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Integrating In Vitro Dissolution and Physiologically Based Pharmacokinetic Modeling for Generic Drug Development:
Evangelos Karakitsios1, Maria-Faidra-Galini Angelerou2, Iasonas Kapralos1
1Department of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece.
Pharmaceutics
|February 26, 2025
Summary
Physiologically based pharmacokinetic (PBPK) modeling accurately predicted tacrolimus (Prograf) pharmacokinetics for amorphous solid dispersion (ASD) formulations. This aids generic drug development by assessing biopredictive dissolution methods.
Area of Science:
- Pharmacokinetics and Drug Development
- Biopharmaceutics and Formulation Science
Background:
- Tacrolimus, a Biopharmaceutics Classification System (BCS) class II drug, requires enhanced bioavailability for transplant patients.
- Amorphous solid dispersion (ASD) formulations are developed to improve tacrolimus bioavailability.
- In-house USP IV dissolution method was used to study release properties of ASD formulations.
Purpose of the Study:
- To evaluate amorphous solid dispersion (ASD) tacrolimus formulations.
- To compare pharmacokinetics (PK) of a test formulation with Advagraf® in a pilot bioequivalence study.
- To validate and apply a physiologically based pharmacokinetic (PBPK) model for predicting human pharmacokinetics of tacrolimus ASD formulations.
Main Methods:
- Pilot clinical bioequivalence study with 12 healthy subjects comparing test product and Advagraf®.
- Validation of a published tacrolimus PBPK model using in vivo data.
- Application of PBPK model to predict PK of various tacrolimus ASD formulations, including analysis of dissolution profile and dissolution-limited dissolution (DLM) approaches.
Main Results:
- Both PBPK methodologies (direct dissolution profile integration and DLM) accurately predicted Cmax and Tmax.
- The dissolution profile approach slightly underestimated AUC, while the DLM method adequately predicted AUC.
- Sensitivity analysis refining DLM scalars optimized PK parameter predictions.
- Formulation composition, like Eudragit-S100, significantly influenced dissolution and bioavailability, as predicted by PBPK.
Conclusions:
- Key factors influencing performance of tacrolimus ASD formulations were identified.
- PBPK modeling is crucial for early-stage generic drug development, simplifying assessment of biopredictive dissolution methods.
- Insights from qualitative, quantitative, and manufacturing aspects aid generic drug development.
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