Pharmacokinetics of Diclazuril in the Plasma and Cerebrospinal Fluid of Healthy Adult Horses After a Single Oral Dose Administered as a Pelleted Topdressing.

Overview

• This study examined how the drug diclazuril behaves in the blood and cerebrospinal fluid (CSF) of healthy adult horses after a single oral dose, particularly investigating when the drug reaches effective levels against the parasite Sarcocystis neurona, the cause of equine protozoal myeloencephalitis (EPM).

Background and Objective

• Equine protozoal myeloencephalitis (EPM) is a neurological disease in horses caused by the parasite Sarcocystis neurona.
• The infection leads to rapid onset of neurologic signs, requiring prompt treatment with antiprotozoal drugs such as diclazuril.
• The research objective was to determine when diclazuril attains the minimum inhibitory concentration (MIC) of 1 ng/mL in the CSF, which is necessary to effectively inhibit S. neurona, after a single oral administration.

Methodology

• Six healthy adult horses were selected for the study.
• Diclazuril was administered orally as a pelleted topdressing at a dose of 1 mg/kg mixed with 8 oz of sweet feed.
• Blood samples were collected via intravenous jugular catheters, and CSF samples were obtained through intrathecal catheters placed in the lumbosacral space.
• Sampling times were carefully scheduled before administration and at multiple intervals thereafter (1, 4, 8, 12, 16, 24, 48, 72, 96, 120, 144, 168, and 192 hours post-dose) to track drug concentration over time.
• Collected blood and CSF samples were centrifuged to separate plasma and CSF supernatant, which were then frozen at -80°C until laboratory analysis.
• Diclazuril concentrations were measured using a liquid chromatography-mass spectrometry assay developed specifically for this study, ensuring high sensitivity and accuracy.

Results

• Plasma diclazuril concentrations peaked at 48 hours post-administration, with a mean concentration of approximately 395.6 ng/mL ± 109.4 ng/mL.
• CSF diclazuril concentrations peaked earlier at 24 hours, reaching a mean level of 9.0 ng/mL ± 5.4 ng/mL.
• Importantly, the MIC of 1 ng/mL for S. neurona was reached in the CSF by 12 hours after dosing, with a mean concentration of 2.6 ng/mL ± 1.8 ng/mL.
• Diclazuril levels in the CSF remained above the MIC for the entire 192-hour (8-day) sampling period.

Conclusions and Implications

• A single oral dose of pelleted diclazuril at 1 mg/kg effectively delivers drug concentrations above the MIC for S. neurona in the CSF of healthy adult horses within 12 hours.
• This supports the potential for rapid onset of antiprotozoal activity in treating EPM after oral administration of diclazuril.
• The sustained drug levels in the CSF suggest prolonged therapeutic coverage that might reduce frequency of dosing.
• These pharmacokinetic data provide important guidance on timing and dosing strategies for managing EPM with diclazuril in clinical settings.