Population pharmacokinetics and clinical evaluation of intravenous acetaminophen and its metabolites in Andalusian horses

To date, no intravenous pharmacokinetics (PK) studies have assessed acetaminophen or its major metabolites (acetaminophen-glucuronide and acetaminophen-sulphate) in horses. The influence of sex on acetaminophen metabolism in horses is unclear, and Monte Carlo simulations have not been applied to explore potential clinical applications. This study aimed to determine the intravenous PK and safety of acetaminophen in Andalusian horses at 10 and 20 mg/kg, evaluate sex as a covariate, and simulate clinical regimens. Twenty mares and twenty stallions received intravenous acetaminophen, and plasma concentrations were analysed by LC-MS/MS and modelled using non-linear mixed-effects models (MonolixSuite®). Safety was evaluated via clinical examinations and by haematological and biochemical profiles 24 h after administration. Two constant-rate infusion (CRI) regimens were examined in PK simulations that did not involve surgery: a short-duration, high-dose infusion (3 h) for peri-operative scenarios (short-infusion group at 3.33, 6.66, and 10.0 mg/kg/h) and a longer-duration, lower-dose infusion (8 h) for post-operative analgesia scenarios (long-infusion group at 1.25, 2.50, and 3.75 mg/kg/h). After modelling, glucuronide and sulphate levels were 2.1 and 4.53 times higher, respectively, than acetaminophen levels. Half-lives were 3.5, 5.6, and 3.2 h for acetaminophen, glucuronide, and sulphate, respectively. Clearance was influenced by sex (mares: 0.47 L/h/kg; stallions: 0.35 L/h/kg). No adverse effects were observed. Steady-state concentrations observed in the CRI simulations ranged from 1.75-5.21 µg/mL (short-infusion group) and 0.62-2.02 µg/mL (long-infusion group). Acetaminophen exhibited sex-dependent PK variability and high-level formation of metabolites. These findings support further clinical evaluation of acetaminophen CRIs in equine analgesia.