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

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Jianmei WuJing Li

Abstract

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. 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. RO4929097 was extensively bound in human plasma, with the total binding constant of 1.0 × 10(6) and 1.8 × 10(4) L/mol for α1-acid glycoprotein (AAG) and albumin, respectively. GDC-0449 competitively inhibited RO4929097 binding to AAG. In patients, RO4929097 fraction unbound (Fu) exhibited large intra- and interindividual variability; GDC-0449 increased RO4929097 Fu by an average of 3.7-fold. Concomitant GDC-0449 significantly decreased total (but not unbound) RO4929097 exposure. RO4929097 Fu was strongly correlated with the total drug exposure. Binding to AAG abrogated RO49...Continue Reading

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Citations

Aug 1, 2014·Journal of Medicinal Chemistry·Kin Sing Stephen LeeBruce D Hammock
Sep 6, 2015·Cancer Letters·Xun YuanKongming Wu
Jul 17, 2015·Cancer Cell International·Khalid O AlfaroukCyril Rauch
Mar 22, 2019·International Journal of Cancer. Journal International Du Cancer·Han LiYanna Zhang
Sep 16, 2017·Current Opinion in Oncology·Marzia Locatelli, Giuseppe Curigliano

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