Pharmacokinetics, clinical efficacy and safety of acetaminophen (paracetamol) in adult horses with naturally occurring chronic lameness

Abstract

BackgroundAcetaminophen is used clinically in horses with musculoskeletal pain; however, no studies have been performed in horses with chronic lameness.ObjectivesTo determine the pharmacokinetics, safety and efficacy of chronic dosing of acetaminophen in horses with naturally occurring chronic lameness.Study designLongitudinal.MethodsTwelve adult horses with chronic lameness were treated with acetaminophen (30 mg/kg PO) every 12 h for 21 days. Plasma concentrations of acetaminophen were analysed on days 7 and 21 via LC–MS/MS and noncompartmental pharmacokinetic analysis. Lameness was evaluated by body‐mounted inertial sensor (BMIS) and 10‐point subjective lameness score on day 21 and compared to untreated baseline evaluation on day 35. Clinicopathological analysis (n = 12), hepatic biopsy (n = 6) and gastroscopy (n = 6) were evaluated on days −1 and 22.ResultsMaximum plasma acetaminophen concentration (Cmax) was 20.83 ± 10.25 μg/mL at time (Tmax) 0.40 ± 0.22 h on day 7. The Cmax on day 21 was 17.33 ± 6.91 μg/mL with a Tmax of 0.67 ± 0.26 h. Subjective lameness scores significantly improved at 2 and 4 h post‐treatment; Significant percent improvement was detected in PDmax for horses with hindlimb lameness at 1, 2 and 8 h post‐treatment. There were no significant differences in gastroscopy or hepatic biopsy scores between days −1 and 22.Main limitationsSmall sample size, multi‐limb lameness of varying severity and aetiology, lack of intermediary lameness evaluation.ConclusionsIn horses with naturally occurring chronic lameness, acetaminophen at 30 mg/kg produced a transient improvement in subjective lameness and BMIS evaluation. Acetaminophen may not be effective as a monotherapy. Acetaminophen was safe following 21 days of 30 mg/kg PO every 12 h, with no evidence of clinically significant changes in clinicopathological analysis, hepatic biopsy or gastric ulceration scores.

Pharmacokinetic profile of oral and subcutaneous administration of paracetamol in the koala (Phascolarctos cinereus) and prediction of its analgesic efficacy

“…It is problematic to compare apparent clearance between species when there is no intravenous dosing PK information for the koala. However, the oral half-life in the koala (median [range] is longer than in the dog (1.25 hrs [when fed]) [ 35 ], the horse (mean ± SD 2.95 ± 0.62 hrs Day 7; 4.64 ± 3.56 hrs Day 21) [ 37 , 38 ], and in humans (1.9–2.5 hrs) [ 39 ]. The percentage of drug bound to plasma proteins is reported as 49.2 ± 6.80 [ 38 ] or 52.3 ± 8.6% [ 37 ] in the horse and between 15% and 21% for both pigs and humans, respectively [ 40 ], and 11.0 ± 1.2% in the dog [ 41 ].…”

“…However, the oral half-life in the koala (median [range] is longer than in the dog (1.25 hrs [when fed]) [ 35 ], the horse (mean ± SD 2.95 ± 0.62 hrs Day 7; 4.64 ± 3.56 hrs Day 21) [ 37 , 38 ], and in humans (1.9–2.5 hrs) [ 39 ]. The percentage of drug bound to plasma proteins is reported as 49.2 ± 6.80 [ 38 ] or 52.3 ± 8.6% [ 37 ] in the horse and between 15% and 21% for both pigs and humans, respectively [ 40 ], and 11.0 ± 1.2% in the dog [ 41 ]. In contrast, a concentration of 15 μg/mL (similar to plasma C max ) has a percentage of bound drug of 61.23 ± 7.46% in the koala and this may account for the longer half-life in this species.…”

“…Paracetamol undergoes phase II metabolism by both glucuronidation and sulfation in many species [ 8 , 33 , 35 , 37 ]. The reason for paracetamol toxicity in the cat is that the toxic phase I metabolite (NAPQI) cannot undergo phase II conjugation due to the lack of UDP-glucuronosyltransferase (UGT) enzymes [ 9 ].…”

“…There are PK profiles of paracetamol described for some animals such as dogs [32][33][34][35][36] and horses [37,38]. It is problematic to compare apparent clearance between species when there is no intravenous dosing PK information for the koala.…”