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

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

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Age Factors
  • Autoimmune Diseases / diagnosis
  • Autoimmune Diseases / drug therapy*
  • Autoimmune Diseases / enzymology
  • Autoimmune Diseases / genetics
  • Azetidines / administration & dosage*
  • Azetidines / adverse effects
  • Azetidines / pharmacokinetics*
  • Body Weight
  • Child
  • Child, Preschool
  • Compassionate Use Trials
  • Drug Dosage Calculations*
  • Female
  • Genetic Predisposition to Disease
  • Glomerular Filtration Rate
  • Humans
  • Infant
  • Inflammation / diagnosis
  • Inflammation / drug therapy*
  • Inflammation / enzymology
  • Inflammation / genetics
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 1 / metabolism
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / metabolism
  • Janus Kinase Inhibitors / administration & dosage*
  • Janus Kinase Inhibitors / adverse effects
  • Janus Kinase Inhibitors / pharmacokinetics*
  • Male
  • Models, Biological*
  • Sulfonamides / administration & dosage*
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics*
  • Treatment Outcome
  • Young Adult

Substances

  • Azetidines
  • Janus Kinase Inhibitors
  • Sulfonamides
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2
  • baricitinib

Associated data

  • ClinicalTrials.gov/NCT01724580
  • ClinicalTrials.gov/NCT02974595