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Signal Transduction and Targeted Therapy 2022年第4期7卷 1066-1090页

作者： Zhiwen Fu Shijun Li Sifei Han Chen Shi Yu Zhang Department of Pharmacy Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022People’s Republic of China Hubei Province Clinical Research Center for Precision Medicine for Critical Illness Wuhan 430022People’s Republic of China drug Delivery Disposition and DynamicsMonash Institute of Pharmaceutical SciencesMonash University(Parkville Campus)381 Royal ParadeParkvilleVIC 3052Australia Faculty of Pharmacy China Pharmaceutical University639 Longmian AvenueJiangning DistrictNanjing 211198People’s Republic of China

Antibody–drug conjugate(ADC)is typically composed of a monoclonal antibody(mAbs)covalently attached to a cytotoxic drug via a chemical *** combines both the advantages of highly specific targeting ability and highly potent killing effect to achieve accurate and efficient elimination of cancer cells,which has become one of the hotspots for the research and development of anticancer *** the first ADC,Mylotarg®(gemtuzumab ozogamicin),was approved in 2000 by the US Food and drug Administration(FDA),there have been 14 ADCs received market approval so far ***,over 100 ADC candidates have been investigated in clinical stages at *** kind of new anti-cancer drugs,known as“biological missiles”,is leading a new era of targeted cancer ***,we conducted a review of the history and general mechanism of action of ADCs,and then briefly discussed the molecular aspects of key components of ADCs and the mechanisms by which these key factors influence the activities of ***,we also reviewed the approved ADCs and other promising candidates in phase-3 clinical trials and discuss the current challenges and future perspectives for the development of next generations,which provide insights for the research and development of novel cancer therapeutics using ADCs.

关键词： Antibody drugs conjugate

Pharmacokinetics of monoclonal antibodies ]nd Fc-fusion proteins

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Protein & Cell 2018年第1期9卷 15-32页

作者： Liming Liu Department of Pharmacokinetics Pharrnacodynamics and Drug Metabolism MRL West Point PA 19486 USA

There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic anti. bodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation, Glycosyla- tion of a mAb or *** protein can have a significant impact on the PK of these molecules, mAb charge can be important and variants with pl values of 1-2 unit difference are likely to impact PK with lower pl values being favorable for a longer ***. Most mAbs display target mediated drug disposition （TMOO）, which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody （ADA） response and *** binding, which require careful consideration during the discovery stage, mAbs are primarily absor- bed through the lymphatics via convection and can be conveniently administered by the subcutaneous （sc） route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be rea- sonably estimated using cynomolgus monkey data and allometric scaling methods.

关键词： monoclonal antibody (mAb) Fc-fusionprotein pharmacokineUcs FcRn target-mediated drugdisposition (TMDD) glycosylation anti-drug antibody (ADA)human PK prediction

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定量药理学药物研发模式的新进展

定量药理学药物研发模式的新进展

Organic anion transporter 1 and 3 contribute to traditional Chinese medicine-induced nephrotoxicity

药物非临床安全性研究学术研讨会

作者： S．R．B．Allerhelligen Ph．D. drug disposition：ADME and Global PK/PD

问题怎样确定我们正在开发的化学候选物是正确的? 治疗指数如何? 药效的剂量反应性如何?安全性怎样?如何对患者进行个性化给药?

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Chinese Journal of Natural Medicines 2020年第3期18卷 196-205页

作者： SHEN Qing-Qing WANG Jing-Jing ROY Debmalya SUN Li-Xin JIANG Zhen-Zhou ZHANG Lu-Yong HUANG Xin Jiangsu Key Laboratory of drug Screening China Pharmaceutical UniversityNanjing 210009China Jiangsu Center for Pharmacodynamics Research and Evaluation China Pharmaceutical UniversityNanjing 210009China Key Laboratory of drug Quality Control and Pharmacovigilance Ministry of EducationChina Pharmaceutical UniversityNanjing 210009China Center for drug Screening and Pharmacodynamics Evaluation School of PharmacyGuangdong Pharmaceutical UniversityGuangzhou 510006China

With the internationally growing popularity of traditional Chinese medicine(TCM), TCM-induced nephropathy has attracted public attention. Minimizing this toxicity is an important issue for future research. Typical nephrotoxic TCM drugs such as Aristolochic acid, Tripterygium wilfordii Hook. f, Rheum officinale Baill, and cinnabar mainly damage renal proximal tubules or cause interstitial nephritis. Transporters in renal proximal tubule are believed to be critical in the disposition of xenobiotics. In this review, we provide information on the alteration of renal transporters by nephrotoxic TCMs, which may be helpful for understanding the nephrotoxic mechanism of TCMs and reducing adverse effects. Studies have proven that when administering nephrotoxic TCMs, the expression or function of renal transporters is altered, especially organic anion transporter 1 and 3. The alteration of these transporters may enhance the accumulation of toxic drugs or the dysfunction of endogenous toxins and subsequently sensitize the kidney to ***-related drug combination and clinical biomarkers supervision to avoid the risk of future toxicity are proposed.

关键词： Traditional Chinese medicine Nephrotoxicity Renal tubular epithelial cell Organic anion transporter Aristolochic acid Tripterygium wilfordii Hook.f. Rheum officinale Baill

disposition and fate of polyoxyethylene glycerol ricinoleate as determined by LC-Q-TOF MS coupled with MS^(ALL),SWATH and HR MS/MS techniques

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Chinese Chemical Letters 2021年第10期32卷 3237-3240页

作者： Ruifeng Bai Dong Sun Yuqin Shan Zhiqiong Guo Dafeng Chu John Paul Fawcett Jingkai Gu Center for drug Metabolism Research School of Life SciencesJilin UniversityChangchun 130012China

Polyoxyethylene glycerol ricinoleate(PGR) serves as a solubilizer/emulsifier that is commonly used in pharmaceutical formulations despite being associated with severe anaphylactoid hypersensitivity *** EL?(CrEL) is the most representative PGR produced from reacting ethylene oxide with castor *** help clarify the cause of side effects and potentially improve the safety of PGR-based drug delivery vehicle,we have developed separate but related analytical methods for the quantitation of CrEL and its main metabolites,glycerol ethoxylate(GE) and ricinoleic acid(RA).Since CrEL and GE are highly disperse mixtures of polymers that are not amenable to analysis by conventional liquid chromatographytandem mass spectrometry(LC-MS/MS),we used liquid chromatography-triple-quadrupole-time-of-flight mass spectrometry(LC-Q-TOF MS) combined with product ion data acquisition by MSALLand sequential window acquisition of all theoretical fragments mass spectrometry(SWATH MS),respectively to perform the *** contrast,RA is a single molecular entity that could be readily analyzed using conventional LC-HR MS/*** of specific fragment ions for CrEL,GE,RA and their internal standards enabled a precise quantitation of such a complex analytes system in rat plasma after a single and simple sample preparation *** validation indicated linearity for CrEL,GE and RA over the concentration ranges 0.2~20.0 μg/mL,0.1~10.0 μg/mL and 0.1~20.0 μg/m L,respectively with satisfactory results for other validation parameters.A subsequent pharmacokinetic study involving single intravenous 200 mg/kg injections of CrEL to rats showed the methods enable comprehensive and high throughput quantitation of CrEL and its metabolites in a biological *** combination of assays provides effective application in investigating the cause of the hypersensitivity reaction of PGR and potentially to improve its safety for using as a vehicle in drug formulations.

关键词： Polyoxyethylene glycerol ricinoleate Cremophor EL LC-Q-TOF MS Glycerol ethoxylate Ricinoleic acid

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2751-2777页

作者： Yurong Lai Xiaoyan Chu Li Di Wei Gao Yingying Guo Xingrong Liu Chuang Lu Jialin Mao Hong Shen Huaping Tang Cindy Q.Xia Lei Zhang Xinxin Ding drug Metabolism Gilead Sciences Inc.Foster CityCA 94404USA Department of Pharmacokinetics Pharmacodynamics and Drug MetabolismMerck&Co.Inc.KenilworthNJ 07033USA Pharmacokinetics Dynamics and MetabolismPﬁzer Worldwide Research and DevelopmentGrotonCT 06340USA Eli Lilly and Company IndianapolisIN 46221USA drug Metabolism and Pharmacokinetics BiogenCambridgeMA 02142USA drug Metabolism and Pharmacokinetics Accent TherapeuticsInc.LexingtonMA 02421USA Department of drug Metabolism and Pharmacokinetics GenentechA Member of the Roche GroupSouth San FranciscoCA 94080USA drug Metabolism and Pharmacokinetics Department Bristol-Myers Squibb CompanyPrincetonNJ 08540USA Bioanalysis and Biomarkers Glaxo Smith KlineKing of the PrussiaPA 19406USA Department of drug Metabolism and Pharmacokinetics Takeda Pharmaceuticals International Co.CambridgeMA 02139USA Ofﬁce of Research and Standards Ofﬁce of Generic DrugsCDERFDASilver SpringMD 20993USA Department of Pharmacology and Toxicology College of PharmacyUniversity of ArizonaTucsonAZ 85721USA Current afﬁliation:Translational Medicine EMD Serono Research&Development InstituteInc.BillericaMA 01821USA Current afﬁliation:drug Metabolism Gilead Sciences Inc.Foster CityCA 94404USA

drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical *** nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological *** progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the *** importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly *** increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME *** this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

关键词： drug discovery and development New drug application Biologics license application Pharmacokinetics ADME New modalities Model-informed drug development Micro-physiological systems

Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition

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药学学报:英文版 2023年第6期13卷 2383-2402页

作者： Yaochen Xie Qian Zhou Qiaojun He Xiaoyi Wang Jincheng Wang Center for drug Safety Evaluation and Research Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310007China Department of Pharmacy Hangzhou Medical CollegeHangzhou 310053China Department of Nephrology the First Affiliated Hospital of Huzhou Teachers Collegethe First People's Hospital of HuzhouHangzhou 313000China

The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus(T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1,and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of ***, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.

关键词： T2DM Incretins-based hypoglycemic agents GLP-1 receptor agonists DPP-4 inhibitors Physiological disposition Metabolism Excretion drug drug interactions

Population pharmacokinetics of amlodipine in healthy Chinese adult male volunteers

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中国临床药理学与治疗学 2011年第12期16卷 1383-1390页

作者： Huang Xiaohui Huang Jihan Li Lujin Wang Kun Yang Juan Zheng Qingshan Department of Basic and Clinical Pharmacology School of Pharmacy Anhui Medical University Anhui Hefei 230032 Department of Pharmacometrics Center for Drug Clinical Research Shanghai University of Chinese Medicine Shanghai 201203 Department of Pharmacometrics Center for Drug Clinical Research Shanghai University of Chinese Medicine Shanghai Hefei 201203

Amlodipine is a third-generation dihydropyridine calcium channel blocker that is indicated for treatment of hypertension and angina in adults. The population pharmacokinetics of amlodipine was evaluated in 60 healthy volunteers enrolled in three bioequivalence studies. These data, along with a set of covariates, were the subject of a nonlinear mixed-effect modeling analysis using the NONMEM program. A two- compartment model with first order absorption was fitted to the serum amlodipine concentration data. No significant covariates were found in the model-building. The intraindividual（residual） variability expressed as coefficient of variation was 18.7%, whereas the interindividual variability of CL, V_2, V_3 and K_a, was 27.3%, 26.6%, 49.9% and 65.7%, respectively. The relatively high（>40 %） interindividual variability for V_3 and K_a parameters, observed under the controlled experimental settings of bioequivalence trials in healthy volunteers, may result from genetic variability of the processes involved in amlodipine absorption and disposition.

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A physiologically based pharmacokinetic model for the in vivo disposition of poly(ethylene glycol)-poly(ε-caprolactone)(PEG-PCL)P2 Nanoparticles in Xenograft mouse

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A physiologically based pharmacokinetic model for the in viv...