In Vitro–In Vivo Correlation (IVIVC) for SR Dosage Forms

What is IVIVC?

• IVIVC is a mathematical relationship that links in vitro drug release with in vivo drug absorption.
• It helps predict how the drug behaves in the body based on its in vitro performance.

BCS and IVIVC Feasibility

• Class I (High solubility, High permeability): Good IVIVC potential.
• Class II (Low solubility, High permeability): Best suited for IVIVC as dissolution is rate-limiting.
• Class III (High solubility, Low permeability): Challenging due to permeability-limited absorption.
• Class IV (Low solubility, Low permeability): Least suitable for IVIVC.

Types of IVIVC

• Level A: Point-to-point correlation between in vitro dissolution and in vivo absorption. Most robust and preferred for regulatory use.
• Level B: Statistical moment analysis comparing mean dissolution time with mean residence time. Less predictive.
• Level C: Single-point correlation, e.g., % drug dissolved at 4h vs Cmax. Limited utility.
• Multiple Level C: Correlation using several in vitro time points with multiple in vivo parameters. More useful than Level C, but not as powerful as Level A.

Steps to Develop Level A IVIVC for SR Products

• Develop multiple SR formulations with varying release rates (fast, medium, slow).
• Conduct in vitro dissolution testing using relevant media and apparatus (e.g., USP II paddle, USP IV flow-through).
• Perform in vivo pharmacokinetic (PK) studies in animals or humans.
• Apply deconvolution methods (e.g., Wagner–Nelson, Loo–Riegelman) to derive in vivo absorption profiles.
• Fit a model (e.g., Weibull, first-order) correlating in vitro and in vivo data.
• Validate the model using internal and external predictability (% prediction error).

Regulatory Validation Criteria

• % prediction error for AUC and Cmax should be:
• Mean %PE ≤ 10%
• Individual %PE ≤ 15%

If met, the IVIVC model can support biowaivers and post-approval changes without further clinical studies.

Best Practices for Dissolution Testing in SR IVIVC

• Use media that simulate physiological conditions (e.g., pH 1.2, 4.5, 6.8 or FaSSIF/FeSSIF).
• Employ appropriate apparatus like USP I (basket), USP II (paddle), or USP IV (flow-through cell).
• Ensure sink conditions and discriminatory power between formulations.
• Aim for a dissolution profile where ≥80% drug is released over 12–24 hours.

Applications of IVIVC in SR Development

• Reduces the number of in vivo BE studies during development.
• Supports SUPAC (scale-up and post-approval changes) filings with regulatory agencies.
• Helps in setting clinically relevant dissolution specifications.
• Mitigates risk of bioequivalence failure during formulation changes.

Common Challenges in SR IVIVC

• Variable GI transit time may affect predictability.
• Complex absorption patterns (e.g., multiple peaks or site-specific absorption).
• pH-dependent solubility or permeability can complicate modeling.
• Some APIs may need special media with surfactants due to poor solubility.

Read also:

• In Vitro Strategies to Ensure Bioequivalence of Sustained-Release (SR) Formulations
• Key Considerations for Generic Formulation Development

Resource Person: Moinuddin Syed. Ph.D, PMP®