Assessment of pharmacokinetic parameters, oral bioavailability, and physiological effects of amantadine in horses.

Overview

• This study investigated how amantadine, a drug that blocks NMDA receptors, is absorbed, distributed, and tolerated in horses, to evaluate its potential for managing chronic pain associated with central sensitization in horses.

Background and Rationale

• Chronic or maladaptive pain often develops when acute pain is not adequately managed, due to changes in the central nervous system known as central sensitization.
• Central sensitization involves increased activation of NMDA receptors, which amplifies pain signals.
• Amantadine, an NMDA receptor antagonist, has been utilized in humans and dogs alongside opioids and NSAIDs to help treat pain conditions linked to central sensitization.
• The therapeutic potential and pharmacological profile of amantadine had not yet been characterized in horses.

Study Objectives

• To describe the pharmacokinetics (PK) — how the drug moves through the body — of amantadine in horses.
• To assess the oral bioavailability of amantadine in horses, i.e., the proportion of orally administered amantadine that reaches systemic circulation.
• To evaluate the physiological and behavioral effects of amantadine administration in horses to determine safety and tolerability.

Methods

• Eight horses participated in a randomized 4-way balanced crossover design.
• Each horse received:
  • Intravenous (IV) dose of 5 mg/kg amantadine.
  • Oral doses of 3, 5, and 10 mg/kg amantadine on separate occasions.
• Blood samples were collected pre-administration and up to 96 hours post-dose to measure amantadine concentrations.
• Concentration measurements were done using liquid chromatography-tandem mass spectrometry.
• Pharmacokinetic analyses were conducted to determine key PK parameters like peak concentration (Cmax), time to peak concentration (Tmax), terminal half-life, and absorption rate.
• Behavioral and physiological assessments included observing for sedation, ataxia (loss of full control of bodily movements), locomotor activity, gastrointestinal sounds (borborygmi), and heart rate changes.

Key Pharmacokinetic Findings

• Peak plasma concentrations (Cmax) after oral dosing were:
  • 208.7 ± 70.4 ng/mL for 3 mg/kg
  • 347.9 ± 79.5 ng/mL for 5 mg/kg
  • 478.9 ± 165.6 ng/mL for 10 mg/kg
• Median time to peak concentration (Tmax) ranged between 0.63 and 1.0 hours across oral doses.
• Terminal half-life (the time for plasma concentration to reduce by half) was approximately 3.9 to 4.9 hours for both IV and oral doses.
• The pharmacokinetic data were best described by a 2-compartment population PK model.
• The absorption rate constant after oral administration was 3.16 1/h.
• Oral bioavailability (the fraction of drug absorbed into the bloodstream from oral dosing) was relatively low at 23.2%, meaning less than one-quarter of the oral dose reached systemic circulation as active drug.

Physiological and Behavioral Observations

• Following IV amantadine administration, 5 out of 8 horses exhibited transient side effects such as:
  • Ataxia (coordination problems)
  • Hypometria (incomplete or undershooting movement)
• These effects were temporary and no significant adverse effects were reported from oral dosing at the tested levels.
• Other parameters including sedation, heart rate, gastrointestinal sounds, and locomotion were monitored but no concerning alterations were described.

Conclusions and Implications

• Amantadine administration was generally well tolerated in horses, particularly through oral dosing, supporting feasibility for further research.
• The pharmacokinetic profile and limited safety data established by this study provide important baseline information needed to design future pharmacodynamic studies.
• Pharmacodynamic studies will be crucial to evaluate the therapeutic efficacy of amantadine for managing chronic pain or central sensitization-related conditions in horses.
• Given the low oral bioavailability, future studies might explore formulations or dosing strategies to enhance systemic drug exposure.