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. 2025 Apr 11;18(4):562.
doi: 10.3390/ph18040562.

From In Vivo Predictive Dissolution to Virtual Bioequivalence: A GastroPlus®-Driven Framework for Generic Candesartan Cilexetil Tablets

Hao Ruan  1   2 , Xiaoting Geng  2 , Zijing Situ  3 , Qian Shen  2 , Tianjian Ye  4 , Xin Chen  4 , Weike Su  1
Affiliations

From In Vivo Predictive Dissolution to Virtual Bioequivalence: A GastroPlus®-Driven Framework for Generic Candesartan Cilexetil Tablets

Hao Ruan et al. Pharmaceuticals (Basel). .

Abstract

Background: Candesartan cilexetil, a Biopharmaceutics Classification System (BCS) II prodrug, demonstrates compromised bioavailability attributable to its limited aqueous solubility coupled with P-glycoprotein (P-gp)-mediated efflux and hepatic first-pass metabolism, thereby introducing complexities in generic drug bioequivalence assessments. With the rapid advancement of computational technologies, the integration of biorelevant dissolution methodologies with physiologically based pharmacokinetic (PBPK) modeling is emerging as a transformative paradigm in advancing bioequivalence evaluation strategies for generic drug products. This study presents a GastroPlus®-driven framework integrating in vivo predictive dissolution (IPD) and virtual bioequivalence (VBE) to evaluate the quality consistency of generic candesartan cilexetil tablets. Methods: By developing an oral PBPK model in GastroPlus®, we established an IPD method using a phosphate-buffer-based flow-through cell dissolution apparatus. In vitro dissolution profiles of generic tablets from four manufacturers were measured and incorporated into the model to perform VBE simulations. Results: The results demonstrated that only the product from Company A achieved virtual bioequivalence with the reference product, aligning with real-world quality consistency assessments. Conclusions: The proposed framework exhibited robust predictive capability, bridging in vitro dissolution data to in vivo bioequivalence outcomes, thereby offering a cost-effective and efficient strategy for formulation optimization and preclinical bioequivalence evaluation of generic drugs.

Keywords: GastroPlus®; candesartan cilexetil; flow-through cell; in vivo predictive dissolution; virtual bioequivalence.

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Conflict of interest statement

Authors Tianjian Ye and Xin Chen were employed by the company Zhejiang Yongning Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Framework of this research.
Figure 2
Figure 2
Dissolution profile comparison between the RLD and generic drug product of candesartan cilexetil tablets in different dissolution media. (A) pH 1.0 hydrochloric acid solution (1.0% Tween 20), (B) pH 4.5 acetate buffer (1.0% Tween 20), (C) pH 6.5 phosphate buffer (0.25% Tween 20), (D) pH 6.5 phosphate buffer (0.35% Tween 20), and (E) water (1.0% Tween 20).
Figure 3
Figure 3
Prediction results of candesartan American intravenous PBPK model.
Figure 4
Figure 4
PBPK model predictions of 8 mg candesartan cilexetil tablets administered via preprandial oral route across ethnic populations. (A) Japanese and (B) Chinese.
Figure 5
Figure 5
PBPK-model-predicted pharmacokinetic profiles of 8 mg candesartan cilexetil tablets following fasted oral administration in Chinese.
Figure 6
Figure 6
The absorption percentages of 8 mg candesartan cilexetil tablets in different intestinal segments after oral administration before meals in Chinese.
Figure 7
Figure 7
Comparative analysis between the in vivo release profile of the RLD and in vitro dissolution profiles obtained via USP apparatus 2 under varied biorelevant media conditions.
Figure 8
Figure 8
Comparative analysis of dissolution profiles under varied flow-through cell conditions.
Figure 9
Figure 9
Dissolution profile characterization of candesartan cilexetil tablets (RLD vs. generic drugs) using the flow-through cell.
Figure 10
Figure 10
Predicted VBE results of generic drug products. (A) Company A, (B) Company B, (C) Company C, (D) Company D.
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