Objective
The recent availability of effective GLP-1R agonist (GLP-1RA) based treatments of obesity has provided great benefit to patients. Understanding the balance between body weight (BW) loss and nausea is paramount in predicting the effectiveness of GLP-1RA based medications, as is potential impact of delivery method. Quantitative systems pharmacology (QSP) modeling can aid in predicting both efficacy and adverse events of compounds, in particular assessing sources of similarities and differences between treatment protocols.
Methods
OBESITYsym, a QSP model, was developed to enable simultaneous prediction of BW and nausea due to pharmacologic treatments. This mechanistic mathematical model includes components of energy balance: caloric intake, energy expenditure, body composition, adaptation, as described by Hall 2010. It also includes a novel submodel of nausea sensitivity and tolerance, a pharmacology submodel linking compound exposure, energy balance, and nausea with PK models and compound potency. Calibration and validation are described in Siler 2024, including development for the subcutaneous (sc) semaglutide (sema) response. An oral sema representation was built through incorporation of a literature oral PK model and PD based on the calibrated sc response. Simulated dosing included uptitration in accordance with protocols.
Conclusion
- OBESITYsym can be used to evaluate the efficacy and nausea potential for novel treatments, including oral GLP-1RA and compounds that utilize additional mechanisms to adjust energy balance
- PD/MoA for sc and oral sema was the same in all simulations, indicating that regardless of delivery route similar results can be achieved if similar levels of compound can be reached in the systemic circulation.
By Zackary R. Kenz, Celeste Vallejo, Scott Q. Siler
Fifteenth American Conference of Pharmacometrics (ACoP15), November 10-13, 2024, Phoenix, Arizona