Utilizing Physiologically Based Pharmacokinetic Modeling and Virtual Simulation for Simvastatin Tablets to Evaluate the Sensitivity of Using Parent vs Metabolite as Analyte on Bioequivalence Assessment.

Yi-Hsien Cheng, Fang Wu, Miyoung Yoon, Liang Zhao, Lanyan Fang

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Article in The AAPS journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 authors.

Yi-Hsien ChengDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.ORCID 0000-0002-4314-9732

Fang WuDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA. Fang.Wu@fda.hhs.gov.ORCID 0009-0009-1485-8386

Miyoung YoonDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.ORCID 0000-0002-3653-3488

Liang ZhaoDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.ORCID 0000-0002-0257-9082

Lanyan FangDivision of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, 20993, USA.ORCID 0000-0001-5378-2948

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

Hydroxymethylglutaryl-CoA Reductase InhibitorsModels, BiologicalSimvastatinAdultComputer SimulationCross-Over StudiesFastingFemaleHealthy VolunteersHumansMaleTabletsTherapeutic EquivalencyYoung AdultHydroxymethylglutaryl-CoA Reductase InhibitorsSimvastatinsimvastatin acidTabletsmetaboliteparentphysiologically based pharmacokinetic modelingsimvastatinvirtual bioequivalence

Identifiers

PMID41350955

DOI10.1208/s12248-025-01184-w

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.