Antibodies pharmacokinetic modelling

Mould DR, Sweeney KR. The pharmacokinetics and pharmacodynamics of monoclonal antibodies - mechanistic modelling applied to drug development. Curr Opin Drug Discov Devel 2007 10(l) 84-96. 

Therapeutic monoclonal antibodies are widely recognized to be a most promising means to treat an increasing number of human diseases, including cancers and autoimmunity. To a large extent, the efficacy of monoclonal antibody treatment is because IgG antibodies have greatly extended persistence in vivo. However, conventional rodent models do not mirror human antibody pharmacokinetics. The key molecule responsible for the extended persistence antibodies is the major histocompatibility complex class I family Fc receptor, FcRn. We describe human FcRn transgenic mouse models and how they can be exploited productively for the preclinical pharmacokinetic evaluation of therapeutic antibodies. 

Fig. 9. Schematic of the physiologically based pharmacokinetic model for antibody distribution in mice and humans (reproduced with permission from Baxter et at., 1994a).

The literature contains many examples on the use of physiological pharmacokinetic models. An early, detailed, and influential example is the model for methotrexate [6]. This model used physiological parameters and was applied to mice, monkeys, dogs, and humans. Other papers, which provide good examples on the benefits of physiological modeling, describe the uptake of immu-notoxins in solid tumors [7] and the biodistribution of monoclonal antibodies and antibody fragments [8]. 

Baxter, L.T., et al., Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice. Cancer Research, 1994, 54, 1517-1528. 

Monoclonal antibodies represent a diverse group of therapeutic proteins typically presenting with complex pharmacokinetic properties [10]. For these compounds, more comprehensive, mechanism-based PBPK models have been described [96,97]. Baxter et al. developed and evaluated a bifunctional antibody PBPK model in mice and scaled the model to predict its pharmacokinetics in humans [96]. A membrane-... 

Baxter L T, Zhu H, Mackensen D G, et al. (1995). Biodistribution of monoclonal antibodies Scale-up from mouse to human using a physiologically based pharmacokinetic model. Cancer Res. 55 4611-4622. 

Friedrich S W, Lin S C, Stoll B R, et al. (2002). Antibody-directed effector cell therapy of tumors Analysis and optimization using a physiologically based pharmacokinetic model. Neoplasia. 4 449-463. 

Kletting, R, KuU, T, Bunjes, D., Mahren, B., Luster, M., Reske, S. N. and Glatting, G. 2010. Radioimmunotherapy with anti-CD66 antibody Improving the biodistribution using a ph) iologically based pharmacokinetic model / Nucl Med, 51,484-91. 

Rituximab is a monoclonal antibody to the CD20 receptor expressed on the surface of B lymphocytes the presence of the antibody is determined during flow cytometry of the tumor cells. Cell death results from antibody-dependent cellular cytotoxicity. The pharmacokinetics of rituximab are best described by a two-compartment model, with a terminal half-life of 76 hours after the first infusion and a terminal half-life of 205 hours after the fourth dose.36 Rituximab has shown clinical activity in the treatment of B-cell lymphomas that are CD20+. Side effects include hypersensitivity reactions, hypotension, fevers, chills, rash, headache, and mild nausea and vomiting. 

In contrast to noncompartmental analysis, in compartmental analysis a decision on the number of compartments must be made. For mAbs, the standard compartment model is illustrated in Fig. 3.11. It comprises two compartments, the central and peripheral compartment, with volumes VI and V2, respectively. Both compartments exchange antibody molecules with specific first-order rate constants. The input into (if IV infusion) and elimination from the central compartment are zero-order and first-order processes, respectively. Hence, this disposition model characterizes linear pharmacokinetics. For each compartment a differential equation describing the change in antibody amount per time can be established. For... 

The structural submodel describes the central tendency of the time course of the antibody concentrations as a function of the estimated typical pharmacokinetic parameters and independent variables such as the dosing regimen and time. As described in Section 3.9.3, mAbs exhibit several parallel elimination pathways. A population structural submodel to mechanistically cover these aspects is depicted schematically in Fig. 3.14. The principal element in this more sophisticated model is the incorporation of a second elimination pathway as a nonlinear process (Michaelis-Menten kinetics) into the structural model with the additional parameters Vmax, the maximum elimination rate, and km, the concentration at which the elimination rate is 50% of the maximum value. The addition of this second nonlinear elimination process from the peripheral compartment to the linear clearance process usually significantly improves the fit of the model to the data. Total clearance is the sum of both clearance parts. The dependence of total clearance on mAb concentrations is illustrated in Fig. 3.15, using population estimates of the linear (CLl) and nonlinear clearance (CLnl) components. At low concentra-... 

The statistical submodel characterizes the pharmacokinetic variability of the mAb and includes the influence of random - that is, not quantifiable or uncontrollable factors. If multiple doses of the antibody are administered, then three hierarchical components of random variability can be defined inter-individual variability inter-occasional variability and residual variability. Inter-individual variability quantifies the unexplained difference of the pharmacokinetic parameters between individuals. If data are available from different administrations to one patient, inter-occasional variability can be estimated as random variation of a pharmacokinetic parameter (for example, CL) between the different administration periods. For mAbs, this was first introduced in sibrotuzumab data analysis. In order to individualize therapy based on concentration measurements, it is a prerequisite that inter-occasional variability (variability within one patient at multiple administrations) is lower than inter-individual variability (variability between patients). Residual variability accounts for model misspecification, errors in documentation of the dosage regimen or blood sampling time points, assay variability, and other sources of error. 

As is implicit from all the above, the measured concentration in plasma is directly linked to the observed effect for these simple mechanistic, pharmacokinetic-dynamic models. Accordingly, these models are called direct-link models since the concentrations in plasma can be used directly in (10.6) and (10.7) for the description of the observed effects. Under the assumptions of the direct-fink model, plasma concentration and effect maxima will occur at the same time, that is, no temporal dissociation between the time courses of concentration and effect is observed. An example of this can be seen in the direct-fink sigmoid Emax model of Racine-Poon et al. [418], which relates the serum concentration of the anti-immunglobulin E antibody CGP 51901, used in patients for the treatment of seasonal allergic rhinitis, with the reduction of free anti-immunglobulin E. 

Immunogenicity is a substantial complication for preclinical safety assessment studies. Antibodies can invalidate the animal model species. Antibody production alone, however, should not necessarily prohibit the conduct of these studies. The effect on pharmacokinetics and pharmcodynamics needs to be measured and evaluated. The potential consequences of the antibodies on endogenous molecules also needs to be evaluated. Secondary effects, such as antibody deposition, should be measured. The lack of ability to predict absolute human immunogenicity does not preclude the use of animals to assess the relative potential for an immune response. 

Goldman DL, Casadevall A, Zuckier LS. Pharmacokinetics and biodistribution of a monoclonal antibody to Cryptococcus neoformans capsular polysaccharide antigen in a rat model of cryptococcal meningitis implications for passive immunotherapy. J Med Vet Mycol 1997 35(4) 271-8. 

The pharmacokinetic evaluation of biopharmaceuticals is generally simplified by the usual metabolism of products to small peptides and to amino acids, and thus classical biotransformation and metabolism studies are rarely necessary. Routine studies to assess mass balance are not useful. However, both single- and multiple-dose toxicokinetic data are essential in safety pharmacology asessments, and these can be complicated by two factors (1) biphasic clearance with a saturable, initial, receptor-dependent clearance phase, which may cause nonlinearity in dose-exposure relationships and doseresponses [14] and (2) antibody production against an antigenic biopharmaceutical that can alter clearance or activity in more chronic repeat-dose safety studies in the preclinical model. 

Pharmacokinetic data were collected as well as pharmacodynamic measurements of platelet aggregation support (ristocetin cofactor activity) and cuticle wound blood flow. An important component of these studies was the suitability of the model. These models were chosen because of the biochemical deficiency of the particular factors and the parallel clinical syndromes. Such in vivo data can help in determining activity and dosing when such a product is first used in human trials. The Refacto molecule was also studied in rats and monkeys to determine its no observed adverse effect level, that was more than 10 times normal circulating levels. The major toxicity observed was the development of antibodies to the molecule that blocked activity and resulted in an acquired hemophilia syndrome. Similar findings were demonstrated when plasma-derived material was injected into monkeys [20]. 

Last, population pharmacokinetics of sibrotuzumab, a humanized monoclonal antibody directed against fibroblast activation protein (FAP), which is expressed in the stromal fibroblasts in >90% of malignant epithelial tumors, were analzyed in patients with advanced or metastatic carcinoma after multiple IV infusions of doses ranging from 5 mg/m to a maximum of 100 mg (78). The PK model consisted of two distribution compartments with parallel first-order and Michaelis-Menten elimination pathways from the central compartment. Body weight was significantly correlated with both central and peripheral distribution volumes, the first-order elimination clearance, and ymax of the Michaelis-Menten pathway. Of interest was the observation that body surface area was inferior to body weight as a covariate in explaining interpatient variability. 

Davda JP, Jain M, Batra SK, Gwilt PR, Robinson DH. A physiologically based pharmacokinetic (PBPK) model to characterize and predict the disposition of monoclonal antibody CC49 and its single chain Fv constructs. Int Immunopharmacol. 2008 8(3) 401-413. 

As discussed earlier, high-affinity anti-drug antibodies produce effects on the pharmacokinetics and pharmacodynamics of drugs in animals and humans. For new therapeutic applications, these effects need to be fully tested in animals before administration to humans. In addition, from a basic science viewpoint, it will be necessary to develop relevant pharmacokinetic and pharmacodynamic models of... 

The relationships between antibody dose, antibody affinity (or catalytic antibody K,.j. and their effects on the drug s pharmacokinetics and pharmacodynamics are poorly understood. For instance, if the drug effect compartment is associated with the pharmacokinetic peripheral compartment, the time needed to reverse drug effects with antibodies would be predicted to be slower than if the effect compartment is associated with the pharmacokinetic central compartment. In addition, it appears that high-affmity antibodies block the metabolism and/or change the metabolic profile of drugs (Owens and Mayersohn 1986 Valentine et al. 1994). These are complex changes that need to be studied in detail, and pharmacokinetic and pharmacodynamic models of these effects need to be developed in animal models before use in humans. 

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