The safety of dirlotapide in dogs

Abstract

The safety of dirlotapide in dogs was evaluated in two studies with parallel designs. In an acute tolerance study, 24 beagles (six dogs per treatment) were treated orally once daily for 14 days with placebo or dirlotapide at 2.5, 5.0, or 10.0 mg/kg/day. In a margin-of-safety study, 38 overweight, neutered beagles were treated orally once daily for 3 months with dirlotapide at doses up to 0.5 mg/kg/day (six dogs), 1.5 mg/kg/day (12 dogs) and 2.5 mg/kg/day (six dogs). Control dogs received placebo at 0.3 mL/kg/day (10 dogs) and 0.5 mL/kg/day (four dogs). Results were similar for both studies, and no serious adverse events were observed. Dirlotapide was clinically well-tolerated in dogs at dosages up to 10 mg/kg/day for 14 days and 2.5 mg/kg/day for 3 months. Dirlotapide produced the expected decrease in food intake and body weight (up to 20-40%) without ill effects. Clinical, pathologic, and histopathologic findings were reversible and consistent with suppression of food intake and rapid weight loss produced by elevated dirlotapide dosages. In both studies, sporadic emesis and loose stools were observed in both placebo and dirlotapide-treated dogs. Incidence of emesis generally increased with dose and decreased with treatment time. Elevations in hepatic transaminase activity were seen in dogs treated with more than 1.5 mg/kg dirlotapide daily, but were not associated with clinical signs or microscopic evidence of hepatic degeneration or necrosis.

Evaluation of dirlotapide for sustained weight loss in overweight Labrador retrievers

“…None of these findings were associated with clinical abnormalities. At elevated dosages (up to 10 mg/kg daily), larger increases in ALT and AST have been observed in acute margin of safety studies but were not associated with gross or histopathological changes in the liver (Wren et al. , 2007b).…”

Biologic activity of dirlotapide, a novel microsomal triglyceride transfer protein inhibitor, for weight loss in obese dogs

“…The mechanism responsible for elevation and then return toward baseline of liver enzyme activities observed with dirlotapide administration is not well understood. Cytosolic enzymes (Duncan & Prasse, 1986), ALT and to a lesser degree AST may be susceptible to lipid‐induced fluctuations in hepatocellular membrane permeability (Wren et al. , 2007b).…”

Influence of dirlotapide, a microsomal triglyceride transfer protein inhibitor, on the digestibility of a dry expanded diet in adult dogs

“…In previous studies of dirlotapide‐induced weight loss in dogs, plasma total protein and albumin remained within the normal canine reference range but statistically declined, especially at elevated doses (Wren et al. , 2007b).…”

“…The results of this investigation indicate that reduced dietary protein intake or energy restriction, not protein malabsorption, is likely to be the cause of lowered plasma protein concentrations. Rapid weight loss has been shown to decrease lean body mass and serum albumin levels in dogs (Wren et al. , 2007a,b).…”

“…While substantial reductions in food intake could lead to low nutrient intake, the overall impact of dirlotapide on decreased fat digestibility and nutrient availability in this study is expected to be biologically insignificant. MTP inhibition has been noted to lower total plasma vitamin E concentrations in dogs (Wren et al. , 2007b).…”