Single‐ and Multiple‐dose Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP1128, a Novel Peroxisome Proliferator‐activated Receptor δ Modulator, in Healthy Participants

Abstract

AbstractPeroxisome proliferator‐activated receptor δ (PPARδ) plays a central role in modulating mitochondrial function in ischemia‐reperfusion injury. ASP1128, a potent and selective modulator of PPARδ, is currently under investigation for treating acute kidney injury. This randomized, first‐in‐human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ASP1128 administered intravenously in healthy participants. Forty‐nine participants received a single dose of ASP1128 0.3–10 mg (n = 37) or placebo (n = 12) and 53 received daily (7 days) doses of ASP1128 3–100 mg (n = 39) or placebo (n = 14), including a cohort aged ≥65 years (ASP1128 100 mg, n = 3; placebo, n = 2). Treatment‐emergent adverse events occurred in 37.8%, 59.0%, and 33.3%–35.7% of participants in the single ASP1128, multiple ASP1128, and placebo groups, respectively. All were mild in severity, and the frequency of adverse events did not appear to be dose‐related. One participant (multiple ASP1128 3 mg group) withdrew with an infusion site erythema, possibly related to study drug. Exposure was roughly dose‐proportional, and elimination was generally consistent across doses (mean t½ 14.6–17.4 hours in the 10, 30, and 100 mg groups on day 7). There was little accumulation in plasma following multiple dosing; steady state was reached after ∼4 days. ASP1128 treatment led to rapid and dose‐related upregulation of six fatty acid oxidation‐related PPARδ target genes at ≥10 mg, which lasted >24 hours postdose. In conclusion, single and multiple intravenous doses of ASP1128 were generally well tolerated, with dose‐dependent pharmacokinetics and target gene engagement in healthy participants.