G. Baneyx (2), P-H. Huang (3), C. Meille (1) and V. Duval (2)
Novartis Pharma AG, Translational Clinical Oncology (1) and Oncology Clinical Pharmacology (2), Basel, Switzerland. (3) Novartis Pharmaceuticals Corporation, Oncology Clinical Pharmacology, East Hanover, New Jersey, USA.
Objectives: Buparlisib is an anticancer drug inhibiting the PI3K pathway [1] and presently in Phase 3 development. Visual inspection of buparlisib plasma PK profiles showed multiple peaks after oral administration in healthy volunteers (HVs) and cancer patients. The objective of this study was to develop a PK model able to describe the observed multiple peaks in healthy volunteers and quantify the contribution of this phenomenon.
Methods: In a first step, plasma concentrations of 60 HVs from 3 Phase 1 studies collected up to 240h after a single oral administration were used to develop a PK model structure including a drug recirculation component. Then based on modeling results, an additional sampling time was added to the design of a fourth Phase 1 study enrolling 16 HVs in order to confirm drug recirculation hypothesis and better characterize this phenomenon. Finally, a pooled analysis was performed with all PK data from these studies. Model parameters were estimated using population approach with Monolix 4.3.2 [2].
Results: A third compartment representing the gallbladder was added to a classical 2 compartment disposition model in order to mimic a potential biliary excretion of buparlisib. The release of buparlisib amount stored in the gallbladder compartment was assumed to occur only at 3 meal times per day and directly in depot compartment. Meal times were estimated at 3, 9 and 21h post dose which is in agreement with theoretical lunch, dinner and breakfast times, respectively. Contribution of biliary excretion to buparlisib PK is suggested to be an important component since the fraction of dose excreted in bile was estimated to 10-30%.
Conclusions: Buparlisib multiple peaks occurring around meal times were well described by the proposed PK model suggesting an entero-hepatic circulation which is in agreement with preclinical results. This model will be applied to PK data in cancer patients obtained after continuous daily dosing.
References:
[1] Cantley LC. Science 2002; 296(5573):1655-1657
[2] Kuhn et al. Computational Statistics and Data Analysis 2005; 49:1020-1038
Reference: PAGE 24 () Abstr 3453 [www.page-meeting.org/?abstract=3453]
Poster: Drug/Disease modeling - Absorption & PBPK