TY  - JOUR
A1  - Gerner, Bettina
A1  - Aghai-Trommeschlaeger, Fatemeh
A1  - Kraus, Sabrina
A1  - Grigoleit, Götz Ulrich
A1  - Zimmermann, Sebastian
A1  - Kurlbaum, Max
A1  - Klinker, Hartwig
A1  - Isberner, Nora
A1  - Scherf-Clavel, Oliver
T1  - A physiologically-based pharmacokinetic model of ruxolitinib and posaconazole to predict CYP3A4-mediated drug–drug interaction frequently observed in graft versus host disease patients
T2  - Pharmaceutics
N2  - Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug–drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim\(^®\) Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (C\(_{max}\)) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes.
KW  - physiologically based pharmacokinetic (PBPK) modeling
KW  - ruxolitinib
KW  - posaconazole
KW  - drug–drug interactions (DDIs)
KW  - graft versus host disease
KW  - cytochrome P450 3A4 (CYP3A4)
KW  - pharmacokinetics
Y1  - 2022
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/29726
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-297261
SN  - 1999-4923
VL  - 14
IS  - 12
ER  -