ABSTRACT
AIMS: Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. METHODS: This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. RESULTS: In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l-1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l-1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. CONCLUSIONS: Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia.
Subject(s)
Anemia/drug therapy , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Prolyl-Hydroxylase Inhibitors/administration & dosage , Pyrazoles/administration & dosage , Renal Insufficiency, Chronic/complications , Triazoles/administration & dosage , Administration, Oral , Adult , Anemia/blood , Anemia/etiology , Area Under Curve , Erythropoietin/blood , Half-Life , Healthy Volunteers , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Male , Prolyl-Hydroxylase Inhibitors/adverse effects , Prolyl-Hydroxylase Inhibitors/pharmacokinetics , Proof of Concept Study , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics , Renal Insufficiency, Chronic/blood , Single-Blind Method , Triazoles/adverse effects , Triazoles/pharmacokinetics , Young AdultABSTRACT
Concentrations of tetrachlorobenzenes, pentachlorobenzene, hexachlorobenzene and alpha-, beta-, gamma- and delta-HCH in air and deposition were measured at three different contaminated sites in Greppin, Roitzsch (both near Bitterfeld) and Leipzig during five time intervals of 14 days in the summer months of 1998. The mean values of the chlorobenzene concentrations (gas phase and particle bound portions) over the whole sampling time were 0.11 ng/Nm3 (Leipzig), 0.17 ng/Nm3 (Roitzsch) and 0.37 ng/Nm3 (Greppin), the mean values of the HCH concentrations were 0.22 ng/Nm3 (Leipzig), 0.31 ng/Nm3 (Roitzsch) and 0.69 ng/Nm3 (Greppin). This increase of the concentration values from Leipzig over Roitzsch to Greppin indicates the influences of industrial waste sites in the Bitterfeld region on the atmospheric environment. The significantly higher values of hexachlorobenzene, alpha- and beta-HCH in Greppin are probably caused by emissions from the former chemical plant Bitterfeld-Wolfen and the landfill 'Antonie' near Greppin. Compared with literature data from other industrial impacted areas the measured air concentration and deposition values are relatively low.