贝达喹啉在耐药肺结核患者中生理药动学模型建立与应用

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中图分类号：R9 文献标志码：A

Abstract ObjectiveTo establish a physiologically-based pharmacokinetic （PBPK） model of bedaquiline inmultidrug-resistant tuberculosis （MDR-TB）patientsbased on clinical trialdataofbedaquiline inour hospital. MethodsModel development，optimization，and simulation were conducted using WinNonlin and NLME software. The physical and chemical properties and pharmacokinetic parameters related to bedaquiline were collcted by literature.The PBPK model in MDR-TB patients was built utilizing WinNonlin PML language.The model was optimized and validated using published clinical pharmacokinetic studies from the PubMeddatabase.The final PBPK model was used to predict in vivo exposure of bedaquiline folowing administration in MDR-TB patients and to evaluate the eficacyand safety ofcommonly used clinical dosing regimens.ResultsThe established PBPK model of bedaquiline had good prediction performance in MDR-TB patients.The PBPK model wasused tocalculate the bedaquilinepacests （MFE=Ppre/Pobs） Cmax， （20 Tmax， （20 T1/2， and AUClast of 88.10% 99.55% 77.17% ，and 103.39% ， respectively. External validation showed that 95% of thepredicted values were within the 2-fold errorrange of the observed values，and the MFEofallpharmacokinetic parameters was within the range of >0.5～<2 . Conclusion The PBPK model of bedaquiline in MDR-TB patients was successfully established， which provideda basis for clinically rational use of bedaquiline in MDR-TB patients.

Key wordsBedaquiline; Pharmacokinetics; Physiologically-based pharmacokinetic （PBPK） model; Multidrug. resistant tuberculosis（MDR-TB）

贝达喹啉（bedaquiline，Bdq，TMC207）是自1971年以来首个被FDA批准上市的临床治疗多重耐药结核病（multidrug-resistant tuberculosis，MDR-TB）的药物。（剩余15498字）