Pos1361 a Novel Oral 3d-Printed Delayed- And Extended-Release Tofacitinib (T19) for the Treatment of Rheumatoid Arthritis and Related Inflammatory Diseases

Background: Patients with inflammatory diseases, such as rheumatoid arthritis (RA) frequently continue to suffer from morning symptoms despite treatment with conventional therapies [1,2]. Routine morning administration of tofacitinib results in peak drug concentrations several hours (around 12 noon) after peak cytokine release and disease symptoms. A product designed to be taken at bedtime and exhibiting a delated and extended tofacitinib release profile that releases tofacitinib late in the night providing maximum tofacitinib concentrations in the early morning hours (approximately 4 a.m.), could provide an enhanced opportunity to address morning symptoms. Objectives: T19 is a novel, three-dimensionally (3D) printed tablet being developed for delayed- release and extended- release (DR/ER) of tofacitinib engineered to provide peak tofacitinib concentrations concurrent with the circadian rhythm of endogenous cytokine release and disease symptoms in the early morning hours. The current study was designed to characterize the pharmacokinetics of T19 and evaluate the single-dose relative bioavailability of T19 compared to Xeljanz XR® in healthy participants. Methods: T19 was manufactured by a 3D printing technology called "Melt Extrusion Deposition" (MED®). A total of 24 participants were enrolled in the Phase I, randomized, open-label, single-dose, three-period, three-sequence crossover study to compare the pharmacokinetics (PK) between T19 and the reference listed drug (LD, Xeljanz XR®). Participants were randomized 1:1:1 to receive two formulations of T19 (Z001101 & Z001091; designed to provide differing degrees of delayed release) or LD in the three sequences. T19 was administered orally at bedtime (approximately 22:00) following a standard dinner at approximately 18:00. Following dinner, the participants remained fasted for 4 hours before the administration of T19. Xeljanz XR® was administered orally in the morning after an overnight fast of at least 10 hours. There was a minimum 4-day washout period between treatments. Results: Following administration of T19 and Xeljanz XR®, both formulations of T19 exhibited a delayed time of maximum plasma concentration (Tmax), as expected. Under fasting conditions, the median Tmax was 5.5-6.0 h with a range of 3.0-10.0 h for T19, whereas the median Tmax was 4.5 h (2.5-5.0 h) for the LD. The Tmax of the T19 formulations were significantly different as compared to the LD (Wilcoxon signed-rank test, p <0.001). Other than the delayed drug release (Tmax), the PK profile of T19 was superimposable with the LD, including exhibiting similar PK parameter estimates for drug absorption and elimination. A statistical analysis of relative bioavailability between the formulations demonstrated that the exposure of T19 was similar to that of LD. The area under the concentration-time curve (AUCinf) and maximum plasma concentration (Cmax) of T19 were within the desired bioequivalence range (80% to 125%) relative to LD. The ratio (T19/LD) and 90% confidence intervals of adjusted geometric means for AUCinf and Cmax were 105.46 (102.03, 109.38) and 116.95 (104.92, 130.35) for Z001101, and 104.04 (100.81, 107.38) and 130.89 (113.49, 150.95) for Z001091, respectively. Geometric mean concentration-time profiles of T19 and LD after single-dose administration are shown in Figure 1. Conclusion: The PK results demonstrate that T19 achieved the desired product design properties of delayed- and extended-release, as exhibited by the pharmacokinetic profiles and providing peak plasma concentrations in the early morning hours when morning symptoms are most present. The bioequivalence of exposure (AUC) and Cmax observed suggests a potential pharmacokinetic bridge to Xeljanz XR®, providing a basis for a 505(b)(2) application for the indications similar to the LD, Xeljanz® and a potential therapeutic option for the patients with morning symptoms. REFERENCES: [1] Ursini F, et al. Pharmaceutics. 2021 Nov 2;13(11):1832. [2] Cutolo M, et al. Ann Rheum Dis. 2008 Jul;67(7):905-8. Acknowledgements: NIL. Disclosure of Interests: Yolanda Zhou Triastek, Inc., Meng Ji: None declared, Luo Wang: None declared, Feihuang Deng: None declared, Senping Cheng: None declared, Xiaoling Li: None declared, Yulian Zhang: None declared