GastroPlus® and ADMET Predictor driven predictive model for pharmacokinetic parameters of ENDOL® immediate-release capsule

In silico tools have become indispensable for preclinical assessment of pharmacokinetic parameters of drug. Several commercial software platforms, such as GastroPlus®, PK-Sim®, Stella®, and GISim®, offer comprehensive simulation capabilities for drug absorption, distribution, metabolism, and excretion (ADME)[1]. Among these, GastroPlus® stands out by integrating pharmacokinetic and pharmacodynamic modeling, allowing the construction of ADME models to simulate drug behavior across various routes of administration.This study aims to simulate the pharmacokinetic (PK) profile of indomethacin 25 mg immediate-release (IR) capsules(marketed as Endol®) using an integrated platform of ADMET Predictor^TM and GastroPlus™9.8. For this purpose, ADMET Predictor^TM module was used to generate physicochemical and biopharmaceutical parameters including molecular weight, logP, pKa and solubility etc. Additionally, literature-derived values for clearance (CL), volume of distribution (Vd), the contribution of intestinal metabolism (in vitro KM and Vmax values for CYP2C9 and UGT2B7) [2], free fraction in plasma, permeability in Caco–2 cells, blood to plasma ratio were manually entered into the simulation[3]. These parameters were transferred into GastroPlus™ 9.8 through integrated modeling. In vitro dissolution profiles of Endol® immediate-release capsules (25 mg) were obtained using the method described in the USP dissolution database[4]. Briefly, dissolution used USP Apparatus 1(basket method) at 37 ± 0.5 ?C at 100rpm with three replicates. Medium was 750 mL of PBS (pH7.2):Water (1:4v/v). Samples were taken at determined time points (5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 360 min), filtered through 0.45 mm Millipore filter, and assayed by ultraviolet visible spectrophotometry at 272 nm. Then all were incorporated into the Advanced Compartmental Absorption and Transit model to predict plasma concentration-time profiles following oral administration under fasted conditions in healthy adult subjects. The simulated profiles were compared to the observed PK profile obtained from literature[3, 5]. The dissolution study showed that the Endol® capsules reached 100% dissolved by 20min. The simulated plasma profile showed a peak concentration(Cmax) of approximately 2.22 µg/mL and a time to peak(Tmax) of 0.72 hours, closely aligned with reported clinical literature values (Cmax~2 µg/mL; Tmax~1–2 h). While the observed AUC(0-t) and AUC(0-∞) values were 4.2 and 4.3 μg.h/mL, model-predicted AUC 0-t and AUC0-∞ were found 4.15 and 4.16 μg.h/mL, respectively[5]. All values met the verification criterion, with predicted-to-observed ratios falling within the acceptable range of 0.80 to 1.20. The model effectively captured the rapid absorption and biphasic elimination characteristics of indomethacin, consistent with established pharmacokinetics. This study demonstrates that simulation-based modeling using both experimental dissolution data and compound-specific PK parameters can reliably reproduce clinical pharmacokinetics of a marketed oral formulation. The ADMET Predictor–GastroPlus integrated approach offers a valuable tool for formulation design, in vitro–in silico correlation and early-stage drug development decision-making.