Pharmacokinetics and Ex-Vivo Pharmacodynamics of the Novel Anti-Inflammatory Drug, Doramapimod, in Horses

Background: Novel anti-inflammatory drugs are needed to better manage systemic inflammation in horses. Doramapimod has potent anti-inflammatory effects in horses, but pharmacological studies in horses are lacking.
Hypothesis/objectives: To determine the pharmacokinetics and ex-vivo pharmacodynamics of doramapimod in horses.
Animals: Five healthy Standardbred horses.
Methods: A 0.5 mg/kg bolus dose of doramapimod was administered intravenously to all horses. Blood samples were obtained at baseline and serially over 72 hours. Also, at 6 timepoints peripheral blood leukocytes were isolated, washed, resuspended in 1 ml saline; then frozen. Plasma and leukocyte doramapimod concentrations were assayed by liquid chromatography-mass spectrometry. Further, aliquots of whole blood from each time point were stimulated with lipopolysaccharide (0-1 μg/ml) and supernatant concentrations of TNF-α and IL-1β were measured by multiplex ELISA.
Results: Plasma elimination half-life of doramapimod was 3.88 ±1.05 hours, with concentrations close to the limit of detection by 24 hours. However, doramapimod was still detectable in leukocytes up to 48 hours after administration (0.21±0.04 and 0.05±0.02 ng/107 cells at 24 and 48 hours, respectively). Inhibition of non-lipopolysaccharide-induced pro-inflammatory cytokine response in whole blood was also evident at 48 hours (61.6±23.1% and 47.5±29.4% inhibition of TNF-α and IL-1β production respectively).
Conclusions and clinical importance: Doramapimod appears to bind and accumulate within leukocytes, producing measurable effects well after minimal plasma concentrations are reached. This ‘effect site pharmacokinetics’ suggests that, for the treatment of acute inflammatory conditions where leukocyte activation is targeted (e.g. sepsis), a dosing interval of 24 hours may be suitable despite the short plasma half-life.