Utilizing Physiologically Based Pharmacokinetic Modeling and Virtual Simulation for Simvastatin Tablets to Evaluate...

Typically, parent drug is measured for bioequivalence (BE) assessment because it's more sensitive to detect formulation differences, compared to its metabolite(s). For simvastatin immediate release (IR) tablets, current product-specific guidance (PSG) recommends measuring both parent and metabolite but taking metabolite as supportive data. This study aims to utilize physiologically based pharmacokinetic (PBPK) modeling and virtual BE (VBE) simulation to evaluate the sensitivity of parent vs metabolite as analyte on BE assessment, using simvastatin case and explore relevant mechanism. PBPK model was developed to describe drug exposures of parent drug simvastatin (SV) and metabolite simvastatin acid (SVA) in healthy individuals administered with 20-80 mg IR tablets under fasting condition. VBE simulations were conducted to evaluate the sensitivity of SV and SVA as analytes to assess BE between test product and reference listed drug. PBPK model incorporating enzyme- and transporter-mediated kinetics reasonably captures fasting PK profiles for SV and SVA. VBE simulations indicate that parent drug, in general, is more sensitive to demonstrate BE as compared to metabolite. However, this study highlighted the importance of conducting BE analysis using PK data for both SV and SVA when the test product contains certain excipients in the formulation that may impact transporter activity for changing clearance and subsequent drug exposure of metabolite. The VBE simulation results further implied that in some cases, SVA as analyte is more sensitive to show drug exposure differences and may enhance the assessment of formulation effect, as compared to SV. This aligns with current PSG recommendations.