PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING OF FLUVOXAMINE USING IN VITRO DISSOLUTION DATA IN A VIRTUAL HEALTHY MICE MODEL FOR AN IN SITU FORMING IMPLANT DRUG DELIVERY SYSTEM
DOI:
https://doi.org/10.22159/ijap.2026v18i4.57636Keywords:
Fluvoxamine, Physiologically based pharmacokinetic modeling, In situ forming implant (ISFI), Sustained release, CYP1A2, PK-Sim, Brain pharmacokineticsAbstract
Objective: Physiologically based pharmacokinetic (PBPK) modeling provides a mechanistic framework to study the absorption, distribution, metabolism, and excretion (ADME) of drugs by integrating physiological and biochemical parameters with experimental data. It enables prediction of formulation behavior across biological systems while reducing reliance on extensive in vivo studies. This study aimed to develop and evaluate a PBPK model of fluvoxamine administered as an in situ forming implant (ISFI) to predict plasma and brain concentration–time profiles in a virtual healthy mouse model over a 14-day period.
Methods: A PBPK model was developed using PK-Sim, incorporating physicochemical properties of fluvoxamine and formulation-specific release data obtained from in vitro dissolution studies. A 15 mg ISFI formulation based on a PLGA 50:50 polymer matrix was modelled as a slow-release depot. Systemic circulation interconnected all major organs, with hepatic metabolism via CYP1A2 defined as the primary clearance pathway. Passive diffusion and active efflux mechanisms were incorporated across the blood–brain barrier. Model performance was evaluated using non-compartmental analysis (NCA) and prediction error (PE%) for key pharmacokinetic parameters. Quantitative assessment was based on parameter concordance rather than regression-based concentration–time curve fitting. Sensitivity analysis was performed to identify parameters influencing systemic exposure.
Results: The model successfully simulated biphasic plasma concentration–time profiles characteristic of sustained-release systems. The predicted Cmax was 11.43 μg/L at 3 h, with an extended terminal half-life of 69.00 h, confirming prolonged drug release. Prediction errors were below 15% for Cmax and 10% for AUC, consistent with accepted PBPK evaluation criteria. Linear regression of log10-transformed predicted versus observed exposure parameters yielded an R² value of 0.9825, indicating strong agreement and model robustness. Sensitivity analysis identified hepatic intrinsic clearance (CLint) as the most influential parameter; a 20% increase in CLint reduced AUC by 17% and Cmax by 15%, highlighting the dominant role of CYP1A2-mediated metabolism.
Conclusion: The developed PBPK model effectively predicted systemic and brain pharmacokinetics of fluvoxamine delivered via an ISFI formulation, demonstrating sustained release and continuous central exposure. The model establishes a mechanistic link between in vitro dissolution and predicted in vivo pharmacokinetics in a virtual preclinical setting, supporting rational formulation design and reducing dependence on exploratory animal studies. However, in vivo pharmacokinetic validation of the same formulation is required for complete confirmation.
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