Thomas Wendl, Donato Teutonico, Helen E. Hermes, Sabine Pilari, Thomas Eissing
Bayer Technology Services GmbH, Technology Development, Enabling Technologies, Computational Systems Biology, 51368 Leverkusen, Germany
Objectives: Regulatory authorities, e.g. the FDA, explicitly support PBPK model predictions for evaluating drug-drug interactions during drug development. Therefore, predefined PBPK interaction partner models are of great interest. In this study, a PBPK model for Itraconazole (ITZ), i.e. a potent competitive inhibitor of CYP3A4 is developed. Coadministration of ITZ with drugs mainly metabolized by CYP3A4 may result in increased plasma levels of these drugs. Thus, a dynamic whole-body PBPK model including both ITZ and its main metabolite hydroxy-itraconazole (OH-ITZ) was required to accurately predict drug pharmacokinetics under ITZ coadministration.
Methods: A whole-body PBPK model of ITZ and OH-ITZ in humans was established in PK-Sim® [1] using biometric data, physico-chemical and mass balance information about ITZ and OH-ITZ. The established model was adjusted to plasma concentration-time profiles available in literature [2-4] and validated using independent data. The established model was then coupled to a previously established midazolam PBPK model in order to simulate the impact of ITZ coadministration on midazolam pharmacokinetics.
Results: The established model adequately describes published plasma concentration-time profiles for ITZ and OH-ITZ after i.v. and oral administration. Prediction of drug-ITZ-interactions is demonstrated by coupling the ITZ – OH-ITZ PBPK model to the midazolam whole-body PBPK model. Midazolam plasma concentration-time profiles under ITZ coadministration are adequately predicted by the model as competitive inhibition by both ITZ and OH-ITZ is taken into account.
Conclusions: The established ITZ – OH-ITZ whole-body PBPK model can be used to effectively predict the pharmacokinetics of drugs metabolized by CYP3A4 under ITZ 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] Heykants J, Van Peer A, Van de Velde V, Van Rooy P, Meuldermans W, Lavrijsen K, Woestenborghs R, Van Cutsem J and Cauwenbergh G (1989). The Clinical Pharmacokinetics of Itraconazole: An Overview
[3] Mouton JW, van Peer A, de Beule K, Van Vliet A, Donnelly JP, Soons PA (2006). Pharmacokinetics of Itraconazole and Hydroxyitraconazole in Healthy Subjects after Single and Multiple Doses of a Novel Formulation
[4] Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V (1993). Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers.
Reference: PAGE 24 () Abstr 3517 [www.page-meeting.org/?abstract=3517]
Poster: Methodology - Other topics