Disproportionality Analysis on Hypothyroidism With Roxadustat Using the Japanese Adverse Drug Event Database

Abstract

Hypoxia‐inducible factor prolyl‐hydroxylase inhibitor (HIF‐PHI) is a novel agent for the treatment of renal anemia. HIF‐PHI increases endogenous erythropoietin production by inhibiting the degradation of an erythropoietin transcription factor. Although beneficial effects are expected from HIF‐PHI, its novel mechanism raises concerns regarding the risk of potential adverse events. The cases of hypothyroidism, which had not been reported in clinical trials, were reported after the administration of roxadustat in a real‐world setting. However, the effects of HIF‐PHIs on thyroid function have not yet been fully evaluated. This study aimed to assess the clinical impact of HIF‐PHIs on thyroid function using the Japanese Adverse Drug Event Report database, a spontaneous reporting system in Japan, because HIF‐PHIs were made available in Japan before they were available in other countries. Although a disproportionality signal for hypothyroidism was detected with roxadustat (reporting odds ratio [ROR]:22.1, 95% confidence interval [CI]:18.3‐26.7, no signals were detected with another HIF‐PHI, daprodustat (ROR:1.3, 95%CI:0.3‐5.4), and epoetin beta pegol (ROR:1.2, 95%CI:0.5‐2.7). Signals of hypothyroidism due to roxadustat were also detected regardless of age or sex. Approximately 50% of hypothyroidism cases were reported within 50 days of starting roxadustat use. These results indicate that roxadustat use may be related to the development of hypothyroidism. The need for monitoring of thyroid function should be alerted during roxadustat administration regardless of age or sex.

Hypoxia-inducible Factor Prolyl Hydroxylase Inhibitors and Hypothyroidism: An Analysis of the Japanese Pharmacovigilance Database

“…Recently, Kouki et al evaluated the association between hypothyroidism and roxadustat or daprodustat using data between April 2004 and July 2022 from the JADER database (22). Although unexpected by us, the fact that there was a group attempting to conduct a similar study at approximately the same time is very favorable in assessing the validity of our study.…”

Utilization of Real-World Data in Drug Development

“…Therefore, clinical trials should aim to establish homeostasis in the body, maintain normal physiological functions, and improve adaptability to the external environment. This holistic approach determines the complexity of drug interventions, relying on clinically meaningful endpoints beyond morbidity and mortality [10] . Real-world data (RWD) encompasses the impact of different interventions under unique patient conditions, combined with social and environmental factors.…”

Zinc Supplementation Enhances the Hematopoietic Activity of Erythropoiesis-Stimulating Agents but Not Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitors

“…However, vascular calcification is reportedly suppressed by zinc [ 7 ]. Roxadustat usage has been associated with hypothyroidism [ 8 , 9 ], which is potentially induced by its T3-like allosteric effects [ 10 ] and can be partially alleviated by zinc supplementation [ 11 ]. Zinc supplementation, initiated to restore immune function also improved thyroid function (as evidenced by a decrease in thyroid-stimulating hormone levels) and led to increased T3 and T4 concentrations [ 12 ], suggesting a regulatory effect of zinc on thyroid hormones.…”