Thomas Wendl, Stefan Willmann
Bayer Technology Services GmbH, Technology Development, Enabling Technologies, Computational Systems Biology, 51368 Leverkusen, Germany
Objectives: Ketoconazole (KTZ) is a potent inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme system. As coadministration of KTZ with drugs mainly metabolized by CYP3A4 may lead to increased plasma levels of these drugs, a dynamic whole-body physiologically-based pharmacokinetic (WB-PBPK) model of KTZ is essential to accurately predict drug pharmacokinetics (PK) under KTZ coadministration. In this study, a ready to use WB-PBPK Model for KTZ in different species is developed.
Methods: A WB-PBPK model of KTZ for rats, dogs and humans was established in PK-Sim® and MoBi® [1] using biometrical data, physico-chemical and mass balance information about KTZ. The established model was adjusted to plasma concentration-time profiles available in literature [2-4] and validated using independent data.
Results: The established models describe the plasma concentration-time profiles of KTZ with good accuracy. The performance of predicting drug-KTZ-interactions is demonstrated by linking the KTZ model to a previously established midazolam WB-PBPK model. Midazolam plasma concentration-time profiles under KTZ coadministration are adequately predicted by the model.
Conclusions: The established KTZ WB-PBPK model can be used to predict the PK of drugs undergoing CYP3A4 metabolization under KTZ coadministration.
References:
[1] Eissing T, Kuepfer L, Becker C, Block M, Coboeken K, Gaub T, Goerlitz L, Jaeger J, Loosen R, Ludewig B, Meyer M, Niederalt C, Sevestre M, Siegmund H, Solodenko J, Thelen K, Telle U, Weiss W, Wendl T, Willmann S and Lippert J (2011). A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks.
[2] Remmel RP, Amoh K, Abdel-Monem MM. (1987). The disposition and pharmacokinetics of ketoconazole in the rat.
[3] Baxter JG, Brass C, Schentag JJ, Slaughter RL (1986). Pharmacokinetics of ketoconazole administered intravenously to dogs and orally as tablet and solution to humans and dogs.
[4] Huang YC, Colaizzi JL, Bierman RH, Woestenborghs R, Heykants J (1986). Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers.
Reference: PAGE 21 () Abstr 2508 [www.page-meeting.org/?abstract=2508]
Poster: Absorption and Physiology-Based PK