943-P: Role of Model-Informed Drug Development in Confirming Additional Clinical Benefits of Dulaglutide
| Autor: | Angelyn Bethel, David A. Cox, Cheng Cai Tang, Lai-San Tham, Karen Schneck, Jeanne Geiser, Zvonko Milicevic |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Oncology
medicine.medical_specialty Physiologically based pharmacokinetic modelling Gastric emptying business.industry Endocrinology Diabetes and Metabolism Clinical study design Phases of clinical research Tolerability Internal medicine Pharmacodynamics Internal Medicine medicine Dulaglutide business medicine.drug Glycemic |
| Zdroj: | Diabetes. 69 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db20-943-p |
| Popis: | Throughout the development cycle of dulaglutide, model-informed drug development (MIDD) was applied to facilitate and accelerate decision-making. Currently, dulaglutide 0.75 mg and 1.5 mg given subcutaneously once weekly (QW) is approved for the treatment of type 2 diabetes. Post-approval, pharmacokinetic/pharmacodynamic (PKPD) exposure-response and mechanistic quantitative system pharmacology (QSP) models which leveraged accrued phase 1 data led to the hypothesis that additional glycemic control was possible with higher dulaglutide doses of 3.0 mg and 4.5 mg. MIDD was utilized to design a phase 2 study which explored the safety and efficacy for 3.0 mg and 4.5 mg versus 1.5 mg QW doses and tested a dose escalation approach for mitigating gastrointestinal (GI) nausea/vomiting effects for the investigational doses. Phase 2 data enriched understanding of benefit-risk of the extended doses and refined the dose escalation scheme for the pivotal phase 3 trial (AWARD-11). Efficacy and GI tolerability from AWARD-11 closely resembled model-predictions. While MIDD has been most commonly applied in dose-selection, novel MIDD approaches were also adopted for the dulaglutide program to design a dose escalation scheme and evaluate drug-drug interactions (DDI). Acetaminophen PK from previous gastric emptying studies covering a wide range of dulaglutide doses was used to characterize the extent of gastric-emptying delay (GED) related to 4.5 mg of dulaglutide and this extent of GED was then applied to physiologically based pharmacokinetic (PBPK) models of individual commonly co-administered oral agents to simulate effect of delayed gastric emptying on their PK profiles. Overall, a range of quantitative models were successfully employed to predict effects of and inform clinical trial design for higher dulaglutide doses for patients needing additional glycemic control. Disclosure L. Tham: Employee; Self; Eli Lilly and Company. J. Geiser: Employee; Self; Eli Lilly and Company. C. Tang: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Novartis Pharmaceuticals Corporation. K. Schneck: Employee; Self; Eli Lilly and Company. D. Cox: Employee; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company. A. Bethel: Employee; Self; Eli Lilly and Company. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|