We thank Eleftheriadis et al.1 for their attention to our manuscript, “Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study,”2 and their letter on the potential effects of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors on adaptive immunity.
We support basic scientific research to explore various aspects of HIF biology. However, we would like to emphasize that it is complex to translate findings from in vitro experiments studying the consequences of HIF stabilization to clinical observations. In the findings cited by Eleftheriadis et al.,3 human PBMCs were exposed to various concentrations (1, 5, 10, or 15 μg/ml) of roxadustat for 7 days, resulting in continuous HIF stabilization, with the 5 and 10 μg/ml concentrations being similar to the maximum plasma concentrations reported among patients who received 1.0 or 2.0 mg/kg of roxadustat.4 In the OLYMPUS study,2 roxadustat was administered three times weekly, at least 2 days apart, at a starting dose of 70 mg (maximum dose was capped at the lower of 3.0 mg/kg or 300 mg) for up to 4 years. With three times weekly dosing and a t 1/2 of approximately 12 hours, plasma concentrations of roxadustat generally return to very low levels between doses, resulting in intermittent (not continuous) HIF stabilization.4,5 With this in mind, we recommend caution in considering the applicability of data generated with continuous HIF stabilization in preclinical experiments to intermittent HIF stabilization with roxadustat in clinical settings.
Disclosures
B.P. Van reports research support and consulting fees from AstraZeneca. S. Fishbane reports consultancy agreements with AstraZeneca, Akebia, Cara Therapeutics, and Fibrogen; research funding from AstraZeneca, Cara, Gilead, and Fibrogen; hHonoraria from AstraZeneca and Akebia; and being a scientific advisor or membership from AstraZeneca and Fibrogen. M. EI-Shahawy reports ownership interest in Paramount Hope Dialysis Center and East LA Dialysis Center; research funding from AztraZeneca, Pfizer, Bayer, UCB, and Sanofi; honoraria from AstraZeneca; being a scientific advisor or membership with AztraZeneca and Bayer; and speakers bureau from AstraZeneca. D.J. Little is employed by and has ownership interest in AstraZeneca. D.J. Little also reports other interests/relationships as a volunteer nephrologist at Walter Reed National Military Medical Center.
Funding
Funded was provided by AstraZeneca. Medical writing support was provided by Shaun W. Foley, of Core Medica (London, UK), which was funded by the study sponsor.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
See related letter to the editor, “On the Increased Event Rate of Urinary Tract Infection and Pneumonia in CKD Patients Treated with Roxadustat for Anemia,” on page 1537, and original article, “Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study,” in Vol. 32, Iss. 3, on pages 737–755.
References
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