First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia.

摘要: Aims Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on single oral doses molidustat healthy male volunteers. Methods This was single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat administered at 5, 12.5, 25, 37.5 or 50 mg as polyethylene glycol-based solution. Results In total, 45 volunteers received 14 placebo. absorbed rapidly, mean maximum plasma concentration area under concentration-time curve increased dependently. The terminal half-life 4.64-10.40 h. A significant increase observed following 12.5 above. Geometric peak were 14.8 IU l-1 (90% confidence interval 13.0, 16.9) for who placebo 39.8 interval: 29.4, 53.8) those mg. time course resembled normal diurnal variation EPO. Maximum approximately 12 h postdose returned to baseline after 24-48 All well tolerated there no changes vital signs laboratory safety parameters. Conclusions Oral administration elicited dose-dependent These results support ongoing development potential new treatment anaemia.