Applying MIDD Paradigm to Inform Clinical Relevance of Dissolution Specifications

Dissolution specifications are often essential in assuring the quality and consistency of therapeutic benefits of drug lots released to the market as in vitro dissolution is often considered to be a surrogate for bioavailability. Despite the importance of demonstrating the clinical relevance of the dissolution specifications, it is often challenging to achieve this goal. There is a great potential for leveraging modeling and simulation approaches to support the clinical relevance of dissolution specifications. This talk will cover the background of importance of dissolution specifications and their impact on cost and manufacturing, the importance of setting clinically relevant specifications, the challenges and different approaches that can be used to set clinically relevant specifications. The talk will give special emphasis to the use of in vitro in vivo correlation (IVIVC) coupled with clinical trial simulation approaches to inform the clinical relevance of dissolution specifications. A case study will be presented in details for how IVIVC and modeling and simulation approaches were implemented to support the clinical relevance of the dissolution specifications for upadacitinib extended-release formulation (which is approved for the treatment of several autoimmune diseases).

In the upadacitinib case study, a level A IVIVC was developed and utilized in predicting upadacitinib plasma exposures for formulations which correspond to the upper and lower dissolution limits. Exposure-response models for upadacitinib efficacy and safety in patients with moderate to severe rheumatoid arthritis (RA) were utilized to conduct clinical trial simulations to evaluate the efficacy and safety of formulations at the upper and lower dissolution boundaries. Each simulated clinical trial consisted of three treatment arms: (1) upadacitinib 15 mg QD using the target formulation, (2) upadacitinib 15 mg QD using a formulation at the lower dissolution boundary, and (3) upadacitinib 15 mg QD using a formulation at the upper dissolution boundary. Each simulated trial included 300 patients per arm and simulations were replicated 200 times. Results demonstrated that formulations at the lower and upper dissolution boundaries are predicted to have noninferior efficacy and comparable safety to the target 15 mg extended-release formulation. This approach was successfully utilized in demonstrating the clinical relevance of upadacitinib extended-release tablet dissolution specifications and was critical to support regulatory submissions and approvals.