(W1130-07-40) Integrating Bioaccessibility Data from the Tiny-TIMsg into a Physiologically Based Biopharmaceutics Model (PBBM) of a BCS Class IV Compound to Predict Pharmacokinetic (PK) Performance

Purpose: The aim of this study was to develop and implement a physiologically based biopharmaceutics model (PBBM) to predict the pharmacokinetic (PK) behavior of an orally administered BCS IV drug (compound X) under fasted conditions. The tiny-TIMsg was used to model drug release, dissolution and passive absorption in vitro. The resulting bioaccessibility profile was integrated into the PBBM using GastroPlus®.

Methods: A three-compartmental PK model was developed for compound X using GastroPlus® (v9.9, Simulations Plus). All simulations were carried out using the healthy adult volunteer population. The PK parameters were derived from a healthy adult population. The distribution and elimination model was verified using previously published intravenous (IV) mass balance data. Drug release, dissolution and passive absorption were modelled in tiny-TIMsg, a dynamic, computer-controlled, two-compartmental in vitro model of the stomach and small intestine (SI)^1,2,3,4. A clinically relevant dose of the compound was administered to the stomach compartment with 240 mL water. Media saturated with dissolved drug passed through a filtration unit, located at the end of the SI compartment and was collected at predefined time intervals. The fraction of drug present in the filtrate is referred to as bioaccessible. The tiny-TIMsg bioaccessibility profile was imported to GastroPlus® as an absorption profile, following specific modifications of the dissolution and advanced compartmental absorption and transit (ACAT) models.

Results: The total bioaccessibility) from the small intestinal compartment under fasted conditions was 7.9 ± 1.8% of the total recovered drug (Figure 1). Guided by the bioaccessibility profile, the PBBM accurately predicted the fasted state PK profile (Figure 2), with predicted to observed ratios of C_Max t_Max and AUC of 1.09, 1.25 and 0.7, respectively.

Conclusion: Bioaccessibility results from tiny-TIMsg were integrated into GastroPlus® to predict clinical PK observations of a BCS Class IV compound under fasted state conditions with success. The combination of tiny-TIMsg bioaccessibility data and GastroPlus® may be a valuable tool in the growing array of PBBM approaches for modelling gastrointestinal luminal and PK phenomena of challenging BCS IV compounds.

References: 1 Barker, R. et al., J. Pharm. Sci. 2014, 103 (11), 3704−3712.
2 Bellmann, S., et al., Food Res. Internat., 2016, 88: 191-198.
3 Dickinson, P.A., et al., 2012. The AAPS Journal 14 (2), 196–205.
4 Luo, L. et al, 2022 AAPS PharmSciTech 23:185

Cumulative bioaccessibility profile of compound A from an MR dosage form under fasted conditions in tiny-TIMsg.

Prediction of plasma concentration of compound X following oral administration of a single dose (SD) of the formulation to healthy human adults in the fasted prandial state. Observed data is presented as mean ± standard deviation.