TY  - JOUR
A1  - Fronton, Ludivine
A1  - Pilari, Sabine
A1  - Huisinga, Wilhelm
T1  - Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models
JF  - Journal of pharmacokinetics and pharmacodynamics
N2  - 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.
KW  - mAb disposition
KW  - PBPK
KW  - Extravasation rate-limited tissue model
KW  - Classical compartment model
Y1  - 2014
U6  - https://doi.org/10.1007/s10928-014-9349-1
SN  - 1567-567X
SN  - 1573-8744
VL  - 41
IS  - 2
SP  - 87
EP  - 107
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Fuhrmann, Saskia
A1  - Kloft, Charlotte
A1  - Huisinga, Wilhelm
T1  - Impact of altered endogenous IgG on unspecific mAb clearance
JF  - Journal of pharmacokinetics and pharmacodynamics
N2  - 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.
KW  - mAb disposition
KW  - PBPK
KW  - FcRn salvage mechanism
KW  - Immunodeficient mice models
KW  - Unspecific antibody clearance
Y1  - 2017
U6  - https://doi.org/10.1007/s10928-017-9524-2
SN  - 1567-567X
SN  - 1573-8744
VL  - 44
SP  - 351
EP  - 374
PB  - Springer
CY  - New York
ER  -