Comprehensive Review of Factors Influencing Intrasubject Variability in Bioequivalence Studies
Shrikrishna Bajarang Pawar1,2, Atul N Chandu2, Saravanan Devarajan1
1Sanofi Healthcare India Pvt. Ltd, Verna Industrial Estate, Verna, Goa - 403722, India.
Summary
Intrasubject variability in bioequivalence studies is driven by drug solubility and first-pass metabolism. Optimizing study design, including subject selection and fed conditions, can significantly reduce this variability for generic drug development.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Pharmaceutical Sciences
- Clinical Pharmacology
Background:
- Intrasubject variability (ISV) poses a significant challenge in bioequivalence (BE) studies for generic drug development.
- The underlying mechanistic factors contributing to ISV are not fully understood, hindering effective mitigation strategies.
Purpose of the Study:
- To synthesize evidence on the determinants of ISV across various domains (physicochemical, pharmacokinetic, physiological, study design).
- To develop a mechanistic framework for understanding and managing ISV in BE studies.
- To provide guidance for optimizing BE study design to address ISV.
Main Methods:
- Narrative review of existing literature.
- Analysis of physicochemical, pharmacokinetic, and physiological factors influencing ISV.
- Evaluation of study design elements (e.g., replicate designs, fed conditions, genotyping) on ISV reduction.
- Development of the Intrasubject Variability (ISV) Cascade Model.
Main Results:
- Low solubility (BCS Class II/IV) drugs showed a 4.1-fold higher incidence of highly variable drugs (HVDs).
- First-pass metabolism was a strong predictor of HVD status (83% of HVDs vs. 21% of non-HVDs).
- Genotyping for CYP2D6/CYP3A5 polymorphisms reduced ISV by up to 54%; fed conditions reduced ISV in 79.4% of comparisons.
- Variability in absorption rate (Cmax vs. AUC0-t) was the primary contributor to ISV.
Conclusions:
- A mechanistic hierarchy for ISV determinants was identified, highlighting solubility and first-pass metabolism.
- The developed ISV Cascade Model provides a framework for understanding ISV progression.
- A decision tree is proposed to guide ISV risk assessment and optimize BE study design for generic drugs.
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