Research Article: Development of In Vitro–In Vivo Correlation for Upadacitinib Extended-Release Tablet Formulation

Date Published: October 25, 2019

Publisher: Springer International Publishing

Author(s): Mohamed-Eslam F. Mohamed, Sheryl Trueman, Ahmed A. Othman, Jian-Hwa Han, Tzuchi R. Ju, Patrick Marroum.

http://doi.org/10.1208/s12248-019-0378-y

Abstract

Upadacitinib is a selective Janus Kinase 1 inhibitor which is being developed for the treatment of several inflammatory diseases including rheumatoid arthritis. Upadacitinib was evaluated in Phase 3 studies as an oral extended-release (ER) formulation administered once daily. The purpose of this study was to develop a level A in vitro–in vivo correlation (IVIVC) for upadacitinib ER formulation. The pharmacokinetics of four upadacitinib extended-release formulations with different in vitro release characteristics and an immediate-release capsule formulation of upadacitinib were evaluated in 20 healthy subjects in a single-dose, randomized, crossover study. In vivo pharmacokinetic data and in vitro dissolution data (USP Dissolution Apparatus 1; pH 6.8; 100 rpm) were used to establish a level A IVIVC. Three formulations were used to establish the IVIVC, and the fourth formulation was used for external validation. A non-linear IVIVC best described the relationship between upadacitinib in vitro dissolution and in vivo absorption profiles. The absolute percent prediction errors (%PE) for upadacitinib Cmax and AUC were less than 10% for all three formulations used to establish the IVIVC, as well as for the %PE for the external validation formulation and the overall mean internal validation. Model was cross-validated using the leave-one-out approach; all evaluated cross-validation runs met the regulatory acceptance criteria. A level A IVIVC was successfully developed and validated for upadacitinib ER formulation, which meets the FDA and EMA regulatory validation criteria and can be used as surrogate for in vivo bioequivalence.

Partial Text

Upadacitinib (ABT-494) is a novel, selective Janus kinase (JAK) 1 inhibitor that potently inhibits JAK 1, but is less potent against other JAK isoforms [1]. In addition to several normal physiological functions, JAKs play an essential role in the signaling of numerous cytokines involved in inflammatory disorders and inhibition of JAKs can provide approach for the treatment of patients with chronic systemic inflammatory diseases [2–4]. Upadacitinib is being developed for the treatment of several inflammatory diseases, including rheumatoid arthritis (RA), as the enhanced selectivity of upadacitinib against JAK 1 may offer an improved benefit-risk profile compared to less selective JAK inhibitors [5,6]. Upadacitinib recently demonstrated efficacy in five global Phase 3 trials in subjects with rheumatoid arthritis [7–10] and is currently under regulatory review by different global regulatory agencies for treatment of moderate-to-severe rheumatoid arthritis.

A predictive level A non-linear IVIVC was established for upadacitinib ER formulation using in vivo and in vitro data for formulations containing a range of the release-controlling polymer (HPMC) of 10 to 35%. This range encompasses the target to be marketed formulation (formulation C) which contains 20% HPMC. The established IVIVC meets both the internal and external predictability per the FDA and EMA criteria and can potentially be used as surrogate for in vivo study if there is a need for formulation change (within the design space of the IVIVC) or manufacturing process change. Additionally, the established IVIVC enables setting the release specifications based on clinical relevance using the predicted range of upadacitinib exposures for formulations that fall within the proposed specifications. These analyses highlight the importance of evaluating non-linear models when linear IVIVC relationships cannot be established.

A robust non-linear level A correlation that meets the FDA and EMA validation criteria for both internal and external predictability was established for upadacitinib ER formulation. This IVIVC can be used as surrogate for bioequivalence studies in case of future formulation changes that are covered by the IVIVC release rates tested. This correlation will enable the setting of clinically meaningful dissolution specifications based on acceptable differences in plasma concentrations corresponding to the upper and lower limit of the dissolution specifications.

 

Source:

http://doi.org/10.1208/s12248-019-0378-y

 

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