ArticleClinical cancer research : an official journal of the American Association for Cancer Research2012
Implications of plasma protein binding for pharmacokinetics and pharmacodynamics of the γ-secretase inhibitor RO4929097.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
- A Phase Ib/II Randomized Study of RO4929097, a Gamma-Secretase or Notch Inhibitor with or without Vismodegib, a Hedgehog Inhibitor, in Advanced Sarcoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Trial
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- Membrane-targeted schiff base derivatives overcome MRSA resistance through phosphatidylglycerol binding and ROS-mediated killing.Frontiers in chemistry · 2026Article
- One-step Immobilization of Human α-1-acid Glycoprotein on Magnetic Beads: A Rapid Method for Small Molecule hAGP Binding Study.The AAPS journal · 2025Article
- Deriving protein binding-corrected chemical concentrations for in vitro testing.Clinical and translational science · 2023Article
- Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer.Molecular cancer · 2023Review
- Addressing the Accuracy of Plasma Protein Binding Measurement for Highly Bound Compounds Using the Dilution Method.The AAPS journal · 2022Article
- Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy.Science advances · 2022Article
- A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC).Clinical breast cancer · 2022Article
- Consideration of the Unbound Drug Concentration in Enzyme Kinetics.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway.International journal of cancer · 2019Article
- Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp.Cancer cell international · 2015Article
- Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy.Journal of medicinal chemistry · 2014Article
- A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).Investigational new drugs · 2014Article
- A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503).British journal of cancer · 2013Article
- Gamma secretase inhibitors of Notch signaling.OncoTargets and therapy · 2013Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
purposeUnderstanding 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
designRO4929097 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.
resultsRO4929097 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 RO4929097 in vitro Notch-inhibitory activity.
conclusionsRO4929097 is highly bound in human plasma with high affinity to AAG. Changes in plasma protein binding caused by concomitant drug (e.g., GDC-0449) or disease states (e.g., ↑AAG level in cancer) can alter total (but not unbound) RO4929097 exposure. Unbound RO4929097 is pharmacologically active. Monitoring of unbound RO4929097 plasma concentration is recommended to avoid misleading conclusions on the basis of the total drug levels.
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