PI-099 - PBPK MODELING TO SUPPORT THE EXPANSION OF BIOWAIVER TO NON-Q1/Q2 BCS CLASS III DRUG PRODUCTS.
Wednesday, May 28, 2025
5:00 PM - 6:30 PM East Coast USA Time
A. Pal1, P. Ren1, Y. Zhang1, L. Fang2, L. Zhao2, F. Wu2; 1U.S. Food and Drug Administration, Silver Spring, MD, United States, 2U.S. Food and Drug Administration, Silver Spring, MD, USA.
Staff Fellow U.S. Food and Drug Administration Silver Spring, Maryland, United States
Background: Current ICH M9 guidance suggests that a waiver request of in vivo bioequivalence (BE) studies for a BCS Class III product may be considered if it demonstrates high solubility, very rapid dissolution (≥85% dissolved in ≤15 minutes for both test and reference product), and the test product formulation is qualitatively (Q1) same and quantitatively (Q2) similar to the reference listed drug (RLD). The purpose of this research is to use PBPK modeling to determine dissolution safe space to support possible expansion of biowaiver to non-Q1/Q2 BCS Class III drug product using nadolol immediate release (IR) tablets as an example. Methods: Physicochemical properties, pharmacokinetic (PK) data and parameters obtained from the literature and regulatory submissions, and GastroPlus software were used to develop and validate the PBPK model for nadolol IR tablets under fasted conditions. PBPK modeling and virtual BE (VBE) simulations were conducted to evaluate the impact of non-comparable in vitro dissolution on the predicted systemic exposure, and overall BE determination for the generic nadolol IR tablets and RLD. Parameter sensitivity analysis (PSA) were also conducted to evaluate the impact of effective permeability (Peff) and Z-factor on BE parameters (Cmax and AUCs). Results: Development and validation of nadolol oral PBPK model under fasted conditions accurately predicted (prediction errors < 20%) PK profiles of different strengths (1, 2, 10, 30, 60 and 80 mg). PSA showed that BE parameters (Cmax and AUCs) are sensitive to Peff values and Z-factor values. VBE simulations showed that PBPK model prediction by incorporating non-similar dissolution profiles (F2 < 50) did not result in significant difference in drug exposure, indicating a low risk of non-BE between generic and RLD. In addition, dissolution safe spaces were determined based on further VBE simulations by incorporating different theoretical dissolution profiles with different release rates. Conclusion: PBPK modeling and VBE simulations demonstrated that non-Q1/Q2 nadolol IR tablets with dissimilar dissolution profiles are of low risk for non-BE, when the dissolution profiles are within the suggested dissolution safe space. The presented PBPK modeling approach may be utilized in expanding biowaiver to other non-Q1/Q2 BCS Class III drug products.