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CPT Pharmacometrics Syst Pharmacol. 2019 Apr 19. doi: 10.1002/psp4.12415. [Epub ahead of print]

Optimal Scheduling of Bevacizumab and Pemetrexed/Cisplatin Dosing in Non-Small Cell Lung Cancer.

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Iowa State University College of Veterinary Medicine, Ames, Iowa, USA.
SMARTc Unit, Centre de Recherche en Cancérologie de Marseille Unité Mixte de Recherche (UMR) Inserm U1068, Aix Marseille University, Marseille, France.
Multidisciplinary Oncology and Therapeutic Innovations Department, Assistance Publique Hôpitaux de Marseille, Marseille, France.
Mayo Clinic, Rochester, Minnesota, USA.
Team Modelisation en Oncologie, Inria Bordeaux Sud-Ouest, Institut de Mathématiques de Bordeaux, Talence, France.


Bevacizumab-pemetrexed/cisplatin (BEV-PEM/CIS) is a first-line therapeutic for advanced nonsquamous non-small cell lung cancer. Bevacizumab potentiates PEM/CIS cytotoxicity by inducing transient tumor vasculature normalization. BEV-PEM/CIS has a narrow therapeutic window. Therefore, it is an attractive target for administration schedule optimization. The present study leverages our previous work on BEV-PEM/CIS pharmacodynamic modeling in non-small cell lung cancer-bearing mice to estimate the optimal gap in the scheduling of sequential BEV-PEM/CIS. We predicted the optimal gap in BEV-PEM/CIS dosing to be 2.0 days in mice and 1.2 days in humans. Our simulations suggest that the efficacy loss in scheduling BEV-PEM/CIS at too great of a gap is much less than the efficacy loss in scheduling BEV-PEM/CIS at too short of a gap.

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