Pharmacodynamic effects of molidustat on erythropoiesis in healthy cats

Abstract

Abstract Background Inhibition of hypoxia‐inducible factor prolyl hydroxylase (HIF‐PH) stimulates erythropoiesis in rats, dogs, monkeys, and humans. Hypothesis/Objective Determine if molidustat, a novel HIF‐PH inhibitor, stimulates erythropoiesis in healthy cats. Animals Seventeen healthy adult laboratory cats. Methods Randomized, placebo‐controlled study. Cats were treated PO once daily with suspensions of 0 (Group 1; n = 6), 5 (Group 2; n = 6), or 10 (Group 3; n = 5) mg/kg of molidustat. Effects on red blood cell parameters, reticulocyte indices and plasma erythropoietin (EPO) concentrations were evaluated. Molidustat treatment was stopped when hematocrit (HCT) exceeded 60%. Results Compared to placebo, a significant increase in mean HCT was evident starting on Day 14 (Group 2:54.4% vs 40.3%, P < .001, 95% confidence interval [CI] for the difference [8.95‐19.28]; Group 3:61.2% vs 40.3%, P < .001, 95% CI [15.48‐26.43]) and remained significantly higher for the entire treatment period. In molidustat‐treated groups, HCT exceeded 60% on Day 21 (Group 2) and Day 14 (Group 3). Mean HCT in molidustat‐treated cats returned to within the reference range (29%‐45%) after Day 56 and was numerically comparable to placebo from Day 70 onwards. Red blood cell count and hemoglobin concentrations followed a similar pattern as HCT. Mean EPO concentrations significantly increased after molidustat administration on all assessment days. Molidustat treatments were well tolerated. Conclusions and Clinical Importance Marked erythropoietic effects were identified after daily administration of molidustat to healthy cats and additional studies are warranted to evaluate the effects in anemic cats.

Keywords

• anemia
• erythropoietin
• hematocrit
• hypoxia‐inducible factor
• molidustat