ATCvet code:
QB03XA09 Pharmacotherapeutic group: other antianemic preparations.
Pharmacodynamics
The veterinary medicinal product is a competitive and reversible inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH). Within six hours after oral administration, molidustat induced dose‑dependent peak EPO concentrations in rodents, dogs, monkeys and healthy cats. The inhibition of HIF-PH induces an increase of endogenous erythropoietin (EPO) by stabilising HIF (key transcriptional activator of EPO), resulting in increased erythropoiesis (red blood cell production) in the bone marrow. This leads to a gradual increase in PCV, reticulocytes, haemaglobin and haematocrit.
Pharmacokinetics
Absorption:
After oral administration of 5 mg/kg molidustat to fasted healthy cats, plasma concentration time curves are characterised by rapid absorption with maximum plasma concentrations (Cmax) achieved within 1.5 hour (Tmax). Mean peak concentrations (Cmax) ranged from 3.6 to 5.1 mg/l after single dosing. Overall exposure (AUCinf) following administration of 5 mg/kg molidustat was between 8.6 and 14.1 mg/h/l, with an oral bioavailability between 63% and >84%. Oral administration to recently fed cats resulted in lower peak concentrations with comparable overall exposure.
After repeated daily administration of 2.5 and 5 mg/kg molidustat to health cats over 56 days, a slight increase of exposure (approximately 1.5-fold) was observed. In addition, exposure was considered dose proportional for AUC, with a slight trend to less than proportional rate of exposure (Cmax) within a dose range of 2.5 to 10 mg/kg.
Distribution:
An in vitro study using cat plasma showed low (18.0% to 19.8%) plasma protein binding. Plasma protein binding appeared independent of drug concentration in cats in the tested concentration range.
An in vivo study in rats assessing the organ distribution of [14C] molidustat demonstrated that the highest systemic exposure was observed in the kidneys, liver and adrenal glands. There was no relevant penetration across the blood: brain barrier. There was no detectable specific affinity to pigmented tissues. There was a limited distribution of radioactivity to blood cells. There was no evidence of irreversible binding or retention to organs and tissue.
Pharmacokinetics after intravenous administration of 5 mg/kg molidustat in cats showed a mean volume of distribution between 2.57 and 4.82 l/kg. The mean predicted volumes of distribution in steady state (Vss) were between 0.75 and 1.01 l/kg.
Metabolism
The primary metabolic pathways of molidustat observed in vitro were glucuronidation to form the M‑1 metabolite and glycosylation to form the M‑2 metabolite. The extent of metabolic turnover was determined to be 17.0% at 1 h and 47.0% following 4 h incubation. Molidustat was classified as a highly permeable compound and neither molidustat nor its metabolite M‑1 were substrates or inhibitors of P‑glycoprotein (P‑gp). No relevant inhibitory activity was shown with metabolite M‑1.
Excretion:
Molidustat was cleared from cat plasma at a mean rate of 0.32 l/h/kg. Molidustat was mainly cleared via faeces with mean rates of 0.089 l/h/kg and 0.18 l/h/kg and to a very minor extent via urine, whereas the metabolite M‑1 was mainly cleared renally with rates of 0.050 l/h/kg and 0.14 l/h/kg. After oral administration of 5 mg/kg molidustat sodium using the final formulation to fasted cats, the mean calculated half-life ranged from 4.2 h to 7.8 h.