Priya Sharma 1, Tanveer Naved 2, Arti Thakkar 3
1 School of Pharmacy, Sharda University (Greater Noida, India), 2 Amity Institute of Pharmacy, Amity University (Noida, India), 3 Pumas-AI, Inc (Dover, USA)
Objectives
Rifampicin is a BCS Class II antibiotic whose absorption is governed by solubility-limited dissolution regulated by bile salt–associated micellar solubilization in the gastrointestinal lumen [1]. Hepatobiliary disorders such as Crohn’s disease and cholestasis are associated with altered bile salt concentrations and composition, potentially driving clinically relevant variability in systemic drug exposure cholestasis [2,3]. Despite evidence that bile salts act as absorption enhancers [1] for lipophilic drugs, existing physiologically based pharmacokinetic (PBPK) frameworks lack quantitative, disease-specific parameterization of bile salt physiology. This work bridges biorelevant dissolution data with a disease-informed PBPK framework to mechanistically quantify the impact of bile salt dysregulation on rifampicin pharmacokinetics.
Methods
A whole-body PBPK model was developed using PK-Sim® (Open Systems Pharmacology platform). Drug-specific parameters including logP, pKa, aqueous solubility, permeability, and plasma protein binding etc. were extracted from published clinical data [4]. Model development proceeded in two stages: (i) intravenous datasets (450–600 mg) were used to characterize systemic disposition, and (ii) oral datasets were incorporated to refine dissolution and absorption parameters [5]. Model qualification was based on the criterion that predicted/observed ratios for Cmax and AUC fell within a two-fold error [6]. Biorelevant dissolution profiles, determined experimentally under bile salt concentrations representative of healthy adults (3–5 µmol/L), Crohn’s disease (~1.2 µmol/L), and cholestasis (~10 µmol/L) [7,8], were incorporated directly into the intestinal absorption module. Disease-specific gastrointestinal physiology was parameterized using published data on hepatic function, gastrointestinal transit, and biliary secretion [9,10]. Parameter sensitivity analysis was conducted to quantify the relative contributions of luminal bile salt concentration and hepatic intrinsic clearance to overall pharmacokinetic variability.
Results
The PBPK model accurately reproduced intravenous and oral concentration–time profiles across all dose levels, with Cmax and AUC predictions within the two-fold error criterion, confirming model robustness. Disease simulations demonstrated that bile salt concentration was the primary driver of exposure variability. In Crohn’s disease, reduced micellar solubilization (bile salt ~1.2 µmol/L) decreased dissolution rate and yielded approximately 30% reductions in both Cmax and AUC relative to healthy conditions. In cholestasis (bile salt ~10 µmol/L), enhanced solubilization produced approximately 50% elevation in Cmax and a moderate increase in AUC. Sensitivity analysis identified luminal bile salt concentration as the most influential parameter governing pharmacokinetic variability, with greater impact than alterations in hepatic intrinsic clearance. These findings indicate that absorption-driven variability may outweigh clearance-driven effects in bile salt–associated conditions.
Conclusions
This study presents a quantitatively validated PBPK model that mechanistically links bile salt physiology to rifampicin systemic exposure in healthy and disease states. By translating experimentally measured dissolution variability into clinically relevant pharmacokinetic outcomes, the framework supports model-informed dosing in populations with altered biliary physiology. The approach reduces uncertainty in disease-mediated absorption predictions and provides a scalable methodology applicable to other dissolution-limited compounds. From a regulatory and systems pharmacology perspective, this work establishes a framework for quantitative mechanistic evaluation of drug–disease interactions driven by gastrointestinal physiology.
References:
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Reference: PAGE 34 (2026) Abstr 12015 [www.page-meeting.org/?abstract=12015]
Poster: Drug/Disease Modelling - Absorption & PBPK