I.Paule (1), S.Dumitras (2), R.Woessner (2), S.Ganesan (2), E.Pigeolet (1)
(1) Modeling & Simulation, Novartis Pharma AG, Basel, Switzerland. (2) DMPK, Novartis Institutes of BioMedical Research, Basel, Switzerland.
Objectives: The objective of this analysis was to understand the modified (extended) release formulation PK characteristics of an experimental drug, the extent and sources of its variability in healthy volunteers.
Methods: The population pharmacokinetic analysis was performed using MONOLIX 4.1.3 based on plasma samples from three studies with oral administration (n=65, n=29, n=39) and one study with i.v. administration (n=15) in healthy volunteers. The studies had rich sampling, single and multiple dosing in an almost 10-fold range of doses, were done in several ethnicities, in fasted and fed conditions (different types and timings of meals). The candidate covariates were body weight, BMI, race, sex, food (with different types and timings relative to dosing). Dose-dependencies were also investigated. To best characterize complex patterns in absorption, a transit compartment model was used.
Results:The final model had two disposition compartments, transit compartments for absorption and linear elimination. There were no dose-dependencies in disposition, but some differences between races. Concomitant high-fat high-calorie food had a strong effect on absorption (increase in F, delay of Tmax), with differences between races. Moreover, absorption showed some dose-dependency in fasted conditions.
Conclusions: The present population analysis identified the structural model and most influential factors of the experimental drug’s PK profiles in healthy volunteers. The model will be subsequently updated with patients’ data, where the effects of smoking, age, elimination organ functions can be assessed.
Reference: PAGE 22 () Abstr 2768 [www.page-meeting.org/?abstract=2768]
Poster: Absorption and Physiology-Based PK