Practical Applications of a Nausea and Vomiting Model in the Clinical Development of Additional Doses of Dulaglutide.

Dulaglutide 3.0 and 4.5 mg weekly doses were approved for additional glycemic control in adult patients with type 2 diabetes inadequately controlled with metformin and 0.75 or 1.5 mg weekly doses of dulaglutide. Effects such as nausea and vomiting are commonly reported with dulaglutide and other glucagon-like peptide-1 receptor agonist therapies. Based on a pharmacokinetic/pharmacodynamic model-informed approach, a stepwise dose-escalation scheme with 4-week intervals between dose increments was suggested to mitigate gastrointestinal events for dulaglutide. These gastrointestinal events are dose dependent and attenuate over time with repeated dosing. A Markov chain Monte Carlo pharmacokinetic/pharmacodynamic joint model was developed using AWARD-11 data (N = 1842) to optimize dulaglutide dose escalation to 3.0 and 4.5 mg to mitigate gastrointestinal events. Model simulations evaluated probabilities of nausea and vomiting events for various dosing scenarios in patients needing higher doses for additional glycemic control. The model indicated that patients may dose escalate from 1.5 to 3.0 mg, then 4.5 mg weekly after at least 4 weeks on each dose. No clinically meaningful differences in nausea or vomiting events were expected when patients escalated to 3.0 or 4.5 mg following initiation at 0.75 or 1.5 mg dulaglutide. Based on the findings of this model, a minimum 4-week duration at each dose before escalation was appropriate to reduce gastrointestinal events of dulaglutide, consistent with observed gastrointestinal events data from the AWARD-11 study and supporting the currently recommended dose-escalation regimen of dulaglutide doses of 3.0 and 4.5 mg for additional glycemic control.