Pharmacokinetics and tolerability of multiple-day oral dosing of mycophenolate mofetil in healthy horses

Abstract

Background: Additional efficacious immunomodulatory treatment is needed for the management of immune-mediated disease in horses. Mycophenolate mofetil (MMF) is an immunosuppressive drug that warrants assessment as a viable therapeutic agent for horses.

Hypothesis/objectives: To evaluate the pharmacokinetics (PK) of multiple-day oral dosing of MMF in healthy horses and to determine the tolerability of this dosing regimen.

Animals: Six healthy Standardbred mares.

Methods: Horses received MMF 10 mg/kg PO q12h for 7 days in the fed state. Serial sampling was performed over 12 hours on Days 1 and 7 with trough samples collected every 24 hours, immediately before morning drug administration. Noncompartmental PK analyses were performed to determine primary PK parameters, followed by calculation of geometric means and coefficients of variation. A CBC, serum biochemical profile, physical examination, and fecal scoring were used to assess dose tolerability.

Results: Seven days of treatment resulted in a mycophenolic acid (MPA) area under the curve (AUC_0-12 ) of 12 594 h × ng/mL (8567-19 488 h × ng/mL) and terminal half-life (T_1/2 ) of 11.3 hours (7.5-15.9 hours), yielding minor metabolite accumulation in all horses treated. Salmonellosis was detected in the feces of 2 horses by Day 7, and all horses developed myelosuppression, hyperbilirubinemia, hyporexia, decreased gastrointestinal motility, and decreased fecal output by the seventh day of treatment.

Conclusion and clinical importance: Administration of MMF at 10 mg/kg PO q12h resulted in hematologic and clinical toxicity within 1 week of treatment. A decreased MMF dose, frequency, or both is needed to avoid colic. Drug monitoring should include frequent hemograms, serum biochemical profiles, and strict biosecurity protocols.

Keywords: dermatology; equine; immune-mediated; lymphopenia; neutropenia.

FIGURE 1

Mean concentration‐time curves by analyte for MPA (A), AcMPAG (B), MPAG (C), and MPG (D) for 6 horses. Horses were given twice daily MMF for 13 total doses. Horses received their final MMF dose at 144 hours. Samples were collected on Day 1 at 0 hour (baseline) and then subsequently at—15, 30, 45 minutes, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, and 12 hours. Trough samples were collected at 24, 48, 72, 96, 120, 144, and 168 hours. Day 7 serial sampling was performed at 144, 144.25, 144.5, 144.75, 145, 145.5, 146, 146.5, 147, 148, 149, 152, 154, 156, and 168 hours. Pink and black solid lines are the continuous geometric mean plasma concentrations at each sampling time on Days 1 and 7, whereas discontinuous trough geometric means are shown in blue; error bars, geometric SD. AcMPAG, mycophenolic acid acyl glucuronide; MPA, mycophenolic acid; MPAG, mycophenolic acid glucuronide; MPG, mycophenolic acid phenol glucoside.

FIGURE 2

Comparison of mean relevant hematologic and biochemical results between baseline and Day 7 of MMF treatment. Scatter dot plot displays glucose, triglyceride, total bilirubin, total leukocyte, neutrophil, and lymphocyte counts from baseline and Day 7 of PO MMF treatment. Baseline results are represented by red circles; Day 7 results are represented by black triangles. Individual shapes represent individual horse results. Panel (A) has 2 y‐axes; the left y‐axis shows serum glucose and triglyceride concentrations in mg/dL; the right y‐axis displays serum total bilirubin concentrations in mg/dL. Bars represent the mean and SD of each data set. The y–axis on panel (B) represents total blood cell counts/L; the x–axis represents total leukocytes, neutrophils, and lymphocytes specifically.