Abstract
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. In this case study, a modeling and simulation approach was utilized to support the clinical relevance of the dissolution specifications for upadacitinib extended-release tablets. A level A in vitro in vivo correlation 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.Graphical
Highlights
Dissolution specifications are often essential in assuring the quality of the drug lots that are released to the market as dissolution testing is often utilized as a surrogate for in vivo performance and bioavailability of drug products [1–3]
Clinical trial simulations using the Markov chain efficacy models demonstrated that a formulation that is at the lower dissolution limit is predicted to provide ACR20, ACR50, ACR70, low disease activity (LDA), and clinical remission (CR) that is within 2% of the estimated respective responses for the target 15 mg ER formulation
Simulations using the exposure-safety logistic regression models demonstrated that a formulation at the upper boundary of the dissolution specifications is predicted to result in similar percentage of subjects experiencing > 2 g/dL decrease from baseline in hemoglobin at week 12, lymphopenia grade 3 or higher at week 12, or a serious infection during 24 weeks of treatment safety profile to the target 15 mg ER formulation (Figure 3)
Summary
Dissolution specifications are often essential in assuring the quality of the drug lots that are released to the market as dissolution testing is often utilized as a surrogate for in vivo performance and bioavailability of drug products [1–3]. The dissolution specifications for a drug product are selected to ensure that the released batches of an oral formulation for a drug have acceptable release characteristics leading to the desired pharmacokinetic performance and a consistent clinical profile. The dissolution specifications are set based on a clinical outcome (e.g., the bioequivalence criteria or efficacy/safety of formulations at the boundaries) to assure consistent safety and efficacy profiles from lot to lot and within the same lot. Such specifications ensure a more consistent therapeutic effect leading to optimal benefit to the patient.
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