Neelima Patnaikuni 1, Tonpha Luklem 1, Advaith Kannan 1, Atchuta Srinivas Duddu 1, BC Narmada 1, Kannan Thiagarajan 1, Rukmini Kumar 1
1 Vantage Research Inc (Lewes, USA)
Introduction & objectives:
Glucagon-like-peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Peptide (GIP) are peptides secreted primarily by intestinal mucosal cells in response to meal intake and glucose levels. GLP-1 and dual GLP-1/GIP receptor agonists (GLP-1RA and dual GLP-1/GIPRA) mimic action of endogenous GLP-1 and GIP activating GLP-1R and GIPR respectively, enhancing insulin secretion, inhibiting glucagon release, delaying gastric emptying and reducing food intake through satiety/appetite suppression. Despite their potential efficacy, gastrointestinal tract (GI)-related adverse events, especially nausea, is a key safety concern leading to poor adherence and early discontinuation from treatment. This warrants a deep understanding of their mechanism of action and correlation of efficacy to GI adverse events. Several mono GLP-1RA (Semaglutide), and dual GLP1/GIPRA (Tirzepatide) have been approved for treating Type 2 Diabetes Mellitus (T2DM) and subsequently for chronic weight management in adults. Mechanistic models help in deriving insights that can inform dose optimization and design of dosing regimens that improve therapeutic window, which is crucial in more effective long-term weight management therapies. The objectives for the present work are as follows.
1. Develop a multiscale QSP model integrating drug’s pharmacokinetics (PK), mechanistic energy balance (PD), and a hazard-based nausea module to capture efficacy and safety of semaglutide and tirzepatide in non-diabetic obese patients.
2. Estimate the additional weight loss in tirzepatide despite similar reduction in energy intake as semaglutide.
Methods:
We have utilized the published work of (1) that demonstrates short and long-term effects of caloric intake on body weight, and developed a hazard-based nausea module beyond the published work. A simple 1-compartment model of semaglutide and 2-compartment model of tirzepatide were developed based on published POPPK models (2,3). PD effects were calibrated to capture weight loss reported in their respective phase 3 clinical trials (4,5) at various doses. The model also provides secondary endpoints like fat mass, fat-free mass, and additional capability was added to capture fat mass loss reported in tirzepatide by capturing additional tirzepatide-induced fat oxidation as reported in literature (6). We developed a single reference non-diabetic obese virtual patient, and generated a virtual population incorporating variability in certain patient baseline characteristics, PK and PD parameters. In addition to the pharmacodynamic module, we further implemented a safety module to capture the incidence rate of nausea at population level as reported in clinical trial data (4,5) where PK exposure drives the gastric emptying rate inhibition and probability of GI adverse events at population level.
Results:
Our model thus well integrates the drug PK to the weight balance, and downstream PD and safety effects on primary clinical readouts such as weight loss, and nausea for semaglutide and tirzepatide. The model captured PK-PD-safety for semaglutide and tirzepatide in non-diabetic obese adults, including the larger weight loss in tirzepatide for a similar reduction in the energy intake as semaglutide.
Conclusion:
A platform QSP model incorporating energy balance and safety dynamics has been built and calibrated to the observed efficacy and safety of GLP-1R mono agonist semaglutide, and GLP-1/GIPR dual agonist tirzepatide for non-diabetic population reported in clinical literature. Future work will test this model out in the diabetic population to see whether we are able to capture stunted weight reduction in this population.
References:
1. Hall KD. (2010) Predicting metabolic adaptation, body weight change, and energy intake in humans. Am J Physiol Endocrinol Metab, 298(3):E449-66. doi: 10.1152/ajpendo.00559.2009
2. Strathe A, et al. (2023) A model-based approach to predict individual weight loss with semaglutide in people with overweight or obesity. Diabetes Obes Metab, 25(11):3171‐3180. doi:10.1111/dom.15211
3. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215866Orig1s000ClinPharmR.pdf
4. Wilding J, et al. (2021) STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med, 384(11), 989-1002. doi: 10.1056/NEJMoa2032183
5. Jastreboff AM, et al. (2022) SURMOUNT1 Study group. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med, 387(3), 205-216. doi: 10.1056/NEJMoa2206038
6. Look M, et al. (2025) SURMOUNT1 Substudy group. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight. Diabetes Obes Metab, 27:2720–2729. doi: 10.1111/dom.16275
Reference: PAGE 34 (2026) Abstr 11993 [www.page-meeting.org/?abstract=11993]
Poster: Drug/Disease Modelling - Other Topics