@article{FrontonPilariHuisinga2014,
  author    = {Fronton, Ludivine and Pilari, Sabine and Huisinga, Wilhelm},
  title     = {Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models},
  series = {Journal of pharmacokinetics and pharmacodynamics},
  volume    = {41},
  journal   = {Journal of pharmacokinetics and pharmacodynamics},
  number    = {2},
  publisher = {Springer},
  address   = {New York},
  issn      = {1567-567X},
  doi       = {10.1007/s10928-014-9349-1},
  pages     = {87 -- 107},
  year      = {2014},
  abstract  = {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.},
  language  = {en}
}
@phdthesis{Fronton2014,
  author    = {Fronton, Ludivine},
  title     = {Modeling approaches to characterize the disposition of monoclonal antibodies},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-76537},
  school      = {Universit{\"a}t Potsdam},
  pages     = {xxi, 133},
  year      = {2014},
  abstract  = {Monoclonal antibodies (mAbs) are engineered immunoglobulins G (IgG) used for more than 20 years as targeted therapy in oncology, infectious diseases and (auto-)immune disorders. Their protein nature greatly influences their pharmacokinetics (PK), presenting typical linear and non-linear behaviors. While it is common to use empirical modeling to analyze clinical PK data of mAbs, there is neither clear consensus nor guidance to, on one hand, select the structure of classical compartment models and on the other hand, interpret mechanistically PK parameters. The mechanistic knowledge present in physiologically-based PK (PBPK) models is likely to support rational classical model selection and thus, a methodology to link empirical and PBPK models is desirable. However, published PBPK models for mAbs are quite diverse in respect to the physiology of distribution spaces and the parameterization of the non-specific elimination involving the neonatal Fc receptor (FcRn) and endogenous IgG (IgGendo). The remarkable discrepancy between the simplicity of biodistribution data and the complexity of published PBPK models translates in parameter identifiability issues. In this thesis, we address this problem with a simplified PBPK model—derived from a hierarchy of more detailed PBPK models and based on simplifications of tissue distribution model. With the novel tissue model, we are breaking new grounds in mechanistic modeling of mAbs disposition: We demonstrate that binding to FcRn is indeed linear and that it is not possible to infer which tissues are involved in the unspecific elimination of wild-type mAbs. We also provide a new approach to predict tissue partition coefficients based on mechanistic insights: We directly link tissue partition coefficients (Ktis) to data-driven and species-independent published antibody biodistribution coefficients (ABCtis) and thus, we ensure the extrapolation from pre-clinical species to human with the simplified PBPK model. We further extend the simplified PBPK model to account for a target, relevant to characterize the non-linear clearance due to mAb-target interaction. With model reduction techniques, we reduce the dimensionality of the simplified PBPK model to design 2-compartment models, thus guiding classical model development with physiological and mechanistic interpretation of the PK parameters. We finally derive a new scaling approach for anatomical and physiological parameters in PBPK models that translates the inter-individual variability into the design of mechanistic covariate models with direct link to classical compartment models, specially useful for PK population analysis during clinical development.},
  language  = {en}
}
@article{FuhrmannKloftHuisinga2017,
  author    = {Fuhrmann, Saskia and Kloft, Charlotte and Huisinga, Wilhelm},
  title     = {Impact of altered endogenous IgG on unspecific mAb clearance},
  series = {Journal of pharmacokinetics and pharmacodynamics},
  volume    = {44},
  journal   = {Journal of pharmacokinetics and pharmacodynamics},
  publisher = {Springer},
  address   = {New York},
  issn      = {1567-567X},
  doi       = {10.1007/s10928-017-9524-2},
  pages     = {351 -- 374},
  year      = {2017},
  abstract  = {Immunodeficient mice are crucial models to evaluate the efficacy of monoclonal antibodies (mAbs). When studying mAb pharmacokinetics (PK), protection from elimination by binding to the neonatal Fc receptor (FcRn) is known to be a major process influencing the unspecific clearance of endogenous and therapeutic IgG. The concentration of endogenous IgG in immunodeficient mice, however is reduced, and this effect on the FcRn protection mechanism and subsequently on unspecific mAb clearance is unknown, yet of great importance for the interpretation of mAb PK data. We used a PBPK modelling approach to elucidate the influence of altered endogenous IgG concentrations on unspecific mAb clearance. To this end, we used PK data in immunodeficient mice, i.e. nude and severe combined immunodeficiency mice. To avoid impact of target-mediated clearance processes, we focussed on mAbs without affinity to a target antigen in these mice. In addition, intravenous immunoglobulin (IVIG) data of immunocompetent mice was used to study the impact of increased total IgG concentrations on unspecific therapeutic antibody clearance. The unspecific clearance is linear, whenever therapeutic IgG concentrations, i.e. mAb and IVIG concentrations are lower than FcRn; it can be non-linear if therapeutic IgG concentrations are larger than FcRn and endogenous IgG concentrations (e.g., under IVIG therapy). Unspecific mAb clearance of immunodeficient mice is effectively linear (under mAb doses as typically used in human). Studying the impact of reduced endogenous IgG concentrations on unspecific mAb clearance is of great relevance for the extrapolation to clinical species, e.g., when predicting mAb PK in immunosuppressed cancer patients.},
  language  = {en}
}