基于PBPK模型预测不同晶型利福平的生物等效性

蔡其霖; 黎文星; 严真; 尹莉芳

doi:10.11665/j.issn.1000-5048.20220211

基于PBPK模型预测不同晶型利福平的生物等效性

1.
中国药科大学药学院药剂系，南京 210009
2.
江苏省缓释智能制剂及关键功能性辅料开发与评价工程研究中心，南京 210009

基金项目: 江苏高校优势学科三期资助项目——“颠覆性理论与技术创新团队”；中国药科大学“重大科技成果转化”项目（高端缓控释制剂产业化研究）

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出版历程
- 收稿日期: 2021-09-13
- 修回日期: 2022-03-29
- 刊出日期: 2022-04-24

Prediction of the bioequivalence of different crystal forms of rifampicin based on physiologically based pharmacokinetic model

1.
Department of Pharmaceutics,School of Pharmacy, China Pharmaceutical University,Nanjing 210009
2.
Engineering Ｒesearch Center for Development and Evaluation of Sustained-Ｒelease Intelligent Preparations and Key Functional Excipients of Jiangsu Province,Nanjing 210009, China

Funds: This study was supported by the Advantage Discipline Project of Jiangsu (III)—The Disruptive Theory and Technology Innovative Research Team Project; and the China Pharmaceutical University "Major Scientific and Technological Achievements Transformation" Project (Research on the Industrialization of High-end Slow and Controlled Release Preparations)

摘要

摘要: 通过基于生理学的药动学（physiologically based pharmacokinetic，PBPK）建模策略预测晶型Ⅰ与晶型Ⅱ利福平在人体内的药动学行为，判断两者是否生物等效。对两种晶型利福平进行体外研究后，以大鼠静脉给药的药动学数据为基础，构建大鼠PBPK模型，再通过大鼠口服给药的药动学数据进行模型优化，种属外推至健康人体，利用外推模型预测两种晶型的利福平在健康人体内的血药浓度-时间曲线、吸收部位及吸收量等药动学行为。健康人体模型预测结果显示，晶型Ⅰ与晶型Ⅱ利福平的c_max分别为8.42和10.35 μg/mL，t_max分别为0.40和0.32 h，AUC_0-_t均为62.90 μg·h/mL。根据吸收情况预测结果，晶型Ⅰ与晶型Ⅱ利福平在胃部均不被吸收，但在肠道被完全吸收，两者吸收部位及吸收量基本一致。晶型Ⅰ与晶型Ⅱ利福平的药动学参数十分接近，预测两者具有生物等效性。
- 利福平 /
- 晶型 /
- GastroPlus^TM /
- 基于生理学的药动学模型 /
- 种属外推
Abstract: The physiologically based pharmacokinetic (PBPK) modeling strategy was adopted to predict the pharmacokinetic behavior of crystal forms I and II of rifampicin in humans, which was used to determine whether the two were bioequivalent.After conducting studies in vitro of the two crystal forms, a rat PBPK model was established based on the pharmacokinetic data of intravenous administration in rats.The model was optimized by the pharmacokinetic data of oral administration in rats.Species were extrapolated to healthy humans, and the extrapolation model was used to predict such pharmacokinetic behaviors as the drug-time curve, absorption site, and absorption amount of the two crystal forms of rifampicin in healthy humans.The prediction results of the healthy human model showed that the c_max of form I and form II rifampicin were 8.42 and 10.35 μg/mL, t_max were 0.40 and 0.32 h,and AUC_0-_t were both 62.90 μg·h/mL.According to the prediction results of absorption, neither crystal form I nor crystal form II rifampicin was absorbed in the stomach, yet both were completely absorbed in the intestinal tract, with both the absorption site and the absorption amount were basically the same.The pharmacokinetic parameters of both crystal forms I and II of rifampicin were very close, which could indicate bioequivalence.
- rifampicin /
- crystal form /
- GastroPlus^TM /
- PBPK model /
- species extrapolation

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参考文献(15)

[1]	．J Occup Environ Med，2020，62（7）：e355-e369．
[2]	Yulug B，Hanoglu L，Ozansoy M，et al．Therapeutic role of rifampicin in Alzheimer''s disease［J］．Psychiatry Clin Neurosci，2018，72（3）：152-159．
[3]	Allen FH．The Cambridge structural database：a quarter of a million crystal structures and rising［J］．Acta Crystallogr B，2002，58（Pt3Pt1）：380-388．
[4]	Censi R， di Martino P．Polymorph impact on the bioavailability and stability of poorly soluble drugs［J］．Molecules，2015，20（10）：18759-18776．
[5]	Guo LL．Investigation on polymorphs and crystallization process of rifampicin（利福平多晶型及其结晶过程研究）［D］．Tianjin：Tianjin University，2018．
[6]	Zhao P，Zhang L，Grillo JA，et al．Applications of physiologically based pharmacokinetic （PBPK） modeling and simulation during regulatory review［J］．Clin Pharmacol Ther，2011，89（2）：259-267．
[7]	Poggesi I，Snoeys J，van Peer A．The successes and failures of physiologically based pharmacokinetic modeling：there is room for improvement［J］．Expert Opin Drug Metab Toxicol，2014，10（5）：631-635．
[8]	Agoram B，Woltosz WS，Bolger MB．Predicting the impact of physiological and biochemical processes on oral drug bioavailability［J］．Adv Drug Deliv Rev，2001，50（Suppl 1）：S41-S67．
[9]	U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research （CDER）：Clinical drug interaction studies -cytochrome P450 enzyme-and transporter-mediated drug interactions guidance for industry［EB/OL］．U.S.Food and Drug Administration，2020［2022-03-09］．https：//www.fda.gov/media/134581/download.
[10]	Amidon GL，Tsume Y．Oral product input to the GI tract： GIS an oral product performance technology［J］．Front Chem Sci Eng，2017，11（4）：516-520．
[11]	de Pinho Pessoa Nogueira L，de Oliveira YS，de C Fonseca J，et al．Crystalline structure of the marketed form of rifampicin：a case of conformational and charge transfer polymorphism［J］．J Mol Struct，2018，1155：260-266.
[12]	Biganzoli E，Cavenaghi LA，Rossi R，et al．Use of a Caco-2 cell culture model for the characterization of intestinal absorption of antibiotics［J］．Farmaco，1999，54（9）：594-599．
[13]	Toutain PL，Bousquet-Mélou A．Plasma clearance［J］．J Vet Pharmacol Ther，2004，27（6）：415-425．
[14]	U.S.Food and Drug Administration.FDA approves RIFADIN^? IV （rifampin for injection USP）［EB/OL］.（2019-02-28）［2021-04-15］https：//www.accessdata.fda.gov/drugsatfda_docs/label/2019/050420s080，050627s023lbl.pdf.
[15]	Becker C，Dressman JB，Junginger HE，et al．Biowaiver monographs for immediate release solid oral dosage forms：Rifampicin［J］．J Pharm Sci，2009，98（7）：2252-2267．