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  -