The effects of food on the pharmacokinetics of mycophenolate mofetil in healthy horses.

Additional immunomodulatory treatment is needed for the management of immune-mediated disease in horses. Mycophenolate mofetil (MMF) is an immunomodulatory agent used in human and veterinary medicine for the prevention of graft rejection and the management of autoimmune diseases. Few studies exist investigating the pharmacokinetics of MMF in horses. The aim of this study was to evaluate the pharmacokinetics of a single dose of MMF in healthy horses in the fed vs. fasted state. Six healthy Standardbred mares were administered MMF 10 mg/kg by a nasogastric (NG) tube in a fed and fasted state. A six-day washout period was performed between the two doses. No statistically significant differences in mycophenolic acid (MPA) concentrations were seen at any time point apart from 8 h, when plasma metabolite concentrations were significantly higher in the fasted state compared to the fed state (p = .038). Evidence of enterohepatic recirculation was seen only in the fasted state; this did not yield clinical differences in horses administered a single-dose administration but may be significant in horses receiving long-term MMF treatment.

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

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 (AUC0-12 ) of 12 594 h × ng/mL (8567-19 488 h × ng/mL) and terminal half-life (T1/2 ) 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.

Pharmacodynamic Effects of Pioglitazone on High Molecular Weight Adiponectin Concentrations and Insulin Response After Oral Sugar in Equids.

Chronic insulin dysregulation is challenging to manage with pharmaceuticals in horses. Pioglitazone improves insulin sensitivity in humans, and the pharmacokinetics of pioglitazone have been evaluated in horses. The objectives of this study were to assess the pharmacodynamic effects of oral pioglitazone on morphometric parameters, hepatic enzyme activity and function, adipokines, and enteroinsular response to oral sugar. A prospective pilot study was performed using fifteen adult equids (8 ponies, 7 horses) to evaluate the effects of short-term pioglitazone administration (2 mg/kg PO q 24 hours, 28 days). Oral sugar tests (OST) were performed before and after treatment. Adipokines were measured at day 0, 14, and 28 of administration. Plasma drug concentrations were measured at day 14 and 28 of administration. The subjects were grouped into horses, ponies, and insulin dysregulated (ID) animals. Baseline values for all parameters were compared with values obtained at day 14 and 28 using one-way or two-way analysis of variance. Mild changes were noted in morphometric parameters and hepatic enzymes. No differences were found in leptin concentrations or the blood glucose response to the OST. Significant decreases were found in the insulin response to OST at 90 and 120 minutes time points and the area under the curve after pioglitazone treatment in the pony and ID groups. High-molecular-weight (HMW) adiponectin concentrations were significantly increased in all groups after pioglitazone treatment. Decreased insulin concentrations in response to oral sugar and increased HMW adiponectin concentrations indicate positive effects of pioglitazone for treatment of metabolic derangements in equine metabolic syndrome, which warrant future clinical study.