French Roadmap for complex Systems 2008-2009

This second issue of the French Complex Systems Roadmap is the outcome of the Entretiens de Cargese 2008, an interdisciplinary brainstorming session organized over one week in 2008, jointly by RNSC, ISC-PIF and IXXI. It capitalizes on the first roadmap and gathers contributions of more than 70 scientists from major French institutions. The aim of this roadmap is to foster the coordination of the complex systems community on focused topics and questions, as well as to present contributions and challenges in the complex systems sciences and complexity science to the public, political and industrial spheres

Simultaneous physiologically-based pharmacokinetic (PBPK) modeling of parent and active metabolites to investigate complex CYP3A4 drug-drug interaction potential: a case example of midostaurin

Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (ASM). It is extensively metabolized by cytochrome P450 (CYP) 3A4 to form 2 major active metabolites, CGP52421 and CGP62221. In vitro and clinical drug-drug interaction (DDI) studies indicated that midostaurin and its metabolites are substrates, reversible and time-dependent inhibitors, and inducers of CYP3A4. A simultaneous pharmacokinetic model of parent and active metabolites was initially developed by incorporating data from in vitro, preclinical, and clinical pharmacokinetic studies in healthy volunteers and in patients with AML or ASM. The model reasonably predicted changes in midostaurin exposure after single-dose administration with ketoconazole (5.8-fold predicted increase vs 6.1-fold observed) and rifampicin (90% predicted reduction vs 94% observed), as well as changes in midazolam exposure (1.0 predicted ratio vs 1.2 observed) with midostaurin after daily dosing for four days. The qualified model was then applied to predict the DDI effect with other CYP3A4 inhibitors/inducers as well as DDI potential with midazolam under steady-state conditions. The simulated midazolam AUC ratio of 0.54 and the accompanying 1.9-fold increase in the CYP3A4 activity biomarker, 4β-hydroxycholesterol, indicated a weak-to-moderate CYP3A4 induction by midostaurin and its metabolites at steady-state in ASM patients. In conclusion, a simultaneous parent and metabolite modeling approach allowed predictions under steady-state conditions that were not possible to achieve in healthy subjects. Furthermore, endogenous biomarker data enabled evaluation of the net effect of midostaurin and its metabolites on CYP3A4 activity at steady-state and increased confidence in DDI predictions

Effect of food, type of food, and time of food intake on deferasirox bioavailability: recommendations for an optimal deferasirox administration regimen.

Deferasirox (ICL670) is representative of a new class of tridentate iron chelators, formulated as tablets for dispersion. Deferasirox has exhibited high potency and a clinically manageable safety profile in preclinical models and in an extensive clinical program. The effect of food and time of food intake on the pharmacokinetics of deferasirox was investigated in healthy volunteers and patients with transfusional hemosiderosis. The bioequivalence of a single oral dose of deferasirox (20 mg/kg) was assessed following administration either before a high-fat or standard breakfast or concurrent with a standard breakfast in comparison with fasted conditions in healthy volunteers. The bioavailability of deferasirox was determined following a single oral dose (20 mg/kg) under fed and fasted conditions in patients. These data show that the type of food, caloric content, and fat content of the meal influence the bioavailability of deferasirox when consumed concomitantly. In contrast, this is not the case when deferasirox is administered at least 30 minutes before a meal. In conclusion, it is recommended that deferasirox be administered at least 30 minutes prior to meals. When this is not feasible, deferasirox should be administered consistently at the same time before meals to limit the sources of variability that affect absorption