Implications of plasma protein binding for pharmacokinetics and pharmacodynamics of the γ-secretase inhibitor RO4929097.

ABSTRACT:

Purpose

Understanding of plasma protein binding will provide mechanistic insights into drug interactions or unusual pharmacokinetic properties. This study investigated RO4929097 binding in plasma and its implications for the pharmacokinetics and pharmacodynamics of this compound.

Experimental design

RO4929097 binding to plasma proteins was determined using a validated equilibrium dialysis method. Pharmacokinetics of total and unbound RO4929097 was evaluated in eight patients with breast cancer receiving RO4929097 alone and in combination with the Hedgehog inhibitor GDC-0449. The impact of protein binding on RO4929097 pharmacodynamics was assessed using an in vitro Notch cellular assay.

Results

RO4929097 was extensively bound in human plasma, with the total binding con

SUBMITTER: Wu J 

PROVIDER: S-EPMC3856649 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature