Evaluation of the Impacts of Formulation Parameters on the Pharmacokinetics and Bioequivalence of Risperidone Orodispers
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Research Article Evaluation of the Impacts of Formulation Parameters on the Pharmacokinetics and Bioequivalence of Risperidone Orodispersible Film: a Physiologically Based Pharmacokinetic Modeling Approach Fang Chen,1 Hongrui Liu,1 Bing Wang,1 Zhou Yang,2 Yusheng Chen,2 Liuliu Yang,1 Bing Wang,1 Zheng Jiao,3 Hai-Shu Lin,4 Yingjun Quan,2,6 Hao Wang,1,6 and Xiaoqiang Xiang5,6
Received 9 March 2020; accepted 8 June 2020 Abstract.
The purpose of this study was to investigate the impacts of the formulation parameters on the pharmacokinetics and bioequivalence of risperidone orodispersible film (ODF) using physiologically based pharmacokinetic model. The pharmacokinetic profiles of two risperidone ODFs, which exhibit different in vitro dissolution, were examined in Beagle dogs after supralingual administration. Subsequently, a physiologically based pharmacokinetic (PBPK) model was constructed to evaluate the in vivo performance of risperidone ODF. The parameter sensitivity analysis (PSA) was used to access the impacts of formulation parameters on the pharmacokinetics of risperidone. Moreover, the validated PBPK model was applied to predict human pharmacokinetic profiles and examine the bioequivalence of these two ODFs. These two ODFs displayed similar risperidone pharmacokinetic profiles in dogs. The parameter sensitivity analysis indicated that the changes in the solubility, particle size, particle density, and diffusion coefficient did not have obvious influence on the in vivo properties of risperidone ODF. Alternation of the in vitro complete dissolution time in water from 15 to 30 min led to a 30% decrease in Cmax and 20% of increase in Tmax. AUC0-∞ would be decreased if risperidone was not fully released within 1 h. As both ODFs completely released risperidone within 15 min, the difference in the extent of in vivo absorption, intestinal regional absorption location, and plasma concentration-time curves between these two ODFs was almost negligible. Consequently, a bioequivalence was foreseen in humans. The in vitro cumulative dissolution percentage in water at 15 min was found to be the major determinant on the in vivo properties of risperidone ODF. PBPK modeling appears to be an innovative strategy to guide the development of risperidone ODF. KEY WORDS: risperidone orodispersible film; pharmacokinetics; bioequivalence; physiologically based pharmacokinetic modeling; parameter sensitivity analysis.
INTRODUCTION
Fang Chen and Hongrui Liu contributed equally to this work. 1
National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, No. 1111 HaLei Road, Shanghai, 201203, China. 2 Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China. 3 Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. 4 Department of Pharmacy, National University of Singapore, Singapore, Singapore. 5 Department of Clinical Pharmacy, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China. 6 To whom cor
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