Veronika Voronova1, Victor Sokolov1, Binbing Yu2, Holly Kimko3, Jing Li4, Marcella Petrone5, Gabriel Helmlinger3, Kirill Peskov1, 6, Rosalin Arends3
1 – M&S Decisions LLC, Moscow, Russia 2 – Oncology Biometrics, Oncology R&D, AstraZeneca, Gaithersburg, USA 3 – Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, USA 4 – Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, South San Francisco, USA 5 – Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK 6 – Computational Oncology group, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with nausea as the most common treatment-related adverse event [1]. Over time tolerance develops to nausea and therefore dose titration can be an effective approach to mitigate nausea [2]. To identify the best titration schedule within the constraints of a particular clinical study, mathematical modeling can serve as a valuable tool. The current study is aimed to quantify the relationship between GLP-1 receptor occupancy and change over time in nausea incidence during treatment with various GLP-1 RAs and understand the differences in nausea dynamics among various GLP-1 RAs.
Methods: Model development and evaluation were performed based on aggregated study-level data from 17 randomized clinical trials in healthy subjects and patients with T2DM receiving placebo, GLP-1 RAs (exenatide immediate or extended release (IR, ER) formulations, oral or subcutaneous semaglutide, liraglutide) or dual GLP-1-glucagon RAs (cotadutide).
The model consists of a system of ordinary differential equations reflecting change in plasma drug concentration, corresponding GLP-1 receptor occupancy and nausea incidence over time. Emerging tolerance was captured by a time-dependent Emax equation with an ET50 parameter (time to achieve 50% of maximum nausea incidence decrease). PK parameters were taken from the literature or estimated based on publicly available study-level PK data. Pharmacodynamic (PD) parameters, including Kd and ET50 for each compound, were estimated with study-level nausea incidence data.
The modeling was performed in R software (version 3.5.1) using the mrgsolve (version 0.8.12) package.
Results: Model diagnostics were adequate although the observed nausea incidence data were very variable for each drug. The estimation of PD parameters resulted in significantly different adaptation rate (reflected by ET50) estimates for the different GLP-1 RAs. The estimated ET50 was the smallest for exenatide extended release (78 hrs), followed by cotadutide (290 hrs), liraglutide (380 hrs), exenatide IR (2270 hs), subcutaneous semaglutide (4793 hrs) and oral semaglutide (10294 hrs).
Various titration schemes were simulated for cotadutide, starting with daily administration of 50 or 100 ug dose and subsequent weekly or bi-weekly increase in dose with an increment of 50 to 100 ug until the maximum dose level of 600 ug. The starting dose was found to have a significant impact on maximal nausea incidence (15% and 20% of patients for 50 and 100 ug, respectively), while the titration schedule effectively reduced nausea incidence during the first 2-3 weeks of treatment.
Conclusions: We successfully developed a model to predict nausea incidence over time for six GLP-1 RA programs. The rate of adaptation to nausea was associated with amplitude and variability of PK oscillations. For compounds with higher initial nausea incidence but faster adaptation, the titration strategy is especially important compared to the compounds with lower rate of adaptation.
References:
[1] Bettge K et al. Occurrence of nausea, vomiting and diarrhea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: A systematic analysis of published clinical trials. Diabetes Obes Metab. 2017;19(3):336–347.
[2] Aroda VR, Ratner R. The safety and tolerability of GLP-1 receptor agonists in the treatment of type 2 diabetes: a review. Diabetes Metab Res Rev. 2011;27(6):528–542.
Reference: PAGE () Abstr 9330 [www.page-meeting.org/?abstract=9330]
Poster: Oral: Drug/Disease Modelling