Abstract B108: Assessment of the hyperglycemia profile of NVP-BYL719, a selective inhibitor of the class Ia PI3K isoform alpha using real-time continuous glucose monitoring via radio-telemetry in rats
Authors: SCHNELL CHRISTIAN R. , Ferrat Thomas , Fritsch Christine , Jensen Michael R. 
Published: May 2016

The gene encoding for the catalytic subunit of the phosphatidylinositol-3-kinase (PI3K), p110a (PIK3CA) is the most frequently mutated kinase in cancer. This discovery triggered the development of small molecule anti-PI3K inhibitors, such as NVP-BYL719. However, the PI3K / Akt signaling pathway plays not only an important role in promoting cell growth, proliferation and survival but also in regulating glucose homeostasis by directly mediating insulin-stimulated glucose uptake into insulin sensitive tissues (adipocytes and muscles). Hyperglycemia has been reported to be one of the most frequent adverse events in clinical trials for PI3K inhibitors. Therefore, NVP-BYL719, a selective inhibitor of the class Ia PI3K isoform-alpha, can impair glucose metabolism. However until now, continuous glucose monitoring options have been very limited in biomedical research. Investigators have used periodic sampling of blood glucose using a glucometer and test strips approach to provide a snap-shot assessment of the effect of PI3K inhibitors to glucose metabolism. Thus, ‘around the clock’ real-time measurements of blood glucose in unstressed, freely moving animals are needed to better assess pharmacokinetic (PK: drug levels in plasma) and pharmacodynamics (PD: glucose levels in blood) relationship in pre-clinical models. The present study evaluates the use of a new radio-telemetry device (HD-XG, Data Sciences International) incorporating an implantable glucose sensor for chronic continuous (every minute) glucose measurements in the arterial blood of brown Norway (BN) rats. We evaluate the day-and-night profile of glucose blood levels as well as the PK/PD relationship of NVP-BYL719 following daily oral treatment at efficacious anti-tumor doses.

In conclusion, our data suggest that the glucose telemetry implant offers a novel solution to obtain continuous, real-time, blood glucose measurements in rats while reducing animal stress and measurement variability commonly associated with glucose test-strips. For the first time, a continuous 24h data profile on blood glucose for NVP-BYL719 could be obtained. This profile is reproducible over time and a clear PK/PD relationship could be demonstrated. NVP-BYL719 treatment in BN rats induced a transient glucose level increase suggestive of glucose metabolism impairment consistent with insulin resistance/insensitivity. It can be emphasized that the use of such a novel technology will enable advances in the understanding of the physiology of glucose metabolism regulation following PI3K inhibition possibly leading to improved therapies in the clinic.

Citation Format: CHRISTIAN R. SCHNELL, Thomas Ferrat, Christine Fritsch, Michael R. Jensen. Assessment of the hyperglycemia profile of NVP-BYL719, a selective inhibitor of the class Ia PI3K isoform alpha using real-time continuous glucose monitoring via radio-telemetry in rats. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B108.