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Clinical Trial
. 2019 Feb;8(2):208-216.
doi: 10.1002/cpdd.462. Epub 2018 Apr 24.

Pharmacokinetics of Upadacitinib With the Clinical Regimens of the Extended-Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials

Mohamed-Eslam F Mohamed  1 , Jiewei Zeng  1 , Patrick J Marroum  1 , In-Ho Song  2 , Ahmed A Othman  1
Affiliations
Clinical Trial

Pharmacokinetics of Upadacitinib With the Clinical Regimens of the Extended-Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials

Mohamed-Eslam F Mohamed et al. Clin Pharmacol Drug Dev. 2019 Feb.

Abstract

Upadacitinib is a Janus kinase 1 inhibitor under development for the treatment of several inflammatory disorders including rheumatoid arthritis (RA). Upadacitinib was administered in the phase 2 RA trials primarily as twice-daily regimens of an immediate-release (IR) formulation. The upadacitinib extended-release (ER) formulation was developed to enable once-daily dosing. In the present study, upadacitinib pharmacokinetics were characterized after the administration of single and multiple once-daily doses of the ER formulation in healthy subjects relative to single and multiple twice-daily doses of the IR formulation. Increase in upadacitinib exposure was dose-proportional over the evaluated 15- to 30-mg ER dose range. Single 15- and 30-mg ER doses provided equivalent AUC0-inf compared with single 12- and 24-mg IR doses, respectively. A high-fat breakfast increased upadacitinib ER Cmax and AUC0-inf by only 20% and 17%, respectively, relative to fasting conditions. The median time to peak plasma concentrations was 2 to 4 hours for the ER formulation, and steady state was achieved by day 4 of once-daily dosing. Doses of 15 and 30 mg once daily using the ER formulation provided equivalent AUC0-24 , comparable Cmax and Cmin , and a fluctuation index over a 24-hour period at steady state similar to 6 and 12 mg twice daily, respectively, using the IR formulation. These results supported the use of upadacitinib 15- and 30-mg doses of the ER formulation in the phase 3 trials in RA.

Keywords: ABT-494; JAK1 inhibitors; extended-release formulation; pharmacokinetics; rheumatoid arthritis; upadacitinib.

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Conflict of interest statement

Mohamed‐Eslam F. Mohamed, Jiewei Zeng, Patrick J. Marroum, In‐Ho Song, and Ahmed A. Othman are employees of AbbVie Inc. and may hold AbbVie stock and/or stock options. Medical writing support was provided by Therese Stickler, a freelance writer under contract with AbbVie.

Figures

Figure 1
Figure 1
Study design. A washout of 4 days was used between consecutive periods. IR, immediate release; ER, extended release; BID, twice daily; QD, once daily.
Figure 2
Figure 2
Upadacitinib mean ± SD plasma concentration‐versus‐time profiles following administration of single oral doses of upadacitinib IR and ER formulations to healthy subjects. The first 24 hours are shown on a larger scale in the inset. IR, immediate‐release; ER, extended‐release.
Figure 3
Figure 3
Upadacitinib mean ± SD steady‐state plasma concentration‐versus‐time profiles following administration of multiple doses of (A) upadacitinib 6 mg twice daily (IR formulation) and 15 mg once daily (ER formulation) under fasting conditions, (B) 12 mg twice daily (IR formulation) and 30 mg once daily (ER formulation) under fasting conditions, and (C) 15 mg once daily and 30 mg once daily (ER formulation) under nonfasting conditions. BID, twice daily; IR, immediate‐release; QD, once daily; ER, extended release.
Figure 4
Figure 4
Upadacitinib mean ± SD predose plasma concentration by study day following administration of (A) 15 mg once daily and (B) 30 mg once daily using the ER formulation. SD, standard deviation; QD, once daily; ER, extended release.
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