Simulation of the pharmacokinetics of flibanserin under itraconazole co-mediaction with an integrated physiologically-based pharmacokinetic model
J. Lippert(1), K. Boland(2), S. Willmann(1), E. Hizaler Hoffmann(1), A. Sensse(1), M. Sevestre(1), R. Pyke(3), A. Staab(2)
(1) Bayer Technology Services, Germany; (2) Boehringer Ingelheim Pharma GmbH & Co. KG, Germany; (3) Boehringer Ingelheim Pharma Inc., USA
Objectives: The aim of this analysis was to evaluate the effect of high dose itraconazole (ITZ) 200 mg BID on the exposure of flibanserin and two CYP3A4 related metabolites by physiologically-based pharmacokinetic (PBPK) simulation. For model evaluation, data was available from a drug drug interaction study where flibanserin was given with and without 200 mg ITZ once daily.
Methods: The coupled PBPK model for flibanserin and metabolites was established by use of physicochemical data, demographics, mass balance and plasma concentrations after i.v. and p.o. dosing from an ADME trial. A previously established and validated itraconazole CYP3A4 inhibition model [1] was then integrated. The model was evaluated by simulating the flibanserin plasma concentrations of a previous interaction study, where 200 mg ITZ was given once daily. The model was then applied to predict flibanserin and metabolite plasma concentrations when given with the highest labelled ITZ dose, 200 mg BID.
Results: With the coupled flibanserin-ITZ PBPK model, the predicted geometric mean increase in AUC0-∞ was 2.93-fold for the previous drug interaction study and thus lies within the reported 90% confidence interval for the point estimator of the AUC0-∞ ratio with/without ITZ (2.56 [90% CI: 2.15-3.06]) while the predicted increase in Cmax was 2.20-fold and thereby slightly outside the reported 90% CI of the point estimator for the observed data (1.69 [90% CI: 1.42-2.02]). The simulation of co-administration with 200 mg BID ITZ led to a 3.32-fold and 2.38-fold increase in flibanserin AUC0-∞ and Cmax. The metabolite's AUC0-∞ and Cmax decreased to 27-28% of initial values.
Conclusion: The simulation showed that increasing the dose of ITZ resulted in only a minor additional increase in flibanserin AUC and Cmax. These results confirm the moderate impact of potent CYP3A4 inhibitors on flibanserin.
Reference:
[1] Vossen M, et al.: Dynamically simulating the interaction of midazolam and the CYP3A4 inhibitor ITZ using individual coupled whole-body physiologically-based pharmacokinetic (WB-PBPK) models. Theor Biol Med Model. Mar 26;4:13 (2007)