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

• DOI: 10.1002/cpt.936
• Publication Date: 2017-11-14T08:32:50Z
• Authors: Hanna Kim; Kristina M. Brooks; Cheng Cai Tang; Paul Wakim; Mary Blake; Stephen R. Brooks; Gina A. Montealeg...; Adriana A. de Jesus; Yan Huang; Wanxia Li Tsai; Massimo Gadina; Apurva Prakash; Jonathan Marcus J...; Xin Zhang; William L. Macias; Parag Kumar; Raphaela Goldbach...
• Keywords: Compassionate Use Trials; Inflammation; Male; 0303 health sciences; Adolescent; Body Weight; Age Factors; Administration, Oral; Infant; Janus Kinase 1; Janus Kinase 2; Autoimmune Diseases; 3. Good health; 03 medical and health sciences; Child, Preschool; Azetidines; Humans; Janus Kinase Inhibitors; Drug Dosage Calculations; Female; Genetic Predisposition to Disease; Child; Glomerular Filtration Rate

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.