Prediction of human plasma concentration-time profiles of monoclonal antibodies from monkey data by a species-invariant time method

We have previously reported that human total body clearance (CL) and steady-state volume of distribution (Vss) of monoclonal antibodies (mAbs) could be predicted reasonably well from monkey data alone using simple allometry with scaling exponents of 0.79 and 1.12 (for soluble targets), and 0.96 and 1.00 (for membrane-bound targets). In the present study, to predict the plasma concentration-time profiles of mAbs in humans, we employed simple dose-normalization and species-invariant time methods (elementary Dedrick plot and complex Dedrick plot), based on the monkey data and the scaling exponents we previously determined. The results demonstrated that the species-invariant time methods were able to provide higher accuracy of prediction than simple dose-normalization, regardless of the type of target antigens (soluble or membrane-bound). The accuracy between elementary Dedrick plot and complex Dedrick plot was nearly equivalent. The predicted human CL and Vss using species-invariant time methods were within mostly 2-fold differences from the observed values. The prediction not only of pharmacokinetic (PK) parameters but also of the plasma concentration-time profile in humans can serve as guidelines for better planning of clinical studies on mAbs.     

The long-awaited magic bullets: therapeutic human monoclonal antibodies from transgenic mice

The ability to produce a diverse repertoire of fully human monoclonal antibodies (mAbs) may have significant applications to human therapy. This update describes the creation of a novel tool for the production of therapeutic human mAbs: a mouse strain engineered to produce a large range of human antibodies in the absence of mouse antibodies. This strain, XenoMouse, has been generated by the introduction of large segments of human immunoglobulin loci, containing the majority of the human antibody gene repertoire, into mice deficient in mouse antibody production. The mice produce a diverse array of authentic fully human IgGkappa antibodies. Upon immunisation with multiple human antigens the mice generate large panels of high affinity, antigen-specific fully human mAbs with therapeutic activities. XenoMouse-derived hybridomas were shown to be stable, producing significant levels of human mAbs. XenoMouse technology represents an efficient and reliable tool for the production of therapeutic human mAbs, which can accelerate the evaluation and validation of antibody therapy in human disease.     

Elimination mechanisms of therapeutic monoclonal antibodies

Targeted therapies using monoclonal antibodies have achieved important therapeutic applications in the treatment of various human diseases. Understanding the factors that impact the pharmacokinetics of monoclonal antibodies is of high importance for effective therapy. Many factors related to the target antigen, antibody and patients can affect antibody elimination. Evaluation of these factors will facilitate the understanding of the processes involved in antibody elimination.     

Predicting human pharmacokinetics from preclinical data

Approaches used for the prediction of pharmacokinetics in relevant populations of human patients mostly rely on in vivo data from animals, using allometric scaling or time-invariant methods. The growth of in vitro and, more recently, in silico screens for evaluating pharmaceutical, pharmacokinetic and toxicity properties can also be used to predict complex in vivo behavior in humans. In most cases, careful and educated application of available approaches provides predictions of pharmacokinetic parameters within 2- or 3-fold of that observed. Attention should now be directed toward integrating information from different sources to increase the precision and accuracy of these pharmacokinetic predictions and to enable a better understanding of the processes underlying ADME behavior in humans.     

Biosimilarity assessment of biosimilar therapeutic monoclonal antibodies

The concept of biosimilar was established in the early 2000s in EU. Currently, the regulatory framework for biosimilar has also been established in the US, Japan, and other countries. As of 2018, biosimilars for infliximab, adalimumab, rituximab, trastuzumab, and bevacizumab have been approved. During the development of a biosimilar, product quality should be evaluated and compared with those of the reference product extensively. Among the quality attributes of therapeutic antibodies, FcRn binding and related structures are well known to affect the pharmacokinetic profile of the product. Other quality attributes such as antigen binding, glycan structure, and isoelectric point are considered to have a potential impact on the pharmacokinetic profile of the product. Based on the high similarity of the quality attributes of the biosimilar to those of its reference product, comparative non-clinical and clinical studies are conducted. Comparable pharmacokinetic profile of the biosimilar and the reference product is important for biosimilar evaluation. In this review, the basic concept of biosimilar development as well as pharmacokinetic data obtained via non-clinical and clinical studies of biosimilar therapeutic antibody is introduced, and future perspective is discussed.     

Trends in therapeutic monoclonal antibodies of cancer

Therapeutic monoclonal antibodies are increasingly applied in clinical application with great success. A variety of antibody products have been approved by the FDA since 1997. Furthermore, the industries have been paying more attention to and efforts in the field of antibody development than ever, suggesting the grand potential of the market and benefits. At present, many monoclonal antibodies have proven their therapeutic value in combination with established treatment for many diseases, as shown in FDA approved expanded indications. This old-fashioned immunotherapy exerts profound effects in many refractory and formidable diseases, especially cancers. With further understanding of the interaction between immune system and cancer, more target molecules were discovered and more promising therapeutic antibodies with improved effects will be feasible in the future. Regardless of initial development or ultimate approved drug, therapeutic monoclonal antibodies have always been associated with numerous patent applications. This review mainly focuses on potential therapeutic monoclonal antibodies in oncology and related antibody patents, and discusses the trend for antibody development and therapeutic applications in humans.     

Predicting pharmacokinetic profile of therapeutic antibodies after iv injection from only the data after sc injection in cynomolgus monkey

1.?The number of developed therapeutic monoclonal antibodies (mAbs) has increased in this decade. This study aims to predict their pharmacokinetic profiles after intravenous (iv) injection using only the data taken after subcutaneous (sc) injection in cynomolgus monkey.

2.?Two-compartment model parameters, Q, V_c and V_p, were collected from the published data after iv injection in cynomolgus monkey for 21 mAbs (Group A). Bioavailability after sc injection (F), CL and serum/plasma concentration after iv injection of other published 19 mAbs (Group B) were predicted using the estimated geometric means of Q, V_c and V_p in Group A and the serum/plasma concentration after sc injection in Group B.

3.?F and CL of 18 out of 19 mAbs in Group B were successfully predicted within 30% difference of observed value. Moreover, most of the observed serum/plasma concentrations after iv injection of mAbs in Group B were successfully predicted within 2-fold difference. Our approach suggests that iv injection might not be required to evaluate absorption of mAbs after sc injection in cynomolgus monkey. Therefore, our approach might reduce the time and cost of drug development, reduce the burden on resources, and also contribute to animal welfare.     

Prediction of human pharmacokinetics of panipenem, a new carbapenem antibiotic, from animal data.

The prediction of human pharmacokinetics of Panipenem (PAPM), which is a new carbapenem antibiotic, was investigated using animal data. The plasma concentration-time curve after intravenous administration of PAPM in each animal showed biexponential elimination. There were good allometric correlations between pharmacokinetic parameters (CLtotal and Vd,ss) calculated from the plasma concentration in animal species and body weight of experimental animals. Predicted human pharmacokinetic parameters calculated by these allometric equations agreed with the values observed in humans.     

Prediction of aztreonam pharmacokinetics in humans based on data from animals

Interspecies correlations of pharmacokinetic parameters obtained in animals were used to predict human pharmacokinetics in order to design the first clinical study of an investigational drug. The serum pharmacokinetics of aztreonam, a novel monocyclic beta-lactam antibiotic, were described for mice, rats, rabbits, and monkeys, using serum clearance and apparent volume of distribution. A one-compartment pharmacokinetic model yielded predictions for aztreonam clinical pharmacokinetics that were very helpful in choosing doses and serum sampling times for the first kinetic study in healthy male volunteers. Predicted serum aztreonam concentrations agreed well with subsequently measured values in man.     

Prediction of aztreonam pharmacokinetics in humans based on data from animals

Interspecies correlations of pharmacokinetic parameters obtained in animals were used to predict human pharmacokinetics in order to design the first clinical study of an investigational drug. The serum pharmacokinetics of aztreonam, a novel monocyclic beta-lactam antibiotic, were described for mice, rats, rabbits, and monkeys, using serum clearance and apparent volume of distribution. A one-compartment pharmacokinetic model yielded predictions for aztreonam clinical pharmacokinetics that were very helpful in choosing doses and serum sampling times for the first kinetic study in healthy male volunteers. Predicted serum aztreonam concentrations agreed well with subsequently measured values in man.     

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。     

Prediction of pharmacokinetics and drug-drug interactions from in vitro metabolism data

There is great interest within the pharmaceutical industry in predicting the in vivo pharmacokinetics (PKs) and metabolism-based drug-drug interactions (DDIs) of compounds from their in vitro metabolism data. Metabolism-based DDIs are largely due to changes in levels of drug-metabolizing enzymes caused by one drug, leading to changes in the PK parameters (mainly clearance) of another. The search for alternative approaches to time-consuming and costly clinical PK drug interaction studies for predicting human DDIs, has been ongoing for decades. In vitro enzyme-mediated biotransformation reactions provide a foundation for predictions that relate PK concepts to enzyme kinetics. This review discusses the principles, assumptions, tools and approaches to in vitro/in vivo prediction, especially in the context of hepatic clearance (the most important PK parameter) and its prediction from in vitro data. Enzyme inhibition is a common cause of DDIs and involves various mechanisms (eg, reversible and mechanism-based inhibition). The models and equations used for predicting DDIs for different types of inhibitor (ie, competitive, partial competitive, non-competitive, partial non-competitive and mixed-type reversible inhibitors, and mechanism-based inhibitors) are extensively presented. Although the methods of prediction are numerous, there remain a number of unresolved factors that may affect the accuracy of the prediction. These factors are also discussed to provide a caution to researchers performing prediction studies.     

Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisited

In this report, the utility of a commonly used interspecies scaling method to predict the systemic clearance (CL) of therapeutic proteins in humans was evaluated. Based on analysis of a pharmacokinetic data set of 34 therapeutic proteins, including 12 monoclonal antibodies (mAbs) and Fc fusion proteins, human CL can generally be predicted reasonably well with simple allometric scaling and a fixed exponent of 0.8:～95% of the cases predicted values within 2‐fold of the observed values when using CL data from multiple species, or～90% simply using CL from monkeys. Specific to mAbs/Fc fusion proteins, scaling from monkey CL using a fixed exponent of 0.8 gave an excellent prediction; all predicted CL values were within 2‐fold of the corresponding observed values. Compared with the simple allometric scaling method that uses a fitted exponent from CL data of ≥3 preclinical species, the fixed exponent approach with 1–2 preclinical species is simple, resource‐saving and minimizes systematic bias. Together with its overall satisfactory prediction accuracy, especially in the absence of non‐linear pharmacokinetics and species‐specific clearance mechanisms, this fixed exponent method affords a viable alternative to other published allometric methods, including the Rule of Exponents (ROE). Copyright © 2010 John Wiley & Sons, Ltd.     

New solid tumor targets for therapeutic monoclonal antibodies

Monoclonal antibodies are a rapidly growing class of drugs used for therapy of human cancers and other diseases. They can be used effectively to target tumor-specific molecules and thereby modulate key signaling pathways that play a role in tumor growth, survival and metastasis. Clinical success of novel antibodies has stimulated great interest in the promise of antibody therapeutics for cancer. In this editorial, the author describes three key characteristics that define an ideal target antigen for a therapeutic antibody.     

New solid tumor targets for therapeutic monoclonal antibodies

Monoclonal antibodies are a rapidly growing class of drugs used for therapy of human cancers and other diseases. They can be used effectively to target tumor-specific molecules and thereby modulate key signaling pathways that play a role in tumor growth, survival and metastasis. Clinical success of novel antibodies has stimulated great interest in the promise of antibody therapeutics for cancer. In this editorial, the author describes three key characteristics that define an ideal target antigen for a therapeutic antibody.     

Pediatric physiology in relation to the pharmacokinetics of monoclonal antibodies

Introduction: Dose design for pediatric trials with monoclonal antibodies (mAbs) is often extrapolated from the adult dose according to weight, age, or body surface area. While these methods account for the size differences between adults and children, they do not account for the maturation of processes that may play a key role in the pharmacokinetics and/or pharmacodynamics of mAbs. With the same weight-based dose, infants and young children typically receive lower plasma exposures when compared to adults.

Areas covered: The mechanistic features of mAb distribution, elimination, and absorption are explored in detail and literature-based hypotheses are generated to describe their age-dependence. This knowledge can be incorporated into a physiologically based pharmacokinetic (PBPK) modeling approach to pediatric dose determination.

Expert opinion: As data from pediatric clinical trials become increasingly available, we have the opportunity to reflect on the physiologic drivers of pharmacokinetics, safety, and efficacy in children with mathematical models. A modeling approach that accounts for the age-related features of mAb disposition can be used to derive first-in-pediatric doses, design optimal sampling schemes for children in clinical trials and even explore new pharmacokinetic end-points as predictors of safety and efficacy in children.     

Factors affecting pharmacokinetics of monoclonal antibodies: A review article

Factors affecting the successful therapy of malignant diseases include the antibody dose used and the schedule of administration, the half-life and fast blood clearance of the antibodies, the presence of circulating antigen, poor tumor penetration of the high/molecular-weight monoclonal antibody (mAb) and the way in which these molecules are catabolized. To circumvent these limitations and achieve higher uptake, increased tumor penetration, faster blood clearance and longer retention in the tumors, there is a need to generate mAbs suitable for diagnosis as well as therapy and to develop novel strategies to increase the efficacy of immunotherapeutic treatments. There is a lack of knowledge about many aspects of the physiological function and metabolism of antibodies. This paper is intended to discuss factors that affect the pharmacokinetics of mAbs in human subjects with the purpose of forming possible strategies to optimize this approach for tumor diagnosis and therapy.