Physiologically Based Pharmacokinetic (PBPK) Modelling of a Gastroretentive Cimetidine Formulation: Predicting Enhanced Bioavailability Through Prolonged Gastric Retention.

Introduction
Cimetidine's clinical utility is limited by its short half-life (~2 h) and narrow absorption window. Gastroenteric drug delivery systems (GRDDS) can overcome these limitations, but development typically requires costly in vivo studies. This study used PBPK modelling (PK-Sim® v11.3) to predict how a pH-responsive buoyant in situ gelling system modulates cimetidine absorption.

Methods
Simulations incorporated cimetidine's properties (pKa 6.8, logP 0.78). As PK-Sim® provides no African population database, an African-American database served as a proxy, with selected parameters adjusted to reflect assumed gastrointestinal conditions (gastric pH 1.5–2.5, gastric emptying > 2 h, intestinal transit, CYP450 metabolism, renal clearance); these are modelled assumptions, not established physiology. Gastric retention was modelled by modifying gastric emptying; pH-responsive release was represented by a formulation-specific release profile; and gel integrity was represented as a sustained retention assumption, as PK-Sim® does not mechanistically model viscosity. The GRDDS (sodium alginate 4% w/v, calcium carbonate 1% w/v, assumed viscosity ≥ 3000 cP, buoyancy > 8 h) was simulated as a single arm.

Results
The model predicted a GRDDS AUC of 27,106 µmol·min/L, a Cmax of 14.31 µmol/L, a tmax of 1.4 h, an MRT of 32.08 h (vs 4–6 h for conventional tablets), and an apparent terminal half-life of 20.11 h (absorption-limited, not a change in intrinsic clearance). The model predicted a 92% probability of maintaining plasma concentrations above the established minimum therapeutic level of 0.5 µg/mL for >12 h, providing a modelling-based rationale for further evaluation of twice-daily dosing. Gastric emptying was the most influential variable; extending retention from 2 to 8 h increased AUC by 34%. Because the simulation modelled only the GRDDS formulation, no model-derived comparator was available; published data for gastroretentive cimetidine systems report approximately 2.3-fold increases in systemic exposure relative to conventional tablets (Mishra et al., 2025; Rovati et al., 1983), though direct comparison should be interpreted cautiously.

Discussion
The simulated GRDDS showed favourable predicted exposure and prolonged MRT. Prospective experimental validation, including a model-derived conventional tablet comparator, is required.