Tofacitinib

by Douglas Black, Pharm.D. last updated 2022-11-26 14:53:26.787073-05:00 © Antimicrobial Therapy, Inc.
Xeljanz, Xeljanz XR

Usage and Dosing

  • Tofacitinib (Xeljanz) is a selective inhibitor of Janus kinase (JAK) 1 and JAK3, with functional selectivity for JAK2. This, plus action on other critical pathways of the inflammatory cascade, may lessen progressive, inflammation-driven lung injury in patients with COVID-19 pneumonia.
  • Studied in patients hospitalized for <72 hours with COVID-10 pneumonia not requiring mechanical ventilation or ECMO (N Engl J Med 2021;385:406).
    • Randomized placebo-controlled trial of 289 patients showed an approximate 40% reduction in risk of progression to death or respiratory failure for Tofacitinib compared to placebo, 18% vs. 29% (risk ratio, 0.63, p=0.04).
      • 79% of patients were receiving supplement oxygen at enrollment and 89% of patients also received glucocorticoid therapy.
      • Patients with a history of or current thrombosis, personal or first-degree family history of blood clotting disorders, immunosuppression, active cancer, or those with certain cytopenias were excluded from this trial.

Adult Dose

  • COVID-19: 10 mg po q12h (for up to 14 days)

Pediatric Dose

Renal Adjustment

Hepatic Adjustment

  • Mild impairment: no dosage adjustment.
  • Moderate impairment: 5 mg po q12h (N Engl J Med 2021;385:406).
  • Severe impairment: no data (use of tofacitinib in severe hepatic impairment not recommended by manufacturer).

Adverse Effects

  • Serious infections (TB, fungal infections, other opportunistic infections)
  • Malignancy and lymphoproliferative disorders
  • Thrombosis, including DVT and PE
  • Gastrointestinal perforations
  • Hypersensitivity reactions
  • Neutropenia, lymphopenia, anemia
  • AST, ALT elevations
  • Lipid elevations (total cholesterol, LDL, HDL)

Pharmacology

Class  Janus kinase inhibitor
PK/PD Index  No data
Pharmaceutical
Preparation
Tab (5, 10 mg)
XR tab (11, 22 mg
Oral soln (1 mg/mL)
Pregnancy
Category		  Insufficient data in humans, toxic in animals
Food Effect1 Take with or without food
Oral
Absorption2 (%)		  74
Tmax (hr)  0.8
Peak Serum Level3
(nanograms/mL)		  84.7 (10 mg po q12h, SS)
Protein Binding
(%)		 40
Average Serum
Half-life4 (hr)		  3
Elimination Hepatic metabolism, renal
Biliary Penetration5 (%)  No data
CSF/Blood
Penetration6 (%)		  No data
Therapeutic Levels in CSF7  No data
Volume of Distribution8
(Vd)		  87 L
AUC9
(nanograms*hr/mL)		 539.6 (10 mg po q12h, 0-24h)
CYP450, Transporter
Interactions		  Substrate for CYP3A4
  • Notes:
    • 1 Adult preparations unless otherwise noted.
    • 2 Absorption under optimal conditions.
    • 3 Total drug; adjust for protein binding to determine free drug concentration.
      • SD = after single dose
      • SS = steady state after multiple doses
    • 4 Assumes CrCl > 80 mL/min
    • 5 Peak concentration in bile/peak concentration in serum x 100
    • 6 CSF levels with inflammation
    • 7 Judgment based on drug dose & organism susceptibility. CSF concentration ideally ≥10x above MIC.
    • 8 Volume of Distribution (Vd):
      • V/F = Vd/oral bioavailability
      • Vss = Vd at steady state
      • Vss/F = Vd at steady state/oral bioavailability
    • 9 Area under the plasma concentration versus time curve

Major Drug Interactions

Drug Effect on concentration Suggested management
Strong CYP3A4 inhibitor ↑ tofacitinib 5 mg q12h (N Engl J Med 2021;385:406)
Moderate CYP3A4 inhibitor plus strong CYP2C19 inhibitor ↑ tofacitinib 5 mg q12h (N Engl J Med 2021;385:406)