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Clin Pharmacol Ther. 2018 Aug;104(2):364-373. doi: 10.1002/cpt.936. Epub 2017 Dec 8.

Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibitor Baricitinib in Pediatric and Young Adult CANDLE and SAVI Patients.

Author information

1
Lawrence Shulman Scholar, Office of the Clinical Director, and Pediatric Translational Research Branch, NIAMS, NIH, Bethesda, Maryland, USA.
2
Clinical Pharmacokinetics Research Unit, Pharmacy Department, NIH Clinical Center, Bethesda, Maryland, USA.
3
Lilly-NUS Centre for Clinical Pharmacology, Singapore.
4
Biostatistics and Clinical Epidemiology Service, NIH Clinical Center, Bethesda, Maryland, USA.
5
Translational Immunology Section, Office of Science and Technology, NIAMS, NIH, Bethesda, Maryland, USA.
6
Biodata Mining and Discovery Section, Office of Science and Technology, NIAMS, NIH, Bethesda, Maryland, USA.
7
Translational Autoinflammatory Disease Studies, NIAID, NIH, Bethesda, Maryland, USA.
8
Eli Lilly and Co, Indianapolis, Indiana, USA.

Abstract

Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance, respectively. The half-life of baricitinib in patients less than 40 kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area-under-the-concentration-vs.-time curve was 2,388 nM*hr, which is 1.83-fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4 mg once-daily. Dose-dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type-1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight- and estimated glomerular filtration rate-based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01724580 NCT02974595.

PMID:
29134648
PMCID:
PMC6089664
DOI:
10.1002/cpt.936
[Indexed for MEDLINE]
Free PMC Article

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