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PK-PD modeling of combination efficacy effect from administration of the MEK inhibitor GDC-0973 and PI3K inhibitor GDC-0941 in A2058 xenografts

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Abstract

Purpose

Mutations and activations of the MEK and PI3K pathways are associated with the development of many cancers. GDC-0973 and GDC-0941 are inhibitors of MEK and PI3K, respectively, currently being evaluated clinically in combination as anti-cancer treatment. The objective of these studies was to characterize the relationship between the plasma concentrations of GDC-0973 and GDC-0941 administered in combination and efficacy in A2058 melanoma xenograft.

Methods

GDC-0973 and GDC-0941 were administered to A2058 tumor-bearing mice daily (QD) or every third day (Q3D) either as single agents or in combination. A semi-mechanistic population anti-cancer model was developed to simultaneously describe the tumor growth following QD/Q3D single-agent and QD combination treatments. The interaction terms ψ included in the model were used to assess whether the combination was additive. Using this model, data from the Q3D combination regimen were simulated and compared with the observed tumor volumes.

Results

The model consisting of saturable tumor growth provided the best fit of the data. The estimates for ψ were not significantly different from 1, suggesting an additive effect of GDC-0973 and GDC-0941 on tumor growth inhibition. The population rate constants associated with tumor growth inhibition for GDC-0973 and GDC-0941 were 0.00102 and 0000651 μM−1 h−1, respectively. Using the model based on single-agent and QD combination efficacy data, simulations adequately described the tumor growth from the Q3D combination regimen.

Conclusions

These findings suggest that, based on minimal data, it is possible to predict the effects of various combinations preclinically and also assess the potential clinical efficacy of combinations using human pharmacokinetic inputs.

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Author information

Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Edna F. Choo & Laurent Salphati

  2. School of Medicine, University of Pennsylvania, Clinical Pharmacology and Therapeutics, Children Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Chee M. Ng

  3. Cancer Signaling and Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Leanne Berry, Marcia Belvin & Mark Merchant

  4. Nonclinical Biostatistics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Nicholas Lewin-Koh

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  1. Edna F. Choo
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  7. Laurent Salphati
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Correspondence to Laurent Salphati.

Electronic supplementary material

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280_2012_1988_MOESM1_ESM.ppt

Representative individual tumor volume–time profiles and model prediction from animals that received a dose of vehicle (A) GDC-0973 6 mg/kg QD (B) GDC-0941 100 mg/kg QD (C) and combination of GDC-0973 6 mg/kg and GDC-0941 10 mg/kg QD (D). Observed tumor volumes (open circles); model-predicted tumor volume (solid line) (PPT 102 kb)

280_2012_1988_MOESM2_ESM.ppt

Representative comparisons of simulated versus. observed results from the xenograft studies. GDC-0973 10 mg/kg and GDC-0941 50 mg/kg Q3D (A). GDC-0973 10 mg/kg and GDC-0941 150 mg/kg Q3D (B); Observed data (solid circle and error bar; mean ± SD; n = 7); mean values of the simulated results (solid line); 5 and 95 % quantile values of simulated results; N = 1000 for the simulated results (dotted line) (PPT 150 kb)

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Choo, E.F., Ng, C.M., Berry, L. et al. PK-PD modeling of combination efficacy effect from administration of the MEK inhibitor GDC-0973 and PI3K inhibitor GDC-0941 in A2058 xenografts. Cancer Chemother Pharmacol 71, 133–143 (2013). https://doi.org/10.1007/s00280-012-1988-6

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