Randomized Phase I Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Topical Daprodustat in Healthy Volunteers and in Patients With Diabetic Foot Ulcers

Abstract

Daprodustat, a small‐molecule inhibitor of prolyl hydroxylases, prevents breakdown of hypoxia‐inducible factor (HIF), leading to increased transcription of HIF‐responsive genes. This randomized, placebo‐controlled study evaluated the safety, tolerability, and pharmacokinetics of a topical formulation of daprodustat in healthy volunteers (intact skin) and in patients with diabetic foot ulcers (DFUs) following single and/or 14‐day repeat‐dose administration. In the diabetic patients, exploratory assessments of wound area, volume, and depth were made to qualitatively assess effectiveness. Systemic absorption via topical application was limited across doses up to 1.0% at 100 mg/cm2 for 14 days. Systemic pharmacokinetics were quantifiable in a few samples from a few patients. Because only sporadic concentrations were observed versus pharmacokinetic profiles, pharmacokinetic parameters were not determined. Wound area, depth, and volume showed consistent but weak improvements in the treatment arm; however, the variability in response and small sample size of the standard‐of‐care and placebo arms limited the ability to assess trends in wound healing compared with the daprodustat arm. Overall, topically applied daprodustat was well tolerated, raised no safety concerns, and provided limited to nonquantifiable systemic exposures. The healing of DFUs will need to be evaluated in studies designed to test this hypothesis over a longer treatment duration.

Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases

“…Stabilization of HIF-1α has been widely reported to be a critical factor in the improvement of wound healing ( Zhu et al, 2020 ). Olson et al (2019) reported improvements in wound healing by evaluating the wound area, volume and depth in daprodustat topical formulation-treated healthy volunteers with intact skin and diabetic foot ulcer patients and the mechanism was illustrated by activation of HIF-1 signaling and promoted vascularization. Zhu et al (2019) reported a similar effect of roxadustat on wound healing in diabetic rats.…”