Monoclonal Antibody Disposition Research Articles

Comparison of monoclonal antibody disposition predictions using different physiologically based pharmacokinetic modelling platforms

Comparison of monoclonal antibody disposition predictions using different physiologically based pharmacokinetic modelling platforms

Translational physiologically-based pharmacokinetic model for ocular disposition of monoclonal antibodies.

We have previously published a PBPK model comprising the ocular compartment to characterize the disposition of monoclonal antibodies (mAbs) in rabbits. While rabbits are commonly used preclinical species in ocular research, non-human primates (NHPs) have the most phylogenetic resemblance to humans including the presence of macula in the eyes as well as higher sequence homology. However, their use in ocular research is limited due to the strict ethical guidelines. Similarly, in humans the ocular samples cannot be collected except for the tapping of aqueous humor (AH). Therefore, we have translated this rabbit model to monkeys and human species using literature-reported datasets. Parameters describing the tissue volumes, physiological flows, and FcRn-binding were obtained from the literature, or estimated by fitting the model to the data. In the monkey model, the values for the rate of lysosomal degradation for antibodies (Kdeg), intraocular reflection coefficients (σaq, σret, σcho), bidirectional rate of fluid circulation between the vitreous chamber and the aqueous chamber (QVA), and permeability-surface area product of lens (PSlens) were estimated; and were found to be 31.5h-1, 0.7629, 0.6982, 0.9999, 1.64 × 10-5 L/h, and 4.62 × 10-7 L/h, respectively. The monkey model could capture the data in plasma, aqueous humor, vitreous humor and retina reasonably well with the predictions being within twofold of the observed values. For the human model, only the value of Kdeg was estimated to fit the model to the plasma pharmacokinetics (PK) of mAbs and was found to be 24.4h-1 (4.14%). The human model could also capture the ocular PK data reasonably well with the predictions being within two- to threefold of observed values for the plasma, aqueous and vitreous humor. Thus, the proposed framework can be used to characterize and predict the PK of mAbs in the eye of monkey and human species following systemic and intravitreal administration. The model can also facilitate the development of new antibody-based therapeutics for the treatment of ocular diseases as well as predict ocular toxicities of such molecules following systemic administration.

Physiologically Based Pharmacokinetic Modeling to Characterize the Effect of Molecular Charge on Whole-Body Disposition of Monoclonal Antibodies.

Motivated by a series of work demonstrating the effect of molecular charge on antibody pharmacokinetics (PK), physiological-based pharmacokinetic (PBPK) models are emerging that relate in silico calculated charge or in vitro measures of polyspecificity to antibody PK parameters. However, only plasma data has been used for model development in these studies, leading to unvalidated assumptions. Here, we present an extended platform PBPK model for antibodies that incorporate charge-dependent endothelial cell pinocytosis rate and nonspecific off-target binding in the interstitial space and on circulating blood cells, to simultaneously characterize whole-body disposition of three antibody charge variants. Predictive potential of various charge metrics was also explored, and the difference between positive charge patches and negative charge patches (i.e., PPC-PNC) was used as the charge parameter to establish quantitative relationships with nonspecific binding affinities and endothelial cell uptake rate. Whole-body disposition of these charge variants was captured well by the model, with less than 2-fold predictive error in area under the curve of most plasma and tissue PK data. The model also predicted that with greater positive charge, nonspecific binding was more substantial, and pinocytosis rate increased especially in brain, heart, kidney, liver, lung, and spleen, but remained unchanged in adipose, bone, muscle, and skin. The presented PBPK model contributes to our understanding of the mechanisms governing the disposition of charged antibodies and can be used as a platform to guide charge engineering based on desired plasma and tissue exposures.

Development of a physiologically-based pharmacokinetic model for ocular disposition of monoclonal antibodies in rabbits.

Development of protein therapeutics for ocular disorders, particularly age-related macular degeneration (AMD), is a highly competitive and expanding therapeutic area. However, the application of a predictive and translatable ocular PK model to better understand ocular disposition of protein therapeutics, such as a physiologically-based pharmacokinetic (PBPK) model, is missing from the literature. Here, we present an expansion of an antibody platform PBPK model towards rabbit and incorporate a novel anatomical and physiologically relevant ocular component. Parameters describing all tissues, flows, and binding events were obtained from existing literature and fixed a priori. First, translation of the platform PBPK model to rabbit was confirmed by evaluating the model's ability to predict plasma PK of a systemically administered exogenous antibody. Then, the PBPK model with the new ocular component was validated by estimation of serum and ocular (i.e. aqueous humor, retina, and vitreous humor) PK of two intravitreally administered monoclonal antibodies. We show that the proposed PBPK model is capable of accurately (i.e. within twofold) predicting ocular exposure of antibody-based drugs. The proposed PBPK model can be used for preclinical-to-clinical translation of antibodies developed for ocular disorders, and assessment of ocular toxicity for systemically administered antibody-based therapeutics.

Predicting monoclonal antibody pharmacokinetics following subcutaneous administration via whole-body physiologically-based modeling.

Use of the subcutaneous (SC) route for administering monoclonal antibodies (mAbs) to treat chronic conditions has been hindered because of an incomplete understanding of fundamental mechanisms controlling mAb absorption from the SC site, and due to the limited translatability of preclinical studies. In this paper, we report on the development and evaluation of a whole-body physiologically-based model to predict mAb pharmacokinetics following SC administration. The circulatory model is based on the physiological processes governing mAb transport and includes two mAb-specific parameters representing differences in pinocytosis rate and the diffusive/convective transport rates among mAbs. At the SC administration site, two additional parameters are used to represent mAb differences in lymphatic capillary uptake and in pre-systemic clearance. Model development employed clinical intravenous (IV) plasma PK data from 20 mAbs and SC plasma PK data from 12 of these mAbs, as obtained from the literature. The resulting model reliably described both the IV and SC measured plasma concentration data. In addition, a metric based on the positive charge across the mAb's complementarity determining region vicinity was found to positively correlate with the model-based estimates of the mAb-specific parameter governing organ/tissue pinocytosis transport and with estimates of the mAb's SC lymphatic capillary clearance. These two relationships were incorporated into the model and accurately predicted the SC PK profiles of three out of four separate mAbs not included in model development. The whole-body physiologically-based model reported herein, provides a platform to characterize and predict the plasma disposition of monoclonal antibodies following SC administration in humans.

Understanding Inter-Individual Variability in Monoclonal Antibody Disposition.

Monoclonal antibodies (mAbs) are currently the largest and most dominant class of therapeutic proteins. Inter-individual variability has been observed for several mAbs; however, an understanding of the underlying mechanisms and factors contributing to inter-subject differences in mAb disposition is still lacking. In this review, we analyze the mechanisms of antibody disposition and the putative mechanistic determinants of inter-individual variability. Results from in vitro, preclinical, and clinical studies were reviewed evaluate the role of the neonatal Fc receptor and Fc gamma receptors (expression and polymorphism), target properties (expression, shedding, turnover, internalization, heterogeneity, polymorphism), and the influence of anti-drug antibodies. Particular attention is given to the influence of co-administered drugs and disease, and to the physiological relevance of covariates identified by population pharmacokinetic modeling, as determinants of variability in mAb pharmacokinetics.

Factors Influencing Drug Disposition of Monoclonal Antibodies in Inflammatory Bowel Disease: Implications for Personalized Medicine.

Monoclonal antibody (mAb) therapies have revolutionized the treatment of several chronic inflammatory diseases, including the inflammatory bowel diseases (IBD), Crohn's disease, and ulcerative colitis. While efficacious, responses to these therapies vary considerably from patient to patient, due in part to inter- and intra-individual variability in pharmacokinetics (PK) and drug exposure. The concept of personalized medicine to monitor drug exposure and to adjust dosing in individual patients is consequently gaining acceptance as a powerful tool to optimize mAb therapy for improved outcomes in IBD. This review provides a brief overview of the different mAbs currently approved or in development for the treatment of IBD, including their presumed mechanisms of action and PK properties. Specifically described are (1) the factors known to affect mAb PK and drug exposure in patients with IBD, (2) the value of population PK/pharmacodynamic (PD) modeling to identify and understand the influence of these factors on drug exposure and effect, and (3) the clinical evidence for the potential of therapeutic drug monitoring (TDM) to improve IBD outcomes in response to mAb-based therapy. Incorporation of PK/PD parameters into clinical decision support tools has the potential to guide therapeutic decision making and aid implementation of personalized medicine strategies in patients with IBD.

Mechanisms Influencing the Pharmacokinetics and Disposition of Monoclonal Antibodies and Peptides.

Monoclonal antibodies (mAbs) and peptides are an important class of therapeutic modalities that have brought improved health outcomes in areas with limited therapeutic optionality. Presently, there more than 90 mAb and peptide therapeutics on the United States market, with over 600 more in various clinical stages of development in a broad array of therapeutic areas, including diabetes, autoimmune disorders, oncology, neuroscience, and cardiovascular and infectious diseases. Notwithstanding this potential, there is high clinical rate of attrition, with approximately 10% reaching patients. A major contributor to the failure of the molecules is often times an incomplete or poor understanding of the pharmacokinetics (PK) and disposition profiles leading to limited or diminished efficacy. Increased and thorough characterization efforts directed at disseminating mechanisms influencing the PK and disposition of mAbs and peptides can aid in improving the design for their intended pharmacological activity, and thereby their clinical success. The PK and disposition factors for mAbs and peptides are broadly influenced by target-mediated drug disposition and nontarget-related clearance mechanisms related to the interplay between the relationship of the structure and physiochemical properties of mAbs and peptides with physiologic processes. This review focuses on nontarget-related factors influencing the disposition and PK of mAbs and peptides. Contemporary considerations around the increasing in silico approaches to identify nontarget-related molecule limitations and enhancing the druggability of mAbs and peptides, including parenteral and nonparenteral delivery strategies that are geared toward improving patient experience and compliance, are also discussed.

FcRn Expression in Wildtype Mice, Transgenic Mice, and in Human Tissues.

Quantitative real-time PCR and Western blot methods were developed to assess neonatal Fc-receptor (FcRn) mRNA and protein expression in human FcRn transgenic mice, Swiss Webster mice, and in select human tissues. Additionally, FcRn turnover was evaluated via pulse-chase. FcRn mRNA expression was significantly higher in transgenic mice when compared to mouse FcRn mRNA in Swiss Webster mice and it ranged from 184-fold higher in the kidney to 109,000-fold higher in the skin. FcRn protein expression was found to be 13-fold lower in kidney to 5.6-fold higher in lung obtained from transgenic mice compared to FcRn protein expression in lung samples obtained from Swiss Webster mice. FcRn protein expression in human liver and small intestine tissues matched more closely with FcRn expression in Swiss Webster mice but were significantly lower when compared to values found from Swiss Webster and transgenic mice. Although FcRn mRNA expression correlated significantly with protein expression (p < 0.0005), the correlation coefficient was only 0.113. As such, the measurement of FcRn protein may be preferred to FcRn mRNA for quantitative applications. Significant differences were found in FcRn expression in transgenic mice, Swiss Webster mice, and human tissues, which may have implications for the use of mouse models in the assessment of monoclonal antibody disposition, efficacy, and safety.

Understanding the Monoclonal Antibody Disposition after Subcutaneous Administration using a Minimal Physiologically based Pharmacokinetic Model.

Monoclonal antibodies (mAbs) are commonly administered by subcutaneous (SC) route. However, bioavailability is often reduced after SC administration. In addition, the sequential transfer of mAbs through the SC tissue and lymphatic system is not completely understood. Therefore, major objectives of this study were a) To understand absorption of mAbs via the lymphatic system after SC administration using physiologically based pharmacokinetic (PBPK) modeling, and b) to demonstrate application of the model for prediction of SC pharmacokinetics (PK) of mAbs. A minimal PBPK model was constructed using various physiological parameters related to the SC injection site and lymphatic system. The remainder of the body organs were represented using a 2-compartment model (central and peripheral compartments), with parameters derived from available intravenous (IV) PK data. The IV and SC clinical PK data of a total of 10 mAbs were obtained from literature. The SC PK data were used to estimate the lymphatic trunk-lymph node (LN) clearance. The mean estimated lymphatic trunk-LN clearance obtained from 37 SC PK profiles of mAbs was 0.00213 L/h (0.001332 to 0.002928, 95% confidence intervals). The estimated lymphatic trunk-LN clearance was greater for the mAbs with higher isoelectric point (pI). In addition, the estimated clearance increased with decrease in the bioavailability. The minimal PBPK model identified SC injection site lymph flow, afferent and efferent lymph flows, and volumes associated with the SC injection site, lymphatic capillaries and lymphatic trunk-LN as important physiological parameters governing the absorption of mAbs after SC administration. The model may be used to predict PK of mAbs using the relationship of lymphatic trunk-LN clearance and the pI. In addition, the model can be used as a bottom platform to incorporate SC and lymphatic in vitro clearance data for mAb PK prediction in the future.

"Catch-and-Release" Anti-Carcinoembryonic Antigen Monoclonal Antibody Leads to Greater Plasma and Tumor Exposure in a Mouse Model of Colorectal Cancer.

In this study, we examined the effects of target expression, neonatal Fc receptor (FcRn) expression in tumors, and pH-dependent target binding on the disposition of monoclonal antibodies (mAbs) in murine models of colorectal cancer. A panel of anti-carcinoembryonic antigen (CEA) mAbs was developed via standard hybridoma technology and then evaluated for pH-dependent CEA binding. Binding was assessed via immunoassay and radioligand binding assays. 10H6, a murine IgG1 mAb with high affinity for CEA at pH = 7.4 (KD = 12.6 ± 1.7 nM) and reduced affinity at pH = 6.0 (KD = 144.6 ± 21.8 nM), and T84.66, which exhibits pH-independent CEA binding (KD = 1.1 ± 0.11 and 1.4 ± 0.16 nM at pH 7.4 and 6.0), were selected for pharmacokinetic investigations. We evaluated pharmacokinetics after intravenous administration to control mice and to mice bearing tumors with (MC38CEA+, LS174T) and without (MC38CEA-) CEA expression and with or without expression of murine FcRn, at doses of 0.1, 1, and 10 mg/kg. 10H6 displayed linear pharmacokinetics in mice bearing MC38CEA+ or MC38CEA- tumors. T84.66 displayed linear pharmacokinetics in mice with MC38CEA- tumors but dose-dependent nonlinear pharmacokinetics in mice bearing MC38CEA+ In addition to the improved plasma pharmacokinetic profile (i.e., linear pharmacokinetics, longer terminal half-life), 10H6 exhibited improved exposure in MC38CEA+ tumors relative to T84.66. In mice bearing tumors with CEA expression, but lacking expression of murine FcRn (LS174T), 10H6 demonstrated nonlinear pharmacokinetics, with rapid clearance at low dose. These data are consistent with the hypothesis that pH-dependent CEA binding allows mAb dissociation from target in acidified endosomes, enabling FcRn-mediated protection from target-mediated elimination in mice bearing MC38CEA+ tumors.

Emerging Role of the Spleen in the Pharmacokinetics of Monoclonal Antibodies, Nanoparticles and Exosomes.

After being absorbed, drugs distribute in the body in part to reach target tissues, in part to be disposed in tissues where they do not exert clinically-relevant effects. Therapeutically-relevant effects are usually terminated by drug metabolism and/or elimination. The role that has been traditionally ascribed to the spleen in these fundamental pharmacokinetic processes was definitely marginal. However, due to its high blood flow and to the characteristics of its microcirculation, this organ would be expected to be significantly exposed to large, new generation drugs that can hardly penetrate in other tissues with tight endothelial barriers. In the present review, we examine the involvement of the spleen in the disposition of monoclonal antibodies, nanoparticles and exosomes and the possible implications for their therapeutic efficacy and toxicity. The data that we will review lead to the conclusion that a new role is emerging for the spleen in the pharmacokinetics of new generation drugs, hence suggesting that this small, neglected organ will certainly deserve stronger attention by pharmacologists in the future.

Scale-up of a physiologically-based pharmacokinetic model to predict the disposition of monoclonal antibodies in monkeys.

Preclinical assessment of monoclonal antibody (mAb) disposition during drug development often includes investigations in non-human primate models. In many cases, mAb exhibit non-linear disposition that relates to mAb-target binding [i.e., target-mediated disposition (TMD)]. The goal of this work was to develop a physiologically-based pharmacokinetic (PBPK) model to predict non-linear mAb disposition in plasma and in tissues in monkeys. Physiological parameters for monkeys were collected from several sources, and plasma data for several mAbs associated with linear pharmacokinetics were digitized from prior literature reports. The digitized data displayed great variability; therefore, parameters describing inter-antibody variability in the rates of pinocytosis and convection were estimated. For prediction of the disposition of individual antibodies, we incorporated tissue concentrations of target proteins, where concentrations were estimated based on categorical immunohistochemistry scores, and with assumed localization of target within the interstitial space of each organ. Kinetics of target-mAb binding and target turnover, in the presence or absence of mAb, were implemented. The model was then employed to predict concentration versus time data, via Monte Carlo simulation, for two mAb that have been shown to exhibit TMD (2F8 and tocilizumab). Model predictions, performed a priori with no parameter fitting, were found to provide good prediction of dose-dependencies in plasma clearance, the areas under plasma concentration versu time curves, and the time-course of plasma concentration data. This PBPK model may find utility in predicting plasma and tissue concentration versus time data and, potentially, the time-course of receptor occupancy (i.e., mAb-target binding) to support the design and interpretation of preclinical pharmacokinetic-pharmacodynamic investigations in non-human primates.

Survey of monoclonal antibody disposition in man utilizing a minimal physiologically-based pharmacokinetic model.

Minimal physiologically based pharmacokinetic (mPBPK) models provide a simple and sensible approach that incorporates physiological elements into pharmacokinetic (PK) analysis when only plasma data are available. With this modeling concept, a second-generation mPBPK model was further developed with specific accommodations for the unique PK properties of monoclonal antibodies (mAb). This study applied this model to extensively survey mAb PK in man in order to seek general perspectives on mAb distributional and elimination features. Profiles for 72 antibodies were successfully analyzed with this model. The model results provide assessment regarding: (1) predominant clearance site, in plasma or interstitial fluid (ISF); (2) mAb ISF concentrations in two groups of lumped tissues with continuous (V(tight)) or fenestrated (V(leaky)) vascular endothelium; (3) Transcapillary escape rate (TER), an indicator of systemic vascular permeability. For 93% of surveyed mAbs, the model assuming clearance from plasma (CL) produced better or at least equivalent model performance than the model with clearance from ISF and yielded most consistent values of vascular reflection coefficients (σ1 and σ2) among all antibodies. The average mAb ISF concentration in V(tight) and V(leaky) at equilibrium was predicted to be about 6.8 and 37.9% of that in plasma. A positive correlation was detected between plasma clearance and TER among most mAbs, which could be interpreted as both parameters having common determinants related to ISF tissue distribution in this model context. The mAbs with relative higher plasma clearance (>0.035 L/h/70 kg) did not reveal such positive correlation between clearance and TER, implying that the factors contributing to high clearance may not necessarily increase tissue distribution and penetration. In conclusion, this mPBPK model offers a more mechanistic approach for analyzing plasma mAb PK than compartment models and generates parameters providing useful intrinsic distributional and elimination insights for a large number of mAbs that were examined in man.

Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models

The structure, interpretation and parameterization of classical compartment models as well as physiologically-based pharmacokinetic (PBPK) models for monoclonal antibody (mAb) disposition are very diverse, with no apparent consensus. In addition, there is a remarkable discrepancy between the simplicity of experimental plasma and tissue profiles and the complexity of published PBPK models. We present a simplified PBPK model based on an extravasation rate-limited tissue model with elimination potentially occurring from various tissues and plasma. Based on model reduction (lumping), we derive several classical compartment model structures that are consistent with the simplified PBPK model and experimental data. We show that a common interpretation of classical two-compartment models for mAb disposition-identifying the central compartment with the total plasma volume and the peripheral compartment with the interstitial space (or part of it)-is not consistent with current knowledge. Results are illustrated for the monoclonal antibodies 7E3 and T84.66 in mice.

Investigation of the Influence of Nephropathy on Monoclonal Antibody Disposition: A Pharmacokinetic Study in a Mouse Model of Diabetic Nephropathy

This study employed a mouse model to evaluate the effects of diabetic nephropathy on the pharmacokinetics of 8C2, a murine monoclonal antibody (mAb). Streptozotocin (STZ) was administered to mice to induce diabetic nephropathy (125mg/kg/day × 2). Mice were grouped (n = 8-10) based on time after STZ-treatment (control, 1, 2, 3, 4, or 6weeks), and injected intravenously with 10mg/kg 8C2. Blood samples were collected up to 7days, and 8C2 plasma concentrations were determined via immunoassay. Inulin clearance and urinary albumin excretion rate (UAE) were determined to assess renal function. UAE, inulin clearance, and 8C2 clearance increased significantly following STZ. Comparing control and 6week STZ-treatment groups, UAE and inulin clearance increased from 25.7 ± 3.3 to 99.3 ± 13.7μg/day, and from 421 ± 31 to 584 ± 78μl/min. 8C2 clearance increased from 121 ± 12.5 to 228 ± 61μl/hr/kg (p < 0.01). 8C2 clearance was highly correlated with UAE (r(2): 0.731). Inclusion of UAE as a covariate in population modeling explained significant residual variability in 8C2 clearance. The clearance of 8C2 increased significantly in STZ-treated mice. Population pharmacokinetic modeling suggests that UAE has potential for use in predicting mAb clearance in subjects with diabetic nephropathy, possibly assisting in the individualization of mAb dosing.

Application of PBPK modeling to predict monoclonal antibody disposition in plasma and tissues in mouse models of human colorectal cancer

This investigation evaluated the utility of a physiologically based pharmacokinetic (PBPK) model, which incorporates model parameters representing key determinants of monoclonal antibody (mAb) target-mediated disposition, to predict, a priori, mAb disposition in plasma and in tissues, including tumors that express target antigens. Monte Carlo simulation techniques were employed to predict the disposition of two mAbs, 8C2 (as a non-binding control mouse IgG1 mAb) and T84.66 (a high-affinity murine IgG1 anti-carcinoembryonic antigen mAb), in mice bearing no tumors, or bearing colorectal HT29 or LS174T xenografts. Model parameters were obtained or derived from the literature. (125)I-T84.66 and (125)I-8C2 were administered to groups of SCID mice, and plasma and tissue concentrations were determined via gamma counting. The PBPK model well-predicted the experimental data. Comparisons of the population predicted versus observed areas under the plasma concentration versus time curve (AUC) for T84.66 were 95.4±67.8 versus 84.0±3.0, 1,859±682 versus 2,370±154, and 5,930±1,375 versus 5,960±317 (nM×day) at 1, 10, and 25mg/kg in LS174T xenograft-bearing SCID mice; and 215±72 versus 233±30, 3,070±346 versus 3,120±180, and 7,884±714 versus 7,440±626 in HT29 xenograft-bearing mice. Model predicted versus observed 8C2 plasma AUCs were 312.4±30 versus 182±7.6 and 7,619±738 versus 7,840±24.3 (nM×day) at 1 and 25mg/kg. High correlations were observed between the predicted median plasma concentrations and observed median plasma concentrations (r (2)=0.927, for all combinations of treatment, dose, and tumor model), highlighting the utility of the PBPK model for the a priori prediction of in vivo data.

Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human

The objectives of the following investigation were (1) development of a physiologically based pharmacokinetic (PBPK) model capable of characterizing the plasma and tissue pharmacokinetics (PK) of nonspecific or antigen specific monoclonal antibodies (mAbs) in wild type, FcRn knockout, tumor bearing and non tumor bearing mice and (2) evaluation of the scale up potential of the model by characterizing the mouse, rat, monkey and human plasma PK of mAbs, simultaneously. A PBPK model containing 15 tissues, a carcass and a tumor compartment was developed by modifying/augmenting previously published PBPK models. Each tissue compartment was subdivided into plasma, blood cell, endothelial, interstitial and cellular sub-compartments. Each tissue was connected through blood and lymph flow to the systemic circulation. Lymph flow was set to a value 500 times lower than plasma flow and vascular reflection coefficients for each tissue were adjusted according to their vascular pore size. In each tissue endothelial space, mAb entered via pinocytosis and the interaction of FcRn with mAb was described by on and off rates. FcRn bound mAb was recycled and unbound mAb was eliminated by a first order process (K(deg)). The PBPK model was simultaneously fit to the following datasets to estimate four system parameters: (1) plasma and tissue PK of nonspecific mAb in wild type mouse with or without simultaneous intravenous immunoglobulin (IVIG) administration, (2) plasma and tissue PK of nonspecific mAb in FcRn knockout mouse, (3) plasma and tissue PK of nonspecific mAb in tumor bearing mouse, (4) plasma and tissue PK of tumor antigen specific mAb in tumor bearing mouse, and (5) plasma PK of mAb in rat, monkey and human. The model was able to characterize all the datasets reasonably well with a common set of parameters. The estimated value of the four system parameters i.e. FcRn concentration (FcRn), rate of pinocytosis per unit endosomal space (CL(up)), K(deg) and the proportionality constant (C_LNLF) between the rate at which antibody transfers from the lymph node compartment to the blood compartment and the plasma flow of the given species, were found to be 4.98E-05 M (CV% = 11.1), 3.66E-02 l/h/l (%CV = 3.48), 42.9 1/h (%CV = 15.7) and 9.1 (CV% > 50). Thus, a platform PBPK model has been developed that can not only simultaneously characterize mAb disposition data obtained from various previously published mouse PBPK models but is also capable of characterizing mAb disposition in various preclinical species and human.

Monoclonal Antibodies: Interspecies Scaling With Minimal Preclinical Information

Interspecies scaling for predicting human pharmacokinetics with information from multiple animal species is an established approach for small-molecule drugs. However, in general, the strategy is not a viable approach for therapeutic monoclonal antibodies, since relevant preclinical information is often limited due to highly specific biological activity and unique disposition mechanisms of these biologic agents. Existing data from a limited database indicates that applying minimal but relevant preclinical information and an appropriate approach; for example, fixed-exponent, provides a pragmatic and reasonably accurate prediction of human pharmacokinetics. This article briefly reviews the factors that affect the disposition of monoclonal antibodies and reiterates the importance of biological similarities between animal species and humans when selecting preclinical information for interspecies scaling. The article outlines the rationalization for utilizing the one-species with fixed-exponent approach, with discussions focused on the assumptions in allometry and monoclonal antibodies disposition mechanisms, and provides specific considerations related to practically applying such an approach.

Gaining insights into the consequences of target-mediated drug disposition of monoclonal antibodies using quasi-steady-state approximations

Target-mediated drug disposition (TMDD) is frequently reported for therapeutic monoclonal antibodies and is linked to the high affinity and high specificity of antibody molecules for their target. Understanding TMDD of a monoclonal antibody should go beyond the empirical description of its non-linear PK since valuable insights on the antibody-target interaction itself can be gained. This makes its mechanistic understanding precious for the drug development process, in particular for the optimization of new antibody molecules, for the design and interpretation of pharmacokinetic studies, and possibly even for the evaluation of efficacy and dose selection of drug candidates. Using the observation that the molecular (microscopic) processes are usually much more rapid than the pharmacokinetic (macroscopic) processes, a series of quasi-steady-state conditions on the microscopic level is proposed to bridge the gap between simple empirical and complex mechanistic descriptions of TMDD. These considerations show the impact of parameters such as target turnover, target expression, and target accessibility on the pharmacokinetics and pharmacodynamics of monoclonal antibodies.