单克隆抗体药物的药代动力学研究进展

单克隆抗体药物在近30年时间里经历了快速的发展。由于极大的理化和生物学特征差异,单克隆抗体和传统小分子药物在药代动力学的特征和形成机制上具有非常大的不同。充分了解这些机制和特征可以有效地指导单克隆抗体药物的筛选和开发,并支持其安全性的评估和临床给药方案的设计。该文的目的就是从吸收、分布和消除等几个方面对单克隆抗体药物的药代动力学的特征和机制,以及其人体药代动力学的预测进行综合的归纳和阐述。     

单克隆抗体药物药代动力学特征、分析方法以及体内分析方法学研究进展

近年来,单克隆抗体药物发展迅速,在肿瘤、免疫、血液等系统疾病领域应用日益广泛。截至2019年其全球处方药物市场占比已达15.3%(1400亿美元)。单克隆抗体药物作为一种大分子蛋白,因其特殊的结构和生理性质,在体内的吸收、分布、代谢及排泄均与小分子药物存在较大差异,具有靶点介导的药物处置、非线性药动学代谢、时间依赖性、较长的半衰期等独特的药代动力学特征,充分了解这些特征有益于该类药物分析方法的开发。单克隆抗体药物在生物体内的处置具有特殊性和复杂性,极大地增加了生物检测的难度,因此必须建立专属、灵敏、准确、可重复的测定分析方法。本文旨在论述单克隆抗体药物的药代动力学特征、常用分析方法及其优缺点、体内分析方法学验证要求等,并逐点与小分子药物进行对比讨论,以期为单克隆抗体药物的分析技术开发提供部分参考。     

生物技术药物的药代动力学研究近况

近年来,生物大分子药物发展迅猛,受到的关注也越来越多。与传统小分子药物相比,生物大分子药物具有相对分子质量大、不易透过生物膜、给药剂量低、易在体内降解等特点,这导致其具有与小分子药物不同的药代动力学特征。以蛋白多肽药物、单克隆抗体药物、抗体药物偶联物和核酸药物4类生物大分子药物为例,综述近年来生物大分子药物的药代动力学研究进展,旨在为生物大分子药物及生物类似药的研发提供参考。

     

抗体偶联药物的分子特点及其药代动力学研究考虑

随着我国药物研发和临床试验水平的不断提高,近年来抗体偶联药物(Antibody-Drug Conjugate, ADC)的相关研究和注册申报也正在增多。ADC类药物由抗体、连接子和小分子毒素组成,在兼具高度靶向性和高细胞毒性优势的同时,由于其结构的多样性和复杂性,以及循环系统中释放的小分子毒素含量较低等特殊性,给其药代动力学研究带来了诸多挑战。本文将从ADC药物的分子设计、药代动力学特征和目标分析物等方面讨论,以期帮助读者更好的理解ADC药物的药代动力学研究。     

高原低氧环境对人体的生理影响以及人体药物代谢动力学特征的研究进展

目的 对近年来高原低氧影响人体生理以及药代动力学特征的研究进展进行简要综述,能够为临床合理用药,避免不良反应和个性化用药做出合理指导。方法 查阅国内外41篇相关文献,从人体生理和药物代谢动力学特征两个方面,总结低氧环境对机体造成的影响。结果与结论 高原具有低氧、低气压、高寒、强辐射、昼夜温差大等特点,其中因高原低氧引起的缺氧对人体造成了生理压力。大部分研究药物的药代动参数变化主要表现为清除率（CL）显著降低,半衰期（t_1/2）和平均驻留时间（MRT）显著延长,表观分布容积（V_d）在急性缺氧组中减小。高原诱导的低压缺氧会导致细胞中氧浓度异常,影响身体的药物代谢能力和药代动力学(PK)特征。     

药物生殖毒性试验中伴随毒代动力学研究方法介绍

<正>毒代动力学(Toxicokinetics,TK)是一门涉及到药代动力学(Pharmacokinetics,PK)和毒理学研究的边缘性分支学科。它运用药代动力学的原理和方法定量地研究毒性剂量下药物在动物体内的吸收、分布、代谢以及排泄过程和特点,进而探讨药物毒性发生和发展的规律性。药物生殖毒代动力学的研究重点是解释生殖毒性试验结果和预测人体安全性,而不是简单描述受试物的基本药代动力学参数特征,该方面的研究已经     

抗体药物的药物代谢动力学特点及研究进展

抗体药物是一种可与相应抗原发生特异性结合的免疫球蛋白。该研究从抗体药物的结构入手，对抗体药物的药物代谢动力学基本特点进行综述，并着重介绍了其不同于小分子药物的独特代谢特征，主要包括与靶点介导的药物处置、新生儿 Fc受体介导的循环再利用、糖基化修饰和电荷异质性对清除速率的影响以及与抗药物抗体相结合导致清除加快。最后总结了纳米抗体、双特异性抗体、抗体药物偶联物等新型抗体药物的药物代谢动力学研究进展。     

抗体偶联药物分析方法的概述及进展北大核心CSCD

单克隆抗体药物的靶点选择性非常高,但其药理活性普遍比较低。近年来抗体偶联药物(antibody-drug conjugate,ADC)的出现,正好弥补了单克隆抗体药物的缺点。ADC是一类通过化学偶联子将单克隆抗体和不同数目的小分子细胞毒素(效应分子)偶联起来的药物。这种新型的药物结合了单克隆抗体的高特异性和小分子毒素的高活性。ADC药物的分析工作非常困难和费时,主要归因于分析物的多样性及分析方法的复杂性。本文将对目前在ADC药物研究的不同方面如理化性质表征、药代动力学和药效学研究、以及免疫原性评价等所用的分析方法做出归纳和阐述,并讨论这些方法所面临的困难和挑战。     

辛伐他汀在稳定血液透析患者的药物代谢动力学特征分析

目的探讨分析辛伐他汀在稳定血液透析患者的药物代谢动力学特征。方法给予稳定血液透析患者辛伐他汀20 mg,制定合适的采血时间进行血液采集,利用HPLC-MS/MS测定患者不同时间的血药浓度。借助非线性混合效应模型法得到药代动力学参数。结果在置信区间为95%下,模型的药代动力学参数如下：Ka：0.59（0.37-0.82）/h;V1：119（32.2-206）L;V2：1 830（905-2 760）L;CL1：663（375-951）L/h,CL2：197（42.7-351）L/h;Tlag：0.49（0.48-0.50）h;由于客观因素（如吸烟、滤器）的影响,通过测算得出的药代动力学参数为：tmax：（0.90±0.27）h;半衰期t1/2：（6.83±10.79）h;AUC0→t：（30.80±25.00）μg·h·L^-1;Cmax：（12.25±8.35）μg·L^-1。和相关文献记载值较为接近。结论所测的药代动力学参数结果具有参考性,可作为制定患者合理给药方案的依据。     

免疫检查点抑制剂治疗恶性肿瘤的群体药代动力学研究进展

以免疫检查点抑制剂（ICIs）为代表的靶向单克隆抗体类抗肿瘤药物可阻断ICIs分子与其配体的结合,从而通过增强T细胞免疫活性促进肿瘤细胞清除,这在改善几种预后不良的恶性肿瘤总生存率方面显示出显著的临床效果。群体药代动力学（PPK）可表征药物在特定人群中的药代动力学（PK）特征,为个体化用药提供参考。目前关于ICIs的PPK研究报道日益增多。本文综述常见抗肿瘤ICIs类药物的PPK研究进展,列举各类药物的PPK模型结构参数及其协变量,并总结药物是否需要根据相关影响因素进行给药方案的调整,以期为临床合理使用ICIs药物及其药动-药效学（PK-PD）研究提供参考。     

Monoclonal antibodies: what are the pharmacokinetic and pharmacodynamic considerations for drug development?

INTRODUCTION: The number of monoclonal antibodies available for clinical use and under development has dramatically increased in the last 10 years. Understanding their pharmacokinetics and pharmacodynamics is essential for selecting the right clinical candidate, correct dose and regimen for a target indication. AREAS COVERED: This article reviews the existing literature and knowledge of monoclonal antibodies. Specifically, the authors discuss monoclonal antibodies with respect to their pharmacokinetics (including absorption, distribution and elimination) and their pharmacodynamics. The authors also look at the pharmacokinetic/pharmacodynamic relationship, scaling from preclinical to clinical studies and selection of the first-in-human dose. EXPERT OPINION: Monoclonal antibodies have complex pharmacokinetic and pharmacodynamic characteristics that are dependent on several factors. Therefore, it is important to improve our understanding of the pharmacokinetics and pharmacodynamics of monoclonal antibodies from a basic research standpoint. It is also equally important to apply mechanistic pharmacokinetic/pharmacodynamic models to interpret the experimental results and facilitate efforts to predict the safety and efficacy of monoclonal antibodies.     

Pharmacokinetic drug-drug interaction potentials for therapeutic monoclonal antibodies: reality check

A formal assessment of the drug-drug interaction potential of any investigational drug product often requires multiple metabolic and pharmacokinetic evaluations. In contrast to a small-molecule drug, investigating the drug-drug interaction potential of a monoclonal antibody is inherently complicated. High molecular weight monoclonal antibodies are often genetically engineered to demonstrate strong specificity for a particular human antigen target. Consequently, monoclonal antibodies usually have few clinically relevant animal models--other than nonhuman primates--in which to conduct appropriate nonclinical studies. Likewise, clinical drug-drug interaction studies of monoclonal antibodies with long elimination half-lives pose definite operational challenges as conventional crossover studies with adequate washout periods are difficult to conduct. Furthermore, the current regulatory guidance on the design and conduct of in vitro and in vivo drug-drug interaction studies applies more readily to small-molecule drugs than protein-based biologics. Nevertheless, a certain amount of clinically useful information has begun to emerge from the published literature on drug-drug interaction potentials of therapeutic monoclonal antibodies. This article provides a systematic review of the current literature and offers some practical considerations for the design and conduct of pharmacokinetic drug-drug interaction assessments involving novel monoclonal antibodies. Ideally, these evaluations should be performed throughout all stages of drug development. In particular, pharmacokinetic interaction studies with any marketed drugs that are likely to be coadministered with the monoclonal antibody will yield the most clinically useful information for practitioners and patients alike.     

Humanized IgG1 variants with differential binding properties to the neonatal Fc receptor: relationship to pharmacokinetics in mice and primates.

It is well established that the neonatal Fc receptor (FcRn) plays a critical role in regulating IgG homeostasis in vivo. As such, modification of the interaction of IgG with FcRn has been the focus of protein-engineering strategies designed to generate therapeutic antibodies with improved pharmacokinetic properties. In the current work, we characterized differences in interaction of IgG between mouse and primate receptors using three humanized anti-tumor necrosis factor alpha antibodies with variant IgG(1) Fc regions. The wild-type and variant IgG showed a differential combination of improved affinity, modified dissociation kinetics, and altered pH-dependent complex dissociation when evaluated on the primate and murine receptors. The observed in vitro binding differences within and between species allowed us to more completely relate these parameters to their influence on the in vivo pharmacokinetics in mice and cynomolgus monkeys. The variant antibodies have different pharmacokinetic behavior in cynomolgus monkeys and mice, which appears to be related to the unique binding characteristics observed with the murine receptor. However, we did not observe a direct relationship between increased binding affinity to the receptor and improved pharmacokinetic properties for these molecules in either species. This work provides further insights into how the FcRn/IgG interaction may be modulated to develop monoclonal antibodies with improved therapeutic properties.     

Combined use of immunoassay and two-dimensional liquid chromatography mass spectrometry for the detection and identification of metabolites from biotherapeutic pharmacokinetic samples

Peptides and monoclonal antibodies have both emerged as important therapeutic modalities, but each has challenges which limit their use. Non-recombinant chemical conjugation of peptides onto antibodies has the potential to minimize or eliminate altogether many of these limitations. Once such approach, pioneered by CovX has created the possibility for rapid stoichiometric fusion of pharmacophores to a single antibody platform. These molecules, called CovX-Bodies, maintain both the pharmacologic properties of a given peptide and the pharmacokinetic properties of a monoclonal antibody. The result is a new class of molecules wherein each component contributes desirable traits. In this paper, we demonstrate the use of immunoassay and two-dimensional liquid chromatography mass spectrometry (2DLC/MS) in combination to investigate the antibody conjugates of Glucagon-like peptide-1 (GLP-1) and analogs for intact protein metabolite identification directly from mouse serum. The information gained from combining these approaches has helped guide and expedite the optimization of our drug product development efforts.     

Evaluation of an immunoassay for human-specific quantitation of therapeutic antibodies in serum samples from non-human primates

Pharmacokinetic characterization of therapeutic antibodies plays an important role during preclinical and clinical development. However, accurate pharmacokinetic evaluation of therapeutic antibodies in serum samples from non-human primates is often complicated by insufficient specificity of the assays to measure drug levels. The present paper describes the use of a murine monoclonal antibody in an immunoassay format to specifically and quantitatively measure human therapeutic antibodies in serum from non-human primates. This murine antibody is directed against a unique epitope on the constant region CH2 domain of all isotypes of human immunoglobulin G (IgG). The antibody, designated anti-human Fcγ-pan: R10Z8E9, does not cross-react with serum from mouse, rat, and the non-human primates marmoset, rhesus macaque, cynomolgus monkey and baboon when using an enzyme-linked immunosorbent assay (ELISA) or surface plasmon resonance technology (Biacore) format for measurement of the therapeutic antibody. Use of the antibody anti-human Fcγ-pan: R10Z8E9 as capturing and detection reagent allowed human-specific quantitation of total therapeutic antibody anti-IGF-1R in spiked cynomolgus monkey serum via a Sandwich ELISA format. In contrast, a commercially available polyclonal antibody (PAB) directed to the Fcγ fragment of human IgG only specifically measured the therapeutic antibody in buffer samples, but not in serum from cynomolgus monkeys. This generic human IgG assay was already applied in several pharmacokinetic studies in cynomolgus monkeys to determine serum levels of different therapeutic antibodies, including the anti-IGF-1R. Validation of the assay for a humanized IgG1 therapeutic antibody against a membrane protein revealed a lower limit of quantitation of 8 ng/mL in undiluted serum. Intra-assay and inter-assay precision was characterized by a coefficient of variation of less than 10% and accuracy was within 15%. Dilutional linearity was evidenced by a recovery of 98.7–114% of expected concentrations. In conclusion, the monoclonal antibody anti-human Fcγ-pan: R10Z8E9 provides a standard means for human-specific quantitation of therapeutic antibodies with high sensitivity in serum samples from non-human primates in a generic human IgG assay.     

Early development of therapeutic biologics--pharmacokinetics

Modern biologics are biotechnology-derived pharmaceuticals. They are mostly used for diagnosis, prevention and treatment of serious and chronic diseases. Today, therapeutic biologics range from traditional biologics like blood and blood components, fractionated blood products, and antitoxins to modern biologics such as monoclonal antibodies, cytokines (e.g. interferon, interleukine), tissue growth factors, vaccines directed against non-infectious disease targets, and gene transfer products. Chemical as well as pre-clinical development are major challenges for biologics due to their different physicochemical properties (mostly protein structure) compared to small molecules. They demonstrate much more complex pharmacokinetic behaviour, which strongly influences their pre-clinical testing strategy. Biologics are often highly species-specific in action and immunogenic in test animal species and humans. Immunogenicity of therapeutic biologics may influence their pharmacokinetic behaviour as well as pharmacodynamics and toxicity. Biologics are frequently regulated by different procedures compared to small molecules. New guidances are evolving which reflect the rapid development of new technologies in this field. Bioanalytical method development and validation is a prerequisite not exclusively for pharmacokinetic studies but for the whole pre-clinical and clinical development. Due to their unique properties, different kinds of bioanalytical assays (mass assays, activity assays, immunogenicity assays) are necessary in early development of biologics.     

Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling

Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity.     

The pharmacokinetics and pharmacodynamics of monoclonal antibodies--mechanistic modeling applied to drug development

The pharmacology of therapeutic monoclonal antibodies (mAbs) is complex and dependant on both the structure of the antibody and the physiological system that it targets. Patient exposure and responses to mAbs are also related to the structure and activity of mAbs. Furthermore, the pharmacokinetics and pharmacodynamics of mAbs are often inter-related. Pharmacokinetic and pharmacodynamic modeling have been used to elucidate or support the mechanisms of antibodies in development and can be used to identify appropriate dose regimens. Consequently, pharmacokinetic and pharmacodynamic modeling often plays a larger role during the development of therapeutic mAbs than for small molecules.     

Clinical pharmacology considerations in biologics development

Biologics, including monoclonal antibodies (mAbs) and other therapeutic proteins such as cytokines and growth hormones, have unique characteristics compared to small molecules. This paper starts from an overview of the pharmacokinetics (PK) of biologics from a mechanistic perspective, the determination of a starting dose for first-in-human (FIH) studies, and dosing regimen optimisation for phase II/III clinical trials. Subsequently, typical clinical pharmacology issues along the corresponding pathways for biologics development are summarised, including drug-drug interactions, QTc prolongation, immunogenicity, and studies in specific populations. The relationships between the molecular structure of biologics, their pharmacokinetic and pharmacodynamic characteristics, and the corresponding clinical pharmacology strategies are summarised and depicted in a schematic diagram.