Date: Monday, November 6, 2017
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: JAK inhibitors reduce IFN-signaling ex vivo. We evaluated the PK and PD of the oral JAK1 and JAK2 inhibitor, baricitinib, from data collected in a compassionate use program in patients with Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) (1), STING Associated Vasculopathy with onset during Infancy (SAVI) (2), and other presumed IFN-driven AIDs with the goal to support a clinically derived dosing regimen for pediatric and young adult patients with CANDLE, SAVI, and other rare IFN-mediated diseases.
Methods: Baricitinib dosing was titrated based on clinical response and safety measures, with PK assessments following dose escalations in a compassionate use program (NCT01724580). Population pharmacokinetic (PopPK) modeling was applied to assess the PK profile of baricitinib. The effect of baricitinib treatment on STAT-1 phosphorylation, IFN-response gene expression (25-gene IFN score), and serum IP-10 levels, was assessed.
Results: A total of 18 patients received between 0.1 to 17 mg of baricitinib daily for up to 53 months. Weight and renal function significantly influenced PK parameters volume of distribution and clearance, respectively. The half-life of baricitinib, particularly in patients less than or equal to 40 kg, was considerably shorter than in adult patients with rheumatoid arthritis (RA), resulting in the need for dosing up to 4 times daily. On effective therapeutic doses (ranging from 6 to 13 mg/day), the daily drug exposure or mean area-under-the-concentration-versus-time curve over a 24-hour period (AUC24,SS) at the final PK assessment was 2388 nM*hr, which is 1.83-fold higher than the mean exposures obtained in adult RA patients receiving baricitinib 4 mg once-daily in phase 3 studies (Table 1). IFN-alpha stimulated STAT-1 phosphorylation (pSTAT-1) in immune cells from CANDLE and SAVI patients negatively correlated with plasma baricitinib levels. A 25-gene IFN score and serum IP-10 levels, both markers of IFN signaling, significantly decrease with increased drug exposure. A subset of CANDLE patients normalized the 25-gene IFN score at AUC24,SS values between ~1500-2000 nM*hr, but higher exposures were required in patients with more severe disease.
Conclusion: Baricitinib blocks IFN signaling in patients with CANDLE, SAVI, and other interferonopathies. PK/PD data suggest that pediatric patients with rare interferonopathies require treatment with higher daily doses and more frequent dosing versus adult RA patients. PopPK and PD data support an empirically derived dosing regimen based on body weight and estimated glomerular filtration rate (eGFR) to guide initial dosing of baricitinib in patients with rare interferonopathies.
Funding: The Intramural Research Program of NIH, NIAID, NIAMS, CC and Eli Lilly and Company.
1) Liu Y et al, Arthritis Rheum 2011
2) Liu Y et al, N Engl J Med 2014
To cite this abstract in AMA style:Kim H, Brooks KM, Wakim P, Blake M, Brooks SR, Montealegre Sanchez GA, Almeida de Jesus A, Huang Y, Tsai WL, Gadina MG, Kumar P, Goldbach-Mansky R. Pharmacokinetics (PK), Pharmacodynamics (PD), and Proposed Dosing of Oral Janus Kinase (JAK)1 and JAK2 Inhibitor Baricitinib in Patients with IFN-Mediated Autoinflammatory Diseases (AIDs) [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/pharmacokinetics-pk-pharmacodynamics-pd-and-proposed-dosing-of-oral-janus-kinase-jak1-and-jak2-inhibitor-baricitinib-in-patients-with-ifn-mediated-autoinflammatory-diseases-aids/. Accessed November 13, 2019.
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