Soyoung Lee (1), Yun Kim (1), Jaeseong Oh (1), Su-jin Rhee (1), SeungHwan Lee (1), In-Jin Jang (1)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
Objectives: DWP14012 is a novel potassium-competitive acid blocker, which reversibly binds to H+, K+-ATPase without acid activation [1]. As expected to show better therapeutic effect for gastroesophageal reflux disease and gastric ulcer, DWP14012 has been under development. Since its exposure shows more than dose proportional manner across 10 to 320 mg dose range, predicting pharmacokinetic profile of DWP14012 is needed. The current study aims to construct a population pharmacokinetic model for DWP14012 in healthy Korean subject.
Methods: A population pharmacokinetic model for DWP14012 was developed by using a nonlinear mixed-effects method in NONMEM (version 7.4). A total of 860 plasma DWP14012 concentration from a phase 1 single ascending dose pharmacokinetic study (n=48), which included 10, 20, 40, 80, 160, 320 mg dose group, were used to construct base model. One or two compartment models with first order or zero order absorption with or without lag time were assessed to identify the best describing absorption profile of DWP14012. In addition, first order elimination or Michaelis Menten elimination were evaluated to determine appropriate DWP14012 pharmacokinetic profile. The model performance was evaluated with basic goodness-of-fit diagnostics and visual predictive checks. Simulations were performed investigating multiple dosing scenario, such as 20 mg, 40 mg, 80 mg daily administration of DWP14012 for 7 days. The peak concentration (Cmax) and minimum concentration (Cmin) of DWP14012 were evaluated for each of the multiple dosing scenarios.
Results: The pharmacokinetic characteristics of DWP14012 were well described with a two-compartment non-linear pharmacokinetic model with first-order absorption and lag time with proportional residual error. Non-linear pharmacokinetic properties were explained by Michaelis Menten elimination. The typical estimates of absorption constant (Ka), central volume of distribution (V2), peripheral volume of distribution (V3), intercompartmental clearance (Q), and lag time was 0.128 h-1, 107 L, 702 L, 54.8 L/h, and 0.238 h, respectively. The typical value of maximum rate (Vmax) and Michaelis constant (Km) was estimated to 6.29 L/h and 38.1 μg/L, respectively. The inter-individual variability (CV%) of V2, Ka, and Vmax was 114.2 %, 17.2 %, and 30.0 %, respectively. Model evaluation by visual predictive checks suggested that the proposed model was adequate and robust with good precision. The simulation results of median Cmax in 20 mg, 40 mg, 80 mg group was 13.24 μg/L, 32.53 μg/L, and 94.65 μg/L, respectively. The simulation results of median Cmin in 20 mg, 40 mg, 80 mg group was 1.84 μg/L, 4.42 μg/L, and 14.41 μg/L, respectively.
Conclusions: The population pharmacokinetic model for DWP14012 was well developed to predict the multiple dose administration of DWP14012. Further model refinement using patient data can be utilized to improve the dosing regimen in patient group with gastroesophageal reflux disease and gastric ulcer.
References:
[1] Sunwoo, J., et al. Safety, tolerability, pharmacodynamics and pharmacokinetics of DWP 14012, a novel potassium‐competitive acid blocker, in healthy male subjects. Alimentary pharmacology & therapeutics, 2018, 48.2: 206-218.
Reference: PAGE 28 (2019) Abstr 8949 [www.page-meeting.org/?abstract=8949]
Poster: Drug/Disease Modelling - Other Topics