Evaluation of Pharmacodynamic Effects of a Hypoxia-Inducible-Factor Prolyl Hydroxylase Inhibitor on Erythropoiesis of Healthy Cats

Background: Inhibition of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) stimulates erythropoiesis in rats, dogs, monkeys, and humans.

Objective: Investigation whether molidustat, a novel HIF-PH inhibitor, stimulates the production of erythrocytes in healthy cats.

Animals: Seventeen healthy adult research colony cats (1-2 years old).

Methods: In a randomized, placebo-controlled pilot laboratory study, cats were treated once daily with oral suspensions of 0 (Group 1; n=6), 5 (Group 2; n=6) or 10 (Group 3; n=5) mg/kg of molidustat. Effects on hematocrit (HCT) and erythropoietin (EPO) concentrations were evaluated weekly. Molidustat treatment was ceased when HCT exceeded 60%.

Results: Compared to placebo, a statistically significant increase in mean HCT was evident starting on Day 14 (Group 2: 54.4% versus 40.3%, p < 0.001, 95% CI [8.95-19.28]; Group 3: 61.2% versus 40.3%, p < 0.001, 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), respectively. Mean HCT in molidustat-treated cats returned to levels within reference range (29-45%) on Day 56 and were numerically comparable to placebo group levels from Day 70 onwards. Red blood cell count and hemoglobin concentrations followed a similar pattern as HCT. Mean EPO concentrations were significantly higher following molidustat administrations in treated groups on all assessment days. Molidustat treatments were well tolerated.

Conclusions and clinical importance: Remarkable erythropoietic effects were demonstrated after daily administrations of molidustat to healthy cats potentially offering a treatment option for cats with anemia.