Pharmacokinetics of the novel 5-HT4 receptor agonist, DA-6886, in dogs

Authors: Lee DY, Kang HE
Publication: Xenobiotica
Keywords: beagle, biopharmaceutics, food effect, gastroplus, mechanistic absorption, nonlinear pk, pbbm, PBPK modeling, physiologically based pharmacokinetics
Software: ADMET Predictor®, GastroPlus®

Abstract

  1. The pharmacokinetics of a new 5-hydroxytryptamine receptor 4 agonist, DA-6886, intended for the treatment of constipation-predominant irritable bowel syndrome, were evaluated in beagle dogs following both intravenous and oral administration of DA-6886 (1–10 mg/kg). The study also examined the effects of gender and food on the pharmacokinetics of DA-6886 in dogs.

  2. DA-6886 demonstrated dose-proportional area under the plasma concentration–time curve (AUC) values and dose-independent clearance (21.0–24.6 mL/min/kg) after administration via both routes. The steady-state volume of distribution (Vss) for DA-6886 was dose-independent and relatively large (6.76–8.57 L/kg), aligning with its observed high distribution in rat tissues.

  3. No significant differences were observed in the pharmacokinetics of DA-6886 between male and female dogs. Post oral administration, extent of absolute oral bioavailability (BA) was relatively high (48.2–96.1%) in contrast to the rates observed in rats (18.9–55.0%).

  4. Dogs that were fed exhibited a significantly lower Cmax and a delayed Tmax in comparison to those that were fasted. However, the AUC values were similar between the two groups. The extended stomach transit time in the fed state may account for this delayed absorption of DA-6886 without substantial changes in AUC.

By Dae Young Lee, Hee Eun Kang