Pharmacokinetics and pharmacodynamics of protamine zinc recombinant human insulin in healthy dogs

Protamine zinc insulins are generally considered to be long acting, with slow absorption from subcutaneous tissue. Protamine zinc recombinant human insulin (PZIR) may be useful to treat diabetic dogs. The purpose of this study was to describe the pharmacokinetics and pharmacodynamics of PZIR in dogs. PZIR was administered subcutaneously to 10 healthy Beagles using an incomplete crossover design, at doses of 0.3 or 0.5U/kg (each n=5), 0.8U/kg (n=10), or 0.8U/kg at three separate sites (n=6). Insulin and glucose concentrations were measured over 24h. The shapes of insulin and glucose curves were variable among dogs, and the relationship between insulin dose, concentration, and glucose-lowering effect was nonlinear. For single-site 0.8U/kg, median (range) onset of action was 3.5h (0.5-10h), time to glucose nadir was 14h (5 to >24h), and duration of action was >24h (16 to >24h). Mathematical model predictions of times to 50% and 90% insulin absorption, and fraction of insulin absorbed in 24h, were not significantly different among protocols. Results confirm the tendency toward a late onset and long duration of action for PZIR in dogs. This insulin may be an alternative treatment option for diabetic dogs.