Evaluation of pharmacokinetics of metoclopramide administered via subcutaneous bolus and intravenous constant rate infusion to adult horses

Abstract

Objective: To determine the pharmacokinetics (PK) of metoclopramide administered via intravenous continuous rate infusion (IV CRI) and subcutaneous (SC) bolus and evaluate for gastrointestinal motility and adverse side effects. Study design: Experimental study; randomized, crossover design. Animals: Six healthy adult horses. Methods: Each horse received metoclopramide via IV CRI (0.04 mg/kg/h for 24 h) and SC bolus (0.08 mg/kg once), with >= 1 week washout period between. Plasma was analyzed by UPLC-MS/MS. Compartmental modeling was used to determine PK parameters for each treatment; nonparametric superposition was used to simulate multiple SC bolus regimens. Gastrointestinal motility and evidence of adverse effects were monitored. Results: Tmax (h) for SC bolus was 0.583 +/- 0.204 versus 17.3 +/- 6.41 for IV CRI, while Cmax (ng/mL) was 27.7 +/- 6.38 versus 43.6 +/- 9.97, respectively. AUC (h x ng/mL) was calculated as 902 +/- 189 for 24 h IV CRI versus 244 +/- 37.4 simulated for 0.08 mg/kg SC bolus every 8 h. Simulations revealed similar exposure between groups with administration of 0.96 mg/kg/day SC bolus, divided into three, four, or six doses. SC bolus bioavailability was estimated as 110 +/- 11.5%. No clear trends in motility alteration were identified. No adverse effects were noted. Conclusion: Repeated SC boluses of metoclopramide at 0.08 mg/kg would result in lower total drug exposure and Tmax than IV CRI administration but would be highly bioavailable. Clinical significance: Higher and/or more frequent SC bolus doses are needed to achieve a similar AUC to IV CRI. No adverse effects were noted; however, evaluation of alternative dosing strategies is warranted.