The Pharmacokinetics of PDE4 Inhibitor Roflumilast in Rodents for Trauma Immunotherapy 9011

Abstract Description Background Roflumilast is the predominant phosphodiesterase-4 inhibitor in immune cells in addition to providing several anti-inflammatory properties. Roflumilast has been approved for the treatment of chronic obstructive pulmonary disease. However, there is a lack of information on the pharmacokinetics (PK) of the drug and an intravenous (IV) formulation is needed to determine if its immune inhibition improves organ failure outcomes for polytrauma injuries. Here, we sought to characterize the PK of roflumilast in a healthy rat model. Method Under general anesthesia, with prophylactic analgesics, 2 mg/kg roflumilast was delivered to group of rats (n = 5) via a single IV bolus. Plasma samples were collected at 0, 5, 10, 15, 30, 60, 120, 240, 480, and 720 minutes (mins) after drug infusion and quantified using mass spectrometry. Plasma PK parameters were calculated using software. Results The Cmax and Tmax of were 2503.45±1187.83 nM and 10±11.8 mins, respectively. The AUC0-t and AUC0-∞ were calculated as 98897.69±25146.28 nM*mins and 99590.46±25038.45 nM*mins. The overall clearance was 0.1±0.025 L⋅min-1⋅kg-1 with plasma half-life of 49.98±13.06 min. The Vd was measured as 7.63±2.83 L⋅kg-1. Conclusion There was large variability in the PK parameters for this group. Roflumilast seems to be quickly absorbed in blood after IV injection with a relatively short half-life. The PK data from this study will be used to develop an optimal dose of roflumilast for efficacy studies. Funding Sources This research was funded by the US Army Medical Research and Development Command (Grant numbers: CO240046 and DM230026). Topic Categories Translational and Interventional Immunology (TI)