642-P: A Model-Based Evaluation of Nausea and Vomiting Events for Additional Doses of Dulaglutide in Existing and Dulaglutide-Naïve Patients with Type 2 Diabetes

Dulaglutide (DU) 3 mg and 4.5 mg once weekly (QW) doses were recently approved for additional glycemic control in adult patients with type 2 diabetes. If needed, a dose-escalation scheme from 1.5 mg to 3 mg and then 4.5 mg can be applied after at least 4-weeks on each dose. For GLP-1 receptor agonists, such as DU, common gastrointestinal (GI) side effects include nausea (N) and vomiting (V). These GI effects are dose-dependent but attenuate over time with chronic dosing. To enhance prescriber understanding of GI effects following dose escalation in existing and DU-naive patients, a Markov chain Monte Carlo pharmacokinetic/pharmacodynamic joint model was developed with Phase 3 AWARD-11 data (n=1842) which compared 3 mg and 4.5 mg DU to 1.5 mg, to evaluate probabilities of daily N and V events. The model was initiated with priors from a similar Phase 2 model (n=317). In this model, dose increment raised the probability of developing a GI event, and preceding N events enhanced the probability of V events. Development of GI tolerance to N and V was both time and DU concentration dependent. Model-predictions of the percentage of patients presenting with ≥1 N or V event per day for a given dosing scenario were generated via simulations of 100 trials with 300 patients per scenario from the AWARD-11 dataset and compared with the AWARD-11 dose-escalation scheme over a 52-week duration. Patients already on DU 1.5 mg QW for at least 4 weeks can escalate to 3 mg QW any time, and if needed increase to 4.5 mg QW after 4 weeks on 3 mg. Simulations showed ≤3% and ≤1% increase in N and V events, respectively compared to AWARD-11 dose escalation scheme. For DU-naive patients starting at 0.75 mg QW, N and V events were reduced by ≤2% and ≤1%, respectively, after escalating to 1.5 mg QW and 3 mg after ≥4 weeks at each dose. Whether in DU-naive patients or those already on 1.5mg, simulations showed no meaningful increase in N and V when dose escalation occurred at intervals of at least 4 weeks. Disclosure L. Tham: Employee; Self; Eli Lilly and Company. J. S. K. Lim: Employee; Self; Eli Lilly and Company. C. Tang: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Novartis AG. H. Jung: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. M. Konig: Employee; Self; Eli Lilly and Company. L. Loo: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Eli Lilly and Company.