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Clinical Pharmacokinetics

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06.06.2016 | Original Research Article

Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis

verfasst von: Mohamed-Eslam F. Mohamed, Heidi S. Camp, Ping Jiang, Robert J. Padley, Armen Asatryan, Ahmed A. Othman

Erschienen in: Clinical Pharmacokinetics | Ausgabe 12/2016

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Abstract

Background

ABT-494 is a potent and selective Janus kinase (JAK) 1 inhibitor being developed for the treatment of several autoimmune disorders, with potential for an improved safety profile compared with non-selective JAK inhibitors. This work characterized the pharmacokinetics, safety, and tolerability of ABT-494 following single and multiple dosing of the immediate-release formulation.

Methods

ABT-494 single (1–48 mg or placebo; n = 56) and multiple (3–24 mg or placebo twice daily for 14 days; n = 44) doses in healthy subjects, as well as multiple doses (3–24 mg or placebo twice daily for 27 days; n = 14) in subjects with rheumatoid arthritis (RA) on a background of methotrexate were evaluated. Pharmacokinetic samples were collected and safety and tolerability were assessed.

Results

ABT-494 followed bi-exponential disposition, with a terminal elimination half-life of 6–16 h and a functional half-life, calculated from maximum observed plasma concentration (C _max) to trough plasma concentration (C _trough) ratio at steady state, of 3–4 h. ABT-494 exposure was approximately dose proportional over the 3–36 mg dose range, with no significant accumulation with repeated dosing. In subjects with RA, no pharmacokinetic interaction between ABT-494 and methotrexate was observed. The fraction of ABT-494 dose eliminated in urine as unchanged ABT-494 was 14–25 %. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE (15.6 % for ABT-494 vs. 16.7 % for placebo) after multiple twice-daily administration to healthy subjects. No clinically significant changes in laboratory parameters, vital signs, or electrocardiogram findings in healthy or RA subjects were observed.

Conclusions

The favorable pharmacokinetics, safety, and tolerability results from these studies supported further evaluations of ABT-494 in phase IIb dose-ranging trials in RA and Crohn’s disease.

Trial Registration

ClinicalTrials.gov (https://clinicaltrials.gov/) identifier: NCT01741493.

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Titel: Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis
verfasst von: Mohamed-Eslam F. Mohamed
Heidi S. Camp
Ping Jiang
Robert J. Padley
Armen Asatryan
Ahmed A. Othman
Publikationsdatum: 06.06.2016
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 12/2016
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-016-0419-y

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis

Abstract

Background

Methods

Results

Conclusions

Trial Registration

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Background

Methods

Results

Conclusions

Trial Registration

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