Abstract

Objective: Assuming a linear one-compartment model for the pharmacokinetics (PK) with and without dose-dependent saturable bioavailability, and a direct inhibitory Emax model for bio-marker effect (PD), develop an interactive PK/PD response simulation tool to guide dose selection for a first-in-human study of an orally administered medication. The tool will simulate various scenarios of target plasma concentration and PD time profiles with and without consideration of discrete dose strength constraints.

Methods: Predicted human PK parameters allometrically scaled from an animal study and concentration required to achieve 50% suppression (IC50) from an in vitro experiment of the bio-marker were provided. Berkeley Madonna® was selected to implement the coding to allow use of interactive sliders for parameter values (PK, absorption type, and IC50) and ‘batch run’ mode to cycle through suppression values of IC10 to IC90. Equations were derived to calculate the exact dose needed to achieve steady-state trough, maximum, and average concentrations equivalent to ICx (x = 10 to 90% suppression). For each exact dose the following information was calculated: discrete dose to be administered, concentration/effect-time profiles, area under the curve (AUC) for concentration/effect-time, average effect, drug holiday (time effect is < 20% suppressed), and doses expected to achieve drug holidays of specific length.

Results: The interactive simulation tool allowed the drug development team to explore numerous scenarios allowing for uncertainty in predicted potency and PK, as well as various scenarios of target PK/PD profiles and dose-strength constraints, in a matter of minutes. The tool also allowed the team to quickly explore new scenarios that were not predefined.

Seventh American Conference on Pharmacometrics (ACoP), October 23-26, 2016, Bellevue, Washington

By Luann Phillips, E Raddad