Increase in glucose as pharmacodynamic biomarker following administration of the PI3K/mTOR inhibitor LY3023414: quantitative description using modelling.
Elizabeth Labell (1), Volker Wacheck (1), Darlene Satonin (1), Xuejing Aimee Wang (1), J.T Diener (1), Aaron Fink (1), Sophie Callies (1)
(1) Eli Lilly and Company, Indianapolis, IND, USA
Introduction: The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is disregulated in many malignant diseases. LY3023414 (LY) is an oral ATP competitive inhibitor of the class I PI3K isoforms, mTOR and DNA-PK currently investigated in patients with advanced solid tumors. PI3K signalling has a major role in insulin homeostasis, mainly via the activation of the Akt/PKB and the PKCζ cascades [1].
Objectives: To quantitatively describe the possible impact of LY3023414 on glucose homeostasis through modelling.
Methods: LY pharmacokinetics (PK), glucose (GL) and Cpeptide (Cpep) data under fasting condition (predose and post LY administration – up to 4 h) from first in man dose escalation study were analysed using non-linear mixed effect modelling (implemented in NONMEM (version VII)). Data: 1192 LY PK N=89 patients, 718 GL N=87, 503 Cpep on N=43.
Results: A two compartment model with first order absorption rate describes LY PK profile (mean values: Clearance 91.1 L/h, volumes, Vc and Vp, 133 and 81.9 L, distribution clearance 5.46 L/h and absorption rate 0.877 h-1). Graphical evaluation indicates LY leads to dose dependent increase in GL (hysteresis loop). Hence, LY impact on GL is described by an indirect response model with a sigmoidal EMAX relationship linking LY to GL input rate (output rate of GL (KeG) 0.788 h-1, baseline GL 102 mg/dL, baseline input rate in GL (KAG) equal to baseline GL times KeG, EmaxG 0.991, LY50 852 ng/mL, hill coefficient 1.5). A similar model describes the effect of GL on Cpep (output rate (KeC) 16.1 h-1, baseline Cpep 824 pMol, baseline input rate (KAC) equal to baseline Cpep times KeC, EmaxC 2.65, GL50 129 mg/dL, hill coefficient 8.8).
The model predicts the maximum increase in GL, 1.2 fold (1.13-1.25 90% CI) following 200 mg, at approximately 3 h post dose followed by a return to baseline GL value by approximately 8h (dosing interval of 12 h). This effect is lower than the reported maximum increase in GL (approximately 1.5 fold) following standard meal [2].
Conclusions: In line with the mechanism of action of LY of inhibiting the PI3K/mTOR pathway, LY do lead to mild and temporary increase in GL. The model developed will help to bring these data in perspective of the literature historical information of the daily variation in GL due to meal consumption. We plan to further develop this model in perspective of the long term assessment of GL homeostasis, HbA1c.
References:
[1] https://www.cellsignal.com/contents/science-pathway-research-cellular-metabolism/insulin-receptor-signaling-pathway/pathways-irs
[2] Freckmann G, Hagenlocher S, Baumstark A, Jendrike N, Gillen R.C, Rössner K, Haug C. Continuous Glucose Profiles in Healthy Subjects under Everyday Life Conditions and after Different Meals. J Diabetes Sci Technol (2007) 1(5) 695-703
