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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Pharmacodynamics of 2-{4-[(1E)-1-(Hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl}ethan-1-ol (GDC-0879), a Potent and Selective B-Raf Kinase Inhibitor: Understanding Relationships between Systemic Concentrations, Phosphorylated Mitogen-Activated Protein Kinase Kinase 1 Inhibition, and Efficacy

Departments of Drug Metabolism and Pharmacokinetics (H.W., E.F.C.), Translational Oncology (K.P.H., L.J.M., L.W.), and Cell Signaling Pathways (M.B., S.H.), Genentech Inc., South San Francisco, California

The Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase signaling pathway is involved in cellular responses relevant to tumorigenesis, including cell proliferation, invasion, survival, and angiogenesis. 2-{4-[(1E)-1-(Hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl}ethan-1-ol (GDC-0879) is a novel, potent, and selective B-Raf inhibitor. The objective of this study was to characterize the relationship between GDC-0879 plasma concentrations and tumor growth inhibition in A375 melanoma and Colo205 colon cancer xenografts and to understand the pharmacodynamic (PD) marker response requirements [phosphorylated (p)MEK1 inhibition] associated with tumor growth inhibition in A375 xenografts. Estimates of GDC-0879 plasma concentrations required for tumor stasis obtained from fitting tumor data to indirect response models were comparable, at 4.48 and 3.27 µM for A375 and Colo205 xenografts, respectively. This was consistent with comparable in vitro potency of GDC-0879 in both cell lines. The relationship between GDC-0879 plasma concentrations and pMEK1 inhibition in the tumor was characterized in A375 xenografts after oral doses of 35, 50, and 100 mg/kg. Fitting pMEK1 inhibition to an indirect response model provided an IC₅₀ estimate of 3.06 µM. pMEK1 inhibition was further linked to A375 tumor volume data from nine different GDC-0879 dosing regimens using an integrated pharmacokinetic-PD model. A simulated PD marker response curve plot of K (rate constant describing tumor growth inhibition) versus pMEK1 inhibition generated using pharmacodynamic parameters estimated from this model, showed a steep pMEK1 inhibition-response curve consistent with an estimated Hill coefficient of 8. A threshold of >40% pMEK1 inhibition is required for tumor growth inhibition, and a minimum of 60% pMEK1 inhibition is required for stasis in A375 xenografts treated with GDC-0879.

Address correspondence to: Dr. Edna F. Choo, Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, MS 412a, South San Francisco, CA 94080. E-mail: choo.edna{at}gene.com