Modelling time varying kinetics using time dependent feedback control on clearance

PDF of poster

Objectives: A population pharmacokinetic model for a new compound under development in psychiatry was built based on data from three Phase I studies. The compound exhibited time dependence pharmacokinetics showing less than expected accumulation at steady state. The objective of the analysis was to characterize the time dependency in the pharmacokinetics of the compound.

Methods: Plasma concentration profiles from 71 healthy volunteers were included in the analysis. Subjects were dose for were dosed for 28 days and plasma concentration time profiles were obtained on days 1, 14 and 28. Data from four different dose levels were available. The analysis was conducted using NONMEM. A mechanistic model implementing a time dependent feedback control on clearance was developed.

Results: A two compartment model in which clearance was assumed to be affected by the amount of enzyme in a hypothetical compartment was used to characterize the time dependency. The change of enzyme over time was characterized by a turnover process in which the compound was able to inhibit the elimination of the enzyme.

Conclusion: The proposed model was able to successfully capture the time dependence in the pharmacokinetics of the compound. The model will serve as a based model in the population PK analysis of the Phase II trials.