available therapy has dramatically improved the management of anaemia and the quality of life. However, safety concerns were raised over ESA use, especially when aiming to reach near-to-normal haemoglobin levels with high doses. Moreover, many patients show hypo-responsiveness to ESA. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors (HIF-PHIs) were developed for the oral treatment of anaemia in CKD to overcome these concerns. They simulate the body's exposure to moderate hypoxia, stimulating the production of endogenous erythropoietin. Some molecules are already approved for clinical use in some countries. Data from clinical trials showed non-inferiority in anaemia correction compared to ESA or superiority for placebo. Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors may also have additional advantages in inflamed patients, improving iron utilisation and mobilisation and decreasing LDL-cholesterol. Overall, non-inferiority was also shown in major cardiovascular events, except for one molecule in the non-dialysis population. This was an unexpected finding, considering the lower erythropoietin levels reached using these drugs due to their peculiar mechanism of action. More data and longer follow-ups are necessary to better clarifying safety issues and further investigate the variety of pathways activated by HIF, which could have either positive or negative effects and could differentiate HIF-PHIs from ESAs.

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Roxadustat and thyroid-stimulating hormone suppression

Cited by 28 publications

References 5 publications

Hyporesponsiveness to Erythropoietin-Stimulating Agents: Possible Solutions

Hyporesponsiveness to Erythropoietin-Stimulating Agents: Possible Solutions

Roxadustat activates thyroid hormone receptors α and β at clinically relevant concentrations

Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors

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