Background/Purpose: 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 after peak cytokine release and disease symptoms.  A product designed to be taken at bedtime and exhibiting a delayed and extended release profile that releases tofacitinib late in the night providing maximum tofacitinib concentrations in the early morning hours, could provide an enhanced opportunity to address morning symptoms.
T19 is a novel, three-dimensionally (3D) printed tablet being developed for delayed- and extended- release (DR/ER) of tofacitinib and engineered to provide peak tofacitinib concentrations concurrent with the circadian rhythm of early morning endogenous cytokine release and disease symptoms. 

Methods: T19 was manufactured by a 3D printing technology called “Melt Extrusion Deposition” (MED^Ò). 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^Ò). 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. 

Results: Following administration of T19 and Xeljanz XR^Ò, both formulations of T19 exhibited a delayed time of maximum plasma concentration (T_max), as expected. Under fasting conditions, the median T_max was 5.5-6.0 h with a range of 3.0-10.0 h for T19, whereas the median T_max was 4.5 h (2.5-5.0 h) for the LD. The T_max of the T19 formulations were significantly different as compared to the LD (Wilcoxon signed-rank test, p < 0.001). 

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 (AUC_inf) and maximum plasma concentration (C_max) 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 AUC_inf and C_max 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 C_max observed suggests a potential pharmacokinetic bridge to Xeljanz XR^Ò, providing a basis for a 505(b)(2) application for the indications similar to the LD, Xeljanz^Ò and a potential therapeutic option for the patients with morning symptoms.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-oral-3d-printed-delayed-and-extended-release-tofacitinib-t19-for-the-treatment-of-rheumatoid-arthritis-and-related-inflammatory-diseases/