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  - Pilari, Sabine
A1  - Preusse, Cornelia
A1  - Huisinga, Wilhelm
T1  - Gestational influences on the pharmacokinetics of gestagenic drugs a combined in silico, in vitro and in vivo analysis
JF  - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, EUFEPS
N2  - During preclinical development of a gestagenic drug, a significant increase of the total plasma concentration was observed after multiple dosing in pregnant rabbits, but not in (non-pregnant) rats or monkeys. We used a PBPK modeling approach in combination with in vitro and in vivo data to address the question to what extent the pharmacologically active free drug concentration is affected by pregnancy induced processes. In human, a significant increase in sex hormone binding globulin (SHBG), and an induction of hepatic CYP3A4 as well as plasma esterases is observed during pregnancy. We find that the observed increase in total plasma trough levels in rabbits can be explained as a combined result of (i) drug accumulation due to multiple dosing, (ii) increase of the binding protein SHBG, and (iii) clearance induction. For human, we predict that free drug concentrations in plasma would not increase during pregnancy above the steady state trough level for non-pregnant women.
KW  - PBPK
KW  - Pregnancy
KW  - Gestagenic drug
KW  - Protein binding
KW  - SHBG
KW  - Clearance induction
Y1  - 2011
U6  - https://doi.org/10.1016/j.ejps.2010.12.003
SN  - 0928-0987
VL  - 42
IS  - 4
SP  - 318
EP  - 331
PB  - Elsevier
CY  - Amsterdam
ER  -