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

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 (V_ss) 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 C_max and a delayed T_max 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.

Keywords:

• DA-6886
• pharmacokinetics
• dose-dependency
• gender-difference
• food effect
• dog

Acknowledgements

Free access to Simulation Plus software was provided by the University + program of Simulations Plus, Inc.

Disclosure statement

All authors declare that they have no conflicts of interest. Dae Young Lee is a full-time employee of Dong-A ST Co. Ltd. The company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Additional information

Funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government [No. 2018R1A6A1A03025108 (Ministry of Education) and 2019R1F1A1052243 (MSIT)] and by the Research Fund, 2021 of The Catholic University of Korea.