title: Population pharmacokinetic modeling of the Qishe pill in three major traditional Chinese medicine-defined constitutional types of healthy Chinese subjects: study protocol for a randomized controlled trial.
abstract: BACKGROUND
  High incidences of neck pain morbidity are challenging in various situations for populations based on their demographic, physiological and pathological characteristics. Chinese proprietary herbal medicines, as Complementary and Alternative Medicine (CAM) products, are usually developed from well-established and long-standing recipes formulated as tablets or capsules. However, good quantification and strict standardization are still needed for implementation of individualized therapies. The Qishe pill was developed and has been used clinically since 2009. The Qishe pill's personalized medicine should be documented and administered to various patients according to the ancient TCM system, a classification of personalized constitution types, established to determine predisposition and prognosis to diseases as well as therapy and life-style administration. Therefore, we describe the population pharmacokinetic profile of the Qishe pill and compare its metabolic rate in the three major constitution types (Qi-Deficiency, Yin-Deficiency and Blood-Stasis) to address major challenges to individualized standardized TCM.
  
  
  METHODS
  Healthy subjects (N = 108) selected based on constitutional types will be assessed, and standardized pharmacokinetic protocol will be used for assessing demographic, physiological, and pathological data. Laboratory biomarkers will be evaluated and blood samples collected for pharmacokinetics(PK) analysis and second-generation gene sequencing. In single-dose administrations, subjects in each constitutional type cohort (N = 36) will be randomly divided into three groups to receive different Qishe pill doses (3.75, 7.5 and 15 grams). Multiomics, including next generation sequencing, metabolomics, and proteomics, will complement the Qishe pill's multilevel assessment, with cytochrome P450 genes as targets. In a comparison with the general population, a systematic population pharmacokinetic (PopPK) model for the Qishe pill will be established and verified.
  
  
  BACKGROUND
  This study is registered at ClinicalTrials.gov, NCT02294448 .15 November 2014.
authors.affiliation: Longhua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. edisonlike2008@gmail.com.|Spine Institute, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. edisonlike2008@gmail.com.
authors.forename: Yue-li
authors.initials: YL
authors.lastname: Sun
authors.affiliation: College of Traditional Chinese Herbal Medicine, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, 201203, P.R. China. houting90@126.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Hou
authors.affiliation: Longhua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. xiaoliufenfen@163.com.|Spine Institute, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. xiaoliufenfen@163.com.
authors.forename: Shu-fen
authors.initials: SF
authors.lastname: Liu
authors.affiliation: Zhe Jiang Biosia Pharmaceutical Co., Ltd, No.1938 Xinqun Road, Pinghu City, Zhejiang Province, P.R. China. 307779122@qq.com.
authors.forename: Zhong-liang
authors.initials: ZL
authors.lastname: Zhang
authors.affiliation: College of Traditional Chinese Herbal Medicine, Shanghai University of Traditional Chinese Medicine, No. 1200 Cailun Road, Shanghai, 201203, P.R. China. ningzh18@126.com.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Longhua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. yaomin19871223@126.com.|Spine Institute, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. yaomin19871223@126.com.
authors.forename: Min
authors.initials: M
authors.lastname: Yao
authors.affiliation: Longhua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. 784472094@qq.com.|Spine Institute, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. 784472094@qq.com.
authors.forename: Long
authors.initials: L
authors.lastname: Yang
authors.affiliation: Longhua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. jzyjs200032@126.com.|Spine Institute, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. jzyjs200032@126.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Longhua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. 13917715524@139.com.|Spine Institute, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. 13917715524@139.com.
authors.forename: Xue-jun
authors.initials: XJ
authors.lastname: Cui
authors.affiliation: Longhua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. yjwang8888@126.com.|Spine Institute, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, P.R. China. yjwang8888@126.com.
authors.forename: Yong-jun
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000328:Adult; D002985:Clinical Protocols; D018592:Cross-Over Studies; D064368:Healthy Volunteers; D006801:Humans; D008516:Medicine, Chinese Traditional; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D057285:Precision Medicine; D019413:Qi
chemical_list: D016328:NF-kappa B