Pharmacokinetics and clinical efficacy of acetaminophen (paracetamol) in adult horses with mechanically induced lameness

Abstract

Background Acetaminophen has been used clinically in horses alone or combined with traditional non‐steroidal anti‐inflammatory drugs for treatment of musculoskeletal pain in horses. Objectives To determine the pharmacokinetics and efficacy of acetaminophen at two doses in horses with mechanically induced lameness compared with phenylbutazone or placebo control. Study design In vivo experiment. Methods Nine healthy mares with mechanical lameness induced via a reversible sole pressure horseshoe model were treated with acetaminophen (20 mg/kg PO; A20), acetaminophen (30 mg/kg PO; A30), phenylbutazone (2.2 mg/kg, PO; PB) and oral placebo (C) in a randomised four‐way Latin square model. Plasma concentrations for A20 and A30 were analysed via LC‐MS/MS and noncompartmental pharmacokinetic analysis. Heart rate and heart rate variability were measured using a portable telemetry. Lameness was scored by three blinded boarded equine surgeons using the AAEP and 10‐point scales. Results Mean maximum plasma concentration (Cmax) for A20 was 20.01 μg/ml within 0.66 h (Tmax) after administration; The mean Cmax for A30 was 30.02 μg/ml with a Tmax of 0.43 h. Post‐treatment heart rate for A30 was significantly lower than A20 at 1 and 7 h; lower than PB at 2, 3, 4.5 and 7 h; lower than C at 2, 3.5, 4.5, 6, 7 and 8 h. 10‐point Lameness scores were significantly improved for A30 than C at 2 and 4 h post‐treatment; PB was significantly improved than C at 8 h post treatment. There were no significant differences in lameness between A20, A30 and PB. Main limitations Small sample size, lack of objective lameness measurement. Conclusions Acetaminophen at 30 mg/kg produced a more rapid improvement in lameness scores and heart rate compared with other treatments in this model. Further evaluation of the pharmacokinetics and safety of repeated oral dosing of acetaminophen at 30 mg/kg is needed to determine clinical utility.

Pharmacokinetics and efficacy of orally administered acetaminophen (paracetamol) in adult horses with experimentally induced endotoxemia

“… 16 The lack of dose proportionality between this study and a previous study in healthy horses suggests that systemic administration of endotoxin might alter acetaminophen pharmacokinetics in horses. 16 …”

“… 16 When calculating the AUC for the first 8 hours of sampling for this study, the geometric mean AUC 0‐8 hours was found to be 44.8 hr μg/mL (range, 38.0‐60.3 hr μg/mL), which is substantially lower than previously reported for a 30 mg/kg dose of acetaminophen in horses with mechanically induced lameness [geometric mean 128.04 hr μg/mL (range, 71.9‐176.2 hr μg/mL)]. 16 The lack of dose proportionality between this study and a previous study in healthy horses suggests that systemic administration of endotoxin might alter acetaminophen pharmacokinetics in horses. 16 …”

“…Plasma concentrations of acetyl‐para‐aminophenol (APAP) were measured by liquid chromatography with tandem mass spectrometry (LC MS/MS, Acquity UPLC and Acquity QDa mass spectrometer, Waters corporation, Milford, Massachusetts) as previously described. 16 All the samples were analyzed on the same analytical day. Standard curves were linear over a concentration range of 0.15 to 30 μg/mL for APAP with an R 2 ≥ .999.…”

“…λ z was reported as arithmetic mean (range), and the remainder of parameters were reported as geometric mean (range). Dose proportionality to a previously published study by acetaminophen at 30 mg/kg PO in healthy horses 16 was calculated by the dose normalized analysis of variance for 2 doses approach from Smith et al for AUC 0‐8 hours . 25 A 90% confidence interval was calculated for each variable, and acceptable range of dose proportionality was set at 80% to 125%.…”

Highlights of recent clinically relevant papers

“…The aim of this study by Melissa Mercer and co‐workers based in the USA was to determine the pharmacokinetics and efficacy of acetaminophen (paracetamol) at two doses (20 and 30 mg/kg) in horses with mechanically induced lameness compared with phenylbutazone or placebo control .…”